Chapter 80: Immunodeficiency Diseases

X-LINKED AND AUTOSOMAL RECESSIVE AGAMMAGLOBULINEMIA

Definition and Genetic Features

X-linked agammaglobulinemia (XLA) is the prototypic antibody deficiency characterized by profound hypogammaglobulinemia caused by a maturation defect in B-cell development.^1,2 XLA, originally described in 1953, is one of the first primary immunodeficiencies in which the underlying defect, a mutation of Bruton tyrosine kinase (BTK) was identified. Autosomal recessive agammaglobulinemia, a variant form of agammaglobulinemia, has been reported in patients with a clinical phenotype resembling XLA including very low B-cell numbers and severe bacterial infections but normal BTK.² Several responsible gene mutations have been identified, including those involving the B-cell receptor complex μ heavy chain (immunoglobulin heavy constant mu [IGHM]), the surrogate light chain component λ5 (immunoglobulin lambda-like polypeptide 1 [IGLL1]), the signal transducer complex of the pre–B-cell receptors immunoglobulin (Ig) α (CD79a), Igβ (CD79b), and mutations in the B-cell adaptor molecule BLINK, the p85α subunit of phosphatidylinositol 3-kinase (PI3K)³ and a dominant negative E47 mutation causing autosomal dominant agammaglobulinemia.⁴

Clinical Features

Because IgG is actively transported across the placenta, infants born with XLA have normal levels of IgG at birth and are frequently asymptomatic for the first few months of life. Following metabolism of the maternal antibodies, affected boys begin to develop recurrent infections usually between 4 and 12 months of age. In a review of 96 XLA patients, 20 percent experienced initial clinical symptoms after their first birthday and approximately 10 percent after 18 months of age.⁵ In an Italian study of 73 patients with mutation-verified XLA, the mean age of onset of symptoms was 2 years.⁶ The presenting symptoms vary greatly and may be mild or severe (Table 80–1). Otitis media and chronic sinusitis, pneumonia, pyoderma, and diarrhea are frequent clinical presentations. Serious complications include septicemia, meningitis, septic arthritis, and osteomyelitis. In young children with XLA, acute infections are often associated with neutropenia. Pyogenic bacteria, such as Haemophilus influenzae, Streptococcus pneumoniae, and Staphylococcus aureus are the most common pathogens observed in XLA. Opportunistic infections, such as Pneumocystis jirovecii, are rarely observed. Infections with Ureaplasma urealyticum have been reported in XLA patients with mycoplasma arthritis.⁷ Although resistance to viral infections is generally intact, XLA patients are unusually susceptible to enteroviruses such as echovirus, coxsackievirus, and poliovirus. Poliomyelitis after live-attenuated (Sabin) poliovirus vaccine, especially if given at a time when maternal antibodies had disappeared, is associated with high morbidity and mortality.⁵ Before the introduction of intravenous immunoglobulin (IVIG), XLA patients frequently developed chronic, disseminated echovirus and coxsackievirus infections presenting as meningoencephalitis, dermatomyositis/fasciitis, and hepatitis.⁸ Gastroenteritis caused by Giardia lamblia, Campylobacter species, or rotavirus is not uncommon and may be associated with malabsorption. Chronic intestinal inflammation resembling Crohn disease may develop in children and adults with XLA. Interestingly, an increased incidence of rectosigmoid cancer with high mortality has been reported.⁹ Pyoderma gangrenosum-like ulcers of the lower extremities have been observed to be caused by Helicobacter species.¹⁰

Laboratory Features

Most patients have markedly reduced levels of all classes of immunoglobulins; circulating B cells are less than 1 percent of total lymphocytes and tonsils are absent. Because of the maturation arrest at the pre–B-cell stage, very few B cells undergo differentiation into plasma cells. As a result, lymph nodes, lymphoid follicles, germinal centers, and intestinal mucosal biopsies lack plasma cells. As expected, specific antibodies to microorganisms or vaccines are markedly reduced or undetectable (Table 80–2).

BTK, a cytoplasmic protein tyrosine kinase known to interact with other cytoplasmic proteins, plays an important role in the pre–B-cell expansion and the survival of mature B cells by facilitating signaling through the B-cell antigen receptor. BTK is present in all hematopoietic cells except T cells, natural killer (NK) cells, and plasma cells. The presence of BTK in normal monocytes and platelets allows assessment of BTK in most XLA patients with low or absent BTK levels using flow cytometry, and to identify carrier females.¹¹ Sequence analysis of the BTK gene confirms the diagnosis of XLA and allows prenatal diagnosis. Autosomal recessive (and dominant) forms of agammaglobulinemia are rare and require sequence analysis of the genes listed above.

Treatment

Intravenous or subcutaneous IgG infusions at a dose of 400 to 600 mg/kg every 3 to 4 weeks are highly effective in preventing chronic infections in agammaglobulinemic patients. Prophylactic antibiotics are indicated in those with chronic lung disease. Adequate IVIG replacement has markedly reduced the incidence of enteroviral infections, but other complications, such as Crohn-like disease, are difficult to prevent, and progressive neurodegeneration has been observed in a small number of XLA patients without identification of an infectious agent.¹²

HYPERIMMUNOGLOBULIN M SYNDROMES

Definition and Genetic Abnormalities

Hyper-IgM syndromes are characterized by recurrent infections associated with low serum levels of IgG, IgA, and IgE, but normal or increased levels of IgM (see Table 80–2). They are the direct result of mutations affecting genes involved in B-cell activation, class switch recombination (CSR), and somatic hypermutation (SHM). Mutations in the genes encoding CD40 ligand (CD40L) or CD40 interfere with the triggering of events that lead to CSR and SHM. Mutations in the B-cell intrinsic enzymes, activation-induced cytosine deaminase (AID) and uracil N-glycosylase (UNG), directly affect CSR and SHM. Mutations in the NEMO gene (nuclear factor [NF]-κB essential modulator), a protein crucial for NF-κB activation, cause clinical features of anhydrotic ectodermal dysplasia with associated immune deficiency in males and incontinentia pigmenti in females.¹³ A novel B-cell–intrinsic CSR deficiency characterized by susceptibility to malignancies was found to be associated with mutations in the gene encoding the postmeiotic segregation increased 2 (Saccharomyces cerevisiae) (PMS2) component of the mismatch repair machinery.¹⁴ A subset of patients with ataxia telangiectasia present with elevated serum IgM and CSR deficiency.¹⁵

X-Linked Hyperimmunoglobulin M as a Result of CD40 Ligand Deficiency

Clinical Features In addition to recurrent bacterial infections, affected infants with X-linked hyperimmunoglobulin M (XHIGM) often present with interstitial pneumonia caused by P. jirovecii approximately 50 percent of affected males will develop neutropenia.¹⁶ Patients with XHIGM are at high risk of developing chronic Cryptosporidium infections complicated by ascending cholangiolitis and chronic liver disease. Progressive neurodegeneration in XHIGM patients similar to those with XLA has been reported.¹² Abortive germinal center formation and severe depletion of follicular dendritic cells of lymph nodes occurs. Affected patients are at risk to develop neoplasms, most often lymphomas, but also tumors of the biliary and gastrointestinal tract,¹⁷ which are rarely observed in other primary immunodeficiencies.

Laboratory Features Circulating lymphocyte subsets are present in normal numbers but B cells are predominantly naïve and few are of the switched memory B-cell subtype (IgD^–, IgM^– CD27⁺).¹⁸ Lymphocyte proliferation in response to mitogens is normal, but responses to specific antigens are often reduced.¹⁹ XHIGM is caused by mutations in CD40L, a surface protein expressed by activated CD4⁺ lymphocytes. CD40L interacts with the CD40 membrane protein constitutively expressed by B cells, macrophages, and dendritic cells (DCs). The interaction of CD40L/CD40 sets in motion a signaling event that results in the expression of AID and UNG, and induces CSR and SHM. Mutations in CD40L are distributed throughout the gene and may result in nonfunctional or absent protein.¹⁶ Several patients with mild cases of XHIGM not treated with IVIG have developed chronic pure red cell aplasia as a result of persistent parvovirus B19 infection.²⁰

Treatment Prophylactic treatment with trimethoprim-sulfamethoxazole is indicated during infancy and childhood to prevent P. jirovecii pneumonia. Intravenous or subcutaneous immunoglobulin at doses similar to patients with XLA is used to prevent chronic infections, including parvovirus B19. Exposure to Cryptosporidium should be prevented by avoiding the use of potentially contaminated water. Because of the high incidence of serious complications and the unfavorable long-term outcome,²¹ allogeneic stem cell transplantation should be considered if an optimal donor can be identified. Severe and persistent neutropenia may require treatment with granulocyte colony-stimulating factor (G-CSF), at least on a temporary basis.

Autosomal Recessive Hyperimmunoglobulin M with CD40 Mutations

Autosomal recessive hyperimmunoglobulin M caused by mutations in CD40 have been reported, mostly in consanguineous families.^16,22 Affected members have similar clinical and laboratory findings as those with CD40L mutations. Treatment and prognosis of CD40 deficiency is similar to XHIGM.

Autosomal Recessive Hyperimmunoglobulin M Syndrome Caused by an Intrinsic B-Cell Defect

Definition AID is expressed only in B cells undergoing CSR or SHM and is thought to affect DNA editing.²³ Because of milder symptoms, the diagnosis of AID deficiency is often established later in life.

Clinical Features AID-deficient patients present with recurrent bacterial infections, mostly affecting the upper and lower respiratory tract. In contrast to patients with XHIGM, AID-deficient individuals have an excellent long-term prognosis, especially if given IVIG prophylaxis. Most affected individuals present with striking lymphoid hyperplasia involving tonsils and lymph nodes as a result of marked follicular hyperplasia. The number of circulating T- and B-cell subsets are normal, including normal proportion of memory B cells; however, all CD27⁺ memory B cells fail to isotype switch and only express IgM and IgD. Mutations of AID affect the entire gene and include missense, nonsense mutations, and small deletions.

UNG is expressed in proliferating cells, including B cells undergoing CSR. Following AID-induced deamination of cytosine into uracil residues on single-stranded DNA, UNG deglycosylates and removes uracil residues, thus leading to a single-stranded DNA break. The repair of the DNA nick leads to successful CSR and SHM. Because AID and UNG are functionally closely linked, lack of UNG results in a clinical phenotype similar to AID deficiency. The three UNG deficient patients reported to date have a history of frequent bacterial infections, lymphadenopathy, and an excellent response to IVIG therapy.²³

X-Linked Anhydrotic Ectodermal Dysplasia with Immunodeficiency Caused by Mutations in Nuclear Factor-κB Essential Modulator

Definition Anhydrotic (or hypohidrotic) ectodermal dysplasia is a rare syndrome with partial or complete absence of sweat glands, sparse hair growth, and abnormal dentition. A subset of these patients has an X-linked mode of inheritance and immunodeficiency characterized by low-serum IgG levels, variably elevated IgM levels, and decreased antibody responses. This syndrome results from mutations in the IKBKG gene encoding NEMO, a key subunit of I-κB kinase that regulates NF-κB dimerization and nuclear transfer.²⁴ Most affected boys have a hypomorphic NEMO mutation that allows some function, and present with bacterial (S. pneumoniae, S. aureus) and often atypical mycobacterial infections. Loss-of-function mutations cause the X-linked dominant condition of incontinentia pigmenti in females and are embryonically lethal in males. A similar phenotype with autosomal dominant inheritance is caused by gain-of-function mutations in IKBA.²⁵

Clinical Features A review of 72 individuals with NEMO mutations has demonstrated a wide spectrum of clinical phenotypes.²⁶ Thirty-two different mutations of NEMO were identified, with 70 percent being associated with ectodermal dysplasia, 86 percent with serious pyogenic infections, 39 percent with mycobacterial infections, 19 percent with serious viral infections, and 21 percent with inflammatory bowel disease. One-third of this cohort of NEMO patients died prematurely (mean age: 6.4 years).

Treatment Treatment with IVIG is useful but does not prevent the occurrence of serious complications. Symptomatic treatment depends on those complications.

COMMON VARIABLE IMMUNODEFICIENCY AND SELECTIVE IMMUNOGLOBULIN A DEFICIENCY

Definition

Common variable immunodeficiency (CVID) is a clinically and molecularly heterogeneous disorder, presenting at any age, but most often during adulthood. CVID is characterized by recurrent bacterial infections, hypogammaglobulinemia, and impaired antibody responses. Together with selective IgA deficiency, CVID is the most common primary immune deficiency, with an incidence of 1 in 10,000 individuals. Familial inheritance is observed in approximately 20 percent of cases and CVID and IgA deficiency may be present in the same families. In rare instances, patients with selective IgA deficiency may progress to CVID. Attempts have been made to associate CVID and IgA deficiency with genes located within the major histocompatibility complex (MHC) region on chromosome 6; however, no specific genes within this region have been identified. A small proportion of patients with CVID have been molecularly defined as having mutations in several genes involved directly or indirectly with B-cell differentiation, including ICOS, TACI, BAFF-receptor, CD19, CD20, CD21, and CD81.²⁷ The recent discovery of CVID-like phenotypes resulting from heterozygous mutations in NF-κB2^28,29 and gain-of-function mutations in PI3Kδ,³⁰ and CVID with autosomal recessive inheritance as a result of mutations in protein kinase Cδ³¹ further support the idea that CVID is a heterogeneous primary immune deficiency disease (PIDD) with strong genetic roots. In addition, patients with mutations in BTK, CD40L, and SH2D1A have been mistakenly diagnosed as CVID.

Clinical Features and Treatment of Common Variable Immunodeficiency

The majority of CVID patients present with recurring sinopulmonary infections, most often bacterial pneumonia.^27,32 If the diagnosis is delayed or if treatment is inadequate, bronchiectasis and chronic lung disease may develop. Gastrointestinal complaints are frequent and may be caused by chronic G. lamblia or Campylobacter infections, resembling chronic inflammatory bowel disease. Lymphoid hyperplasia of the small bowel is a frequent finding. Autoimmune disorders are common and may resemble rheumatoid arthritis, dermatomyositis, or scleroderma. In addition, CVID patients may develop autoimmune hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, pernicious anemia, and chronic active hepatitis. Lymphadenopathy and splenomegaly are common, the result of follicular hyperplasia. Caseating granulomas of the lung, spleen, liver, skin, and other tissues may develop at any age, and a condition resembling sarcoidosis has been described. The cause of this devastating granuloma formation is unknown. A high incidence of lymphoma and gastrointestinal malignancies have been reported in older CVID patients,³³ with a 438-fold increase in the risk of lymphomas in affected women during the fifth and sixth decades.³⁴ Despite normal numbers of blood B lymphocytes and the presence of lymphoid cortical follicles, CVID patients have hypogammaglobulinemia that may be as profound as in XLA (see Table 80–2). Antibody responses to recall and to neoantigens are diminished and some CVID patients have decreased numbers of memory B cells, especially of switched memory B cells. A subset of CVID patients have a substantial T-cell deficiency characterized by decreased expression of CD40L by activated CD4⁺ T cells (without a mutation of CD40L) and by reversed CD4:CD8 ratio. Treatment with IVIG substitution and prophylactic antibiotics is beneficial but often insufficient to prevent serious complications. Allogeneic hematopoietic stem cell transplantation (HSCT) is generally not recommended, except in patients with lymphoid malignancies. There is a rare association between immune deficiency and thymoma, which is estimated to be present in 4 percent of patients with hypogammaglobulinemia.³⁵

Clinical Features and Treatment of Selective Immunoglobulin A Deficiency

The incidence of selective IgA deficiency, defined as IgA less than 5 to 10 mg/dL, differs greatly between ethnic groups, being highest in Scandinavia (1 in 396 in a Finnish study)³⁶ and lowest in Asian populations (1 in 14,000 in Japan).³⁷ Because secretory IgA is considered to be most important in protecting mucus surfaces, it is surprising that most IgA-deficient patients remain healthy. Other defense systems, for example, noncirculatory IgM or neutrophils, may compensate for this deficiency. Symptomatic individuals are not only IgA deficient, but often have deficient antibody responses to specific antigens. IgA deficiency may be associated with IgG₂ and IgG₃ deficiency and poor responses to polysaccharide antigens.³⁸ Selective IgA deficiency, if associated with symptoms, often leads to recurrent sinopulmonary infections and atopic symptoms including allergic conjunctivitis, rhinitis, and eczema. Food allergy may be more common in IgA-deficient patients and asthma associated with IgA deficiency appears to be more refractory to therapy. Gastrointestinal tract disorders include chronic giardiasis, malabsorption, celiac disease, primary biliary cirrhosis, pernicious anemia, and nodular lymphoid hyperplasia. A number of autoimmune diseases are associated with selective IgA deficiency, including rheumatoid arthritis, systemic lupus erythematous, thyroiditis, myasthenia gravis, and ulcerative colitis.

A significant proportion of IgA-deficient individuals has anti-IgA antibodies in their serum and may react to blood products containing IgA, including IVIG preparations with low IgA content. However, patients with selective IgA deficiency who make normal IgG antibody do not need IVIG therapy.

The fundamental defect in selective IgA deficiency is the failure of IgA-bearing B lymphocytes to mature into IgA-secreting plasma cells. There is no specific treatment that would correct this problem. Intermittent or continuous prophylactic antibiotics may be helpful in patients with recurrent respiratory tract infections, who develop chronic symptoms of lung disease. On the other hand, if IgA deficiency is associated with poor antibody responses to selected antigens, for example, to polysaccharides, an attempt with IVIG substitution should be made.

LIPOPOLYSACCHARIDE RESPONSIVE BEIGE-LIKE ANCHOR DEFICIENCY

Lipopolysaccharide responsive beige-like anchor (LRBA) is a broadly expressed, cytosolic protein involved in endocytosis of ligand-activated receptors. LRBA deficiency is inherited as an autosomal recessive trait and is characterized by recurrent bacterial and viral infections, and prominent autoimmune manifestations, cytopenias, and inflammatory bowel disease, in particular.^39,40 Hypothyroidism and myasthenia gravis have been also reported. Immunologic abnormalities include progressive hypogammaglobulinemia, impaired activation and decreased survival of T and B lymphocytes, reduced number of marginal zone-like and switched memory B cells, and defective autophagy.

DEFINITION AND HISTORY

The first description of severe combined immunodeficiencies (SCIDs) dates back to 1950, when Glanzmann and Riniker described infants who died with overwhelming infections, intractable diarrhea, thrush, and profound lymphophenia.⁴¹ The SCID phenotype represents a heterogeneous group of genetic disorders that are characterized by a severe impairment of T-lymphocyte development and function (Fig. 80–1).^42,43,44 Depending on whether the development of B and/or NK lymphocytes is also affected, SCID can be classified into four distinct immunologic phenotypes: (1) T^–B⁺NK^– SCID (the most common variant); (2) T^–B⁺NK⁺ SCID; (3) T^–B^–NK⁺ SCID; or (4) T^–B^–NK^– SCID (see Table 80–2). The term combined immune deficiency (CID) is used to define disorders with residual development and/or function of T lymphocytes. Unless treated by allogeneic HSCT or, in selected cases, by gene therapy or enzyme replacement therapy, SCID is inevitably fatal.

MOLECULAR DEFECTS AND PATHOGENESIS OF SEVERE COMBINED IMMUNE DEFICIENCY

SCIDs are mendelian disorders, and their overall prevalence is estimated to be approximately 1 in 50,000 births. In Western countries, the most common form of SCID is inherited as an X-linked trait; however, a variety of autosomal recessive forms are also known. SCID can be grouped in different categories that illustrate the various pathogenetic mechanisms involved in T-cell development.

Severe Combined Immune Deficiency as a Result of Increased Apoptosis of Lymphocyte Precursors

Adenosine Deaminase Deficiency Approximately 5 to 10 percent of infants with SCID have a deficiency of adenosine deaminase (ADA), the enzyme that converts adenosine and deoxyadenosine into inosine and deoxyinosine, respectively.⁴⁵ In the absence of ADA, high intracellular levels of adenosine, deoxyadenosine, and their toxic phosphorylated metabolites cause apoptosis of lymphoid precursors, and hence result in the virtual absence of T lymphocytes, that is usually associated with marked reduction of B and NK lymphocytes (T^–B^–NK^–SCID).⁴⁶ ADA-SCIDis inherited as an autosomal recessive trait, and its clinical manifestations extend beyond the immune system, reflecting the fact that ADA is a general housekeeping enzyme.

Purine Nucleoside Phosphorylase Deficiency Purine nucleoside phosphorylase (PNP) is another enzyme of the purine salvage pathway. PNP catalyzes the phosphorylation of inosine, guanosine, and deoxyguanosine.⁴⁵ In the absence of PNP, high intracellular levels of deoxyguanosine triphosphatase cause lymphoid and neuronal toxicity. Immature thymocytes are particularly susceptible to PNP deficiency. Accordingly, the immunologic phenotype of PNP deficiency is characterized by decreased T-cell counts, whereas B and NK lymphocytes are often unaffected.⁴⁷ PNP deficiency accounts for 1 to 2 percent of all forms of SCID, and is inherited as an autosomal recessive trait.

Adenylate Kinase 2 Deficiency Another rare variant of autosomal recessive SCID, reticular dysgenesis, is characterized by extreme lymphopenia, absence of neutrophils, and sensorineural deafness.⁴⁸ The disease is caused by mutations of adenylate kinase 2 that result in apoptosis of myeloid precursors of neutrophils, and of lymphoid progenitor cells.^49,50

Severe Combined Immune Deficiency as a Result of Defects of Cytokine-Mediated Signaling

Thymic T-cell progenitors depend on interleukin (IL)-7 for cell proliferation. The IL-7 receptor (IL-7R) is composed of an α chain (encoded by the IL7R gene) and a common γ chain (γc), that is shared also by IL-2R, IL-4R, IL-9R, IL-15R, and IL-21R,⁵¹ and is encoded by the IL2RG gene, located on the X chromosome. Cytokine-mediated signaling through γc—containing receptors involves activation of Janus-associated tyrosine kinase 3 (JAK3).⁵¹ In humans, defects of IL-7–mediated signaling abrogate T-cell development, whereas impaired signaling through IL-15R affects development of NK cells.⁵¹ X-linked SCID, caused by IL2RG mutations,⁵² represents approximately 30 percent of all cases of SCID, and is characterized by lack of T and NK lymphocytes but normal development of B cells (T^–B⁺NK^– SCID). B-lymphocyte function, however, is severely compromised by both the lack of T-cell help and nonfunctional γc. JAK3 deficiency is inherited as an autosomal recessive trait, and its phenotype is identical to that of X-linked SCID (T^–B⁺NK^– SCID).^53,54 In contrast, autosomal recessive IL-7R deficiency caused by mutation of the α chain is characterized by the selective lack of T cells (T^–B⁺NK⁺ SCID).⁵⁵

Severe Combined Immune Deficiency as a Result of Defective Signaling Through the T-Cell Receptor

One of the distinctive features of developing thymocytes is the expression of the pre–T-cell receptor (TCR), that is composed of a pre-Tα chain, a TCRβ chain, and the CD3 γ, δ, ε, and ζ chains. Signaling through the pre-TCR permits rearrangement of the TCRα chain and expression of a mature TCRαβ. Alternatively, thymocytes may express the γδ chains of the TCR. Rearrangement of the TCR loci is accomplished by means of the V(D)J recombination, whereby the lymphoid specific recombination activating gene 1 (RAG1) and recombination activating gene 2 (RAG2) proteins mediate DNA cleavage at the variable (V), diversity (D), and joining (J) elements of the TCR loci. The DNA double-strand break of the coding ends is initially sealed as a hairpin, followed by nonhomologous endjoining via the nuclease Artemis (encoded by the DCLRE1C gene). Eventually, joining of coding (and signal) elements is mediated by a series of proteins, that include the Ku70/80 heterodimer, XRCC4, DNA ligase IV (LIG4), DNA-protein kinase catalytic subunit, and Cernunnos/XLF. Defects in V(D)J recombination affect both T- and B-cell development and hence cause T^–B^–NK⁺ SCID, because this process is also essential to mediate rearrangement of the immunoglobulin genes, a key step in B-cell development. RAG1 or RAG2 deficiencies account for 3 to 20 percent of all SCID cases in different series.^42,56 Artemis (DCLRE1C),⁵⁷ DNA-protein kinase catalytic subunit,⁵⁸ LIG4,^59,60 and Cernunnos/XLF⁶¹ deficiencies are less frequent and their cellular and clinical phenotypes extend beyond impaired T- and B-cell development, because enzymes that mediate DNA double-strand break repair are ubiquitously expressed, and their deficiency results in increased cellular radiosensitivity.^{57,58,59,60,61} The phenotype of LIG4 deficiency can be extremely variable, from T^–B^–NK⁺ SCID to mild or no immunodeficiency, whereas Cernunnos/XLF deficiency is characterized by significant T-cell lymphopenia and progressive decrease in the number of B cells.

Defects of the CD3 δ, ε, or ζ chains affect signaling through the pre-TCR and the TCR and hence cause autosomal recessive T^–B⁺NK⁺ SCID.^62,63,64 In contrast, CD3γ deficiency is associated with mild T-cell lymphopenia and a variable clinical phenotype.^65,66

Mutations of the TCRα constant (TCRA) gene cause impaired differentiation of T cells expressing TCRαβ.⁶⁷

Mutations of CD45, a pan-leukocyte tyrosine phosphatase that has been implicated in signaling through the TCR and the B-cell receptor, have been reported in few patients with T^–B⁺NK⁺ SCID.^68,69

Clinical Features of Severe Combined Immunodeficiency Syndrome

Despite genetic heterogeneity, SCID is characterized by a consistent clinical phenotype. Interstitial pneumonia, often sustained by P. jirovecii, cytomegalovirus (CMV), adenovirus, parainfluenza 3 virus, respiratory syncytial virus, chronic diarrhea, failure to thrive, and persistent candidiasis are common features (see Table 80–1). Typically, infections develop in the first months of life. Skin manifestations (maculopapular rash, erythroderma, alopecia) are also common, especially in infants with maternal T-cell engraftment. Hypoplastic lymphoid tissue (tonsils, lymph nodes), and absence of a thymic shadow on chest radiography are characteristic.⁷⁰

Because of the inability to control replication of live microorganisms, administration of live-attenuated vaccines often leads to severe, life-threatening complications in infants with SCID.⁷¹

T-cell engraftment derived from maternal cells that cross the placenta occurs in more than 50 percent of infants with SCID. Most often asymptomatic, it may cause skin rash or, less frequently, typical graft-versus-host disease with generalized rash, liver disease, profuse diarrhea, jaundice, and severe hematologic abnormalities (thrombocytopenia, anemia, leukopenia) that are indicative of marrow damage.^72,73 Transfusion of un-irradiated blood products often leads to fatal graft-versus-host disease.

Laboratory Features of Severe Combined Immunodeficiency Syndrome

An absolute lymphocyte count less than 2000/μL should prompt immediate investigation for SCID, regardless of the severity of clinical symptoms.⁴² Typically, infants with SCID have markedly reduced or absent circulating T cells which are unable to proliferate in vitro in response to mitogens and specific antigens.⁷⁴ However, T lymphocyte count may be preserved, at least in part, in SCID infants with maternal T-cell engraftment, with “leaky” variants of the disease,⁷⁴ or with somatic reversions that allow for some autologous T-cell development.⁷⁵ Finally, T-lymphocyte count can be normal or modestly reduced in patients with functional T-cell immunodeficiencies (see other combined immunodeficiencies; defective thymic development).

Maternal T-cell engraftment and “leaky” SCID with residual development of autologous T cells are characterized by the expression of the CD45R0 memory/activation antigen on the surface of circulating T lymphocytes (whereas most T cells in normal infants have a naïve CD45RA⁺ phenotype).

TCR excision circles, consisting of circularized signal joints, are a byproduct of V(D)J recombination and are exported to the blood by recent thymic emigrants. Levels of TCR excision circles in circulating lymphocytes are particularly high in newborns and infants, and progressively decline with age. Because TCR excision circles cannot be detected in infants with SCID, assessment of TCR excision circle levels by polymerase chain reaction has been successfully introduced for newborn screening for SCID.⁷⁶

Although the number of circulating B lymphocytes can vary depending on the nature of the genetic defect, serum immunoglobulin levels are low in infants with SCID (see Table 80–2). Normal serum IgG levels early in life reflect transplacental passage of maternal immunoglobulins. Antibody response to immunization antigens is abolished.

Eosinophilia may be observed in SCID, and IgE serum levels may be elevated in spite of hypogammaglobulinemia. Cytopenias, caused by infections or marrow damage, may also be present. Autoimmune hemolytic anemia is frequent in PNP deficiency.⁴⁷ Marrow abnormalities (dysplasia or aplasia) can be observed in ADA,⁷⁷ PNP,⁷⁸ Cernunnos/XLF,^79,80 and LIG4⁸¹ deficiencies.

The diagnosis of ADA and PNP deficiency is facilitated by the demonstration of increased levels of deoxyadenosine triphosphate and deoxyguanosine triphosphate, respectively, in red blood cells.

Differential diagnosis of SCID includes secondary forms of immunodeficiencies, especially HIV infection, congenital rubella, and CMV infections, severe malnutrition, marrow failure syndromes,⁸² and defects of vitamin B₁₂ and folate metabolism.^83,84

Therapy, Course, and Prognosis of Severe Combined Immunodeficiency Syndrome

SCID is a medical emergency and is inevitably fatal if untreated. Confirmation of diagnosis by appropriate laboratory assays, referral to a tertiary care center, and aggressive treatment of infections should be immediately initiated in infants with possible SCID. High-dose intravenous sulfamethoxazole-trimethoprim (20 mg/kg) is effective in treating P. jirovecii pneumonia. CMV should be treated with ganciclovir and adenoviral infections should be treated with cidofovir. Infants who have received bacillus Calmette-Guérin (BCG) vaccination at birth should receive isoniazid and rifampicin, regardless of the presence of overt signs of mycobacteriosis. Administration of IVIG and antimicrobial prophylaxis are necessary to reduce the risk of infections. Parenteral nutrition may be necessary, especially if chronic diarrhea and failure to thrive are present.

Survival, however, is ultimately dependent on immune reconstitution. Allogeneic HSCT was first performed in 1968 in an infant with X-linked SCID,⁸⁵ and is the treatment of choice. A multiinstitutional analysis of outcome of HSCT for SCID performed in North America in the period 2000 to 2009 demonstrates that survival following HSCT from a human leukocyte antigen (HLA)-identical sibling is as high as 97 percent.⁸⁶ T-cell–depleted transplantation from haploidentical donors results in a 79 percent 5-year-survival rate if no conditioning regimen is used. Importantly, survival is as high as 94 percent, regardless of donor type, if the transplant is performed within the first 3.5 months of age.⁸⁶ Moreover, 90 percent survival rate has been reported for older infants who received HSCT and did not have a prior history of infection.⁸⁶ For patients who do not have a matched sibling donor, use of pretransplantation conditioning regimen increases the chance of achieving more robust B-cell reconstitution, but this benefit must be balanced against toxicity of chemotherapy.⁸⁶ By contrast, HSCT from unrelated cord blood is associated with a lower survival rate (58 percent).⁸⁶

Failure to achieve sufficient T- and B-cell reconstitution is associated with prolonged morbidity after transplantation, but most patients with SCID enjoy good quality of life after transplantation.⁵⁶ However, neurologic complications and developmental problems after transplantation are more common in patients with SCID associated with increased radiosensitivity and in patients with defects of purine metabolism.^56,87,88,89

Enzyme replacement therapy offers rapid normalization of the toxic metabolites in ADA deficiency in those who do not have a matched donor, and may result in immune reconstitution and significant clinical improvement in patients with ADA deficiency, although T-cell counts often remain low.⁴⁵

Gene therapy is an attractive form of therapy for SCID patients who lack fully matched donors. Transplantation of gene-modified autologous hematopoietic stem cells (aHSCs) may lead to immune reconstitution without the risk of graft-versus-host disease. More than 40 patients with ADA deficiency have received gene therapy using nonmyeloablative conditioning regimen and transfusion of aHSCs transduced with ADA-encoding retroviral vectors. All of these patients are alive, and approximately 75 percent of them have attained sufficient immune reconstitution.^90,91,92

Twenty patients with X-linked SCID received gene therapy with retroviral vectors in Paris and London, without conditioning regimen. Seventeen of them are alive (as of this writing) with robust T-cell immune reconstitution, but variable B-cell function.^93,94 However, five patients developed leukemia as the result of insertional mutagenesis.^95,96 This prompted development of novel, hopefully safer, vectors. A new multiinstitutional trial of gene therapy for X-linked SCID with a self-inactivating γ-retroviral vector is being conducted as of this writing. Of nine patients treated, eight are surviving, and seven have attained good T-cell reconstitution. No leukemic proliferations have been observed.⁹⁷ Variable, but often poor, B-cell reconstitution has been reported after gene therapy for X-linked SCID without conditioning. To overcome this problem, a new trial based on use of a self-inactivating lentiviral trial and reduced intensity conditioning is under way at the National Institutes of Health as of this writing.

In some cases, significant impairment of T-cell immunity is associated with residual development and/or function of T lymphocytes. These conditions are also known as CID to distinguish them from SCID, in which both T-cell development and function are abrogated. The clinical features of CID overlap with SCID, but also include autoimmunity and/or inflammatory manifestations reflecting unbalanced immune homeostasis. CID is caused by two main mechanisms: (1) hypomorphic mutations in SCID-causing genes that allow for some T-cell development; and (2) genetic defects that affect late stages in T-cell development or peripheral T-cell function.

OMENN SYNDROME

Definition

Originally described in 1965, Omenn syndrome is characterized by severe infections, associated with early onset diffuse rash or generalized erythroderma, alopecia, eosinophilia, lymphadenopathy, hepatosplenomegaly, hypoproteinemia with edema, and oligoclonal expansion of activated autologous T lymphocytes that infiltrate and damage target tissues.^98,99

Genetic Abnormalities

Various gene defects can cause this syndrome. Hypomorphic mutations in the RAG1 and RAG2 genes are most common,¹⁰⁰ but virtually any gene defect that severely impairs, but does not abolish, T-cell development may cause the disease.¹⁰¹

Pathophysiology

Defects of immunologic tolerance have been implied in the pathophysiology of Omenn syndrome. Thymic expression of AIRE (autoimmune regulator), a transcription factor involved in presentation of self-antigens and negative selection of autoreactive thymocytes, is reduced.¹⁰² Impaired generation of natural regulatory T cells, and homeostatic proliferation of T lymphocytes in a lymphopenic environment, may also play a critical role in the pathophysiology of the disease.¹⁰³

Laboratory Features

Laboratory investigations demonstrate that leukocytosis with eosinophilia and hypogammaglobulinemia are common findings, and that serum IgE is often elevated. The number of circulating T lymphocytes may vary, but they have a characteristic activated/memory (CD45R0+) phenotype. T cells have a restricted repertoire, and the distribution of CD4 and CD8 subsets is generally skewed. There is also a skewing to a T-helper (Th) type 2 (Th2) profile, with increased production of IL-4 and IL-5. The in vitro lymphocyte response to antigens is abrogated; responses to mitogens are variable, but in general are reduced.^74,104 The number of circulating B and NK lymphocytes may vary, depending on the nature of the underlying genetic defect. Absence of invariant NK T cells has been reported in RAG-deficient Omenn syndrome.¹⁰⁵

Differential Diagnosis

Differential diagnosis includes maternal T-cell engraftment in patients with SCID, complete atypical DiGeorge syndrome, CHARGE syndrome (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness), immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome and other conditions of neonatal erythroderma.^{106,107,108,109} Male infants with NEMO deficiency can also present with severe skin manifestations resembling Omenn syndrome.

Treatment

In preparation for allogeneic HSCT, the only curative treatment available,⁵⁶ patients require aggressive nutritional support, correction of hypoproteinemia, and treatment or prevention of infections with antibiotics, antifungals, and immunoglobulin replacement therapy. Immune suppression with steroids or cyclosporine is beneficial in controlling T-cell–mediated tissue damage.

DEFECTS OF T-CELL–RECEPTOR SIGNALING

Definition

TCR ligation promotes activation of the p56Lck kinase, which mediates phosphorylation of components of the CD3 complex. This allows recruitment and phosphorylation of the zeta-associated protein of 70 kDa (ZAP-70), activation of downstream signaling molecules, release of Ca²⁺ from intracellular endoplasmic reticulum stores, and initiation of Ca²⁺ influx. Mutations of lymphocyte-specific protein tyrosine kinase (LCK), ZAP-70, and of other TCR-associated signaling molecules (RHOH, MST1, IL-2–inducible T-cell kinase [ITK]) result in various forms of CID with dysfunctional T cells.^{110,111,112,113,114,115} Finally, PI3K, composed of a p110δ and a p85 subunit, is involved in generation of phosphatidylinositol 4,5-triphosphate (PIP₃) and activation of mammalian target of rapamycin (mTOR) and AKT. Activating mutations of the PI3KD gene (encoding for the PI3K subunit p110δ) results in increased activation-induced cell death of T lymphocytes, and consequently immunodeficiency.^29,30

Clinical and Laboratory Features

Patients with these disorders present with early onset and severe infections. Warts, molluscum contagiosum, infections caused by herpes viruses, and a high risk of Epstein-Barr virus (EBV)-driven lymphoproliferative disease have been reported in patients with LCK, RHOH, and MST1 deficiency, and with activating PI3KD mutations.^{29,30,110,113,114} Moreover, autoimmunity and lung granulomatous disease may also occur. From a laboratory standpoint, selective loss of CD8⁺ lymphocytes is observed in patients with ZAP-70 deficiency, and although the number of CD4⁺ lymphocytes is preserved, in vitro response to mitogens is markedly reduced, consistent with a signaling defect.^111,112 Patients with LCK, RHOH, MST1, and ITK deficiency and with gain-of-function PI3KD mutations have a reduced number of naïve CD4⁺ T cells. Oligoclonality of the T-cell repertoire and an increased proportion of exhausted CD8⁺ T memory (T_EMRA) cells have been reported in these patients.^{29,30,107,113,114,115}

Differential Diagnosis

Differential diagnosis of ZAP-70 deficiency includes MHC class I deficiency and CD8α deficiency, two conditions characterized by a severe reduction of CD8⁺ lymphocytes. Patients with CD8α deficiency have an unusual population of CD3⁺ TCR αβ⁺ CD4^– CD8^– cells that have normal proliferative responses and usually survive to adulthood, although a late death from infections has been reported.^116,117 The other defects of TCR signaling have an overlapping phenotype. Ultimately, biochemical and molecular tests are needed to define the diagnosis.

Treatment

The only curative treatment of this group of disorders is allogeneic HSCT. Treatment with rapamycin (an mTOR inhibitor) or phosphoinositide 3-kinase inhibitor may reduce lymphoproliferation and hepatosplenomegaly in patients with activating PI3KD mutations.^29,30

T-CELL IMMUNODEFICIENCIES WITH IMPAIRED NUCLEAR FACTOR-κB ACTIVATION

Following TCR signaling, the complex composed of MALT1, BCL-10, and caspase recruitment domain-containing protein (CARD)-11 proteins is activated, resulting in recruitment of TRIF-related adaptor molecule (TRAF) 6 and activation of IKK, permitting nuclear translocation of the p50 and p65 subunits of NF-κB and consequently induction of activation of NF-κB–dependent genes. Mutations of MALT1,¹¹⁸ CARD11,^119,120 and IKBKB¹²¹ (encoding for the IKKβ component of the IKK complex) genes are associated with increased susceptibility to bacterial, viral and fungal infections. Although the number of circulating T lymphocytes is normal, generation of memory T cells is impaired and proliferative responses to CD3 stimulation are decreased. Patients with CARD11 mutations have a block in B-cell development at the transitional stage,^119,120 and virtual absence of class-switched memory B cells is observed in patients with IKBKB mutations.¹²¹

As reported above, mutations of the IKBKG/NEMO gene are responsible for X-linked immunodeficiency with ectodermal dysplasia, whose clinical manifestations may also include opportunistic infections, resembling CID. Finally, gain-of-functions mutations of the IKBA gene, that prevent phosphorylation and degradation of the IKB-α subunit of the IKB complex, cause T-cell immunodeficiency with ectodermal dystrophy. The immunologic phenotype includes deficiency of memory T cells, impaired in vitro proliferation of naïve T cells to TCR/CD3 stimulation, and hypogammaglobulinemia with inability to mount specific antibody responses.¹²² In addition to TCR signaling, activation of toll-like receptor (TLR) and tumor necrosis factor (TNF) pathways can also be compromised, causing increased susceptibility to a broad range of pathogens (pyogenic bacteria, mycobacteria, Candida, other opportunistic pathogens).¹²³

CORONIN-1A DEFICIENCY

Coronin-1A is an actin regulator that is predominantly expressed in hematopoietic cells, plays a key role in regulating T-cell survival and migration. Mutations affecting both alleles of the CORO1A gene have been reported in patients with CID and an increased risk of severe varicella and EBV lymphoproliferative disease.^124,125 The immunologic phenotype includes naïve T-cell lymphopenia with normal numbers of B and NK cells, oligoclonal T-cell repertoire and reduced number of circulating invariant NKT (iNKT) cells and mucosa-associated invariant T (MAIT) lymphocytes. Immunoglobulin serum levels are low, and antibody responses to antigens are absent. The disease can be treated by allogeneic HSCT.¹²⁴

CD27 DEFICIENCY

The CD27 costimulatory molecule regulates survival and activation of T, B, and NK cells. CD27 deficiency is a CID with risk of EBV lymphoproliferative disease. In vitro T-cell proliferation to mitogens and antigens is reduced.¹²⁶ Immunoglobulin serum levels may be initially high, but patients eventually become hypogammaglobulinemic.

CTPS1 DEFICIENCY

Cytidine 5-triphosphate synthase 1 (CTPS1) is involved in de novo synthesis of cytidine 5-triphosphate (CTP), a nucleotide required for DNA and RNA metabolism. Impaired de novo synthesis of CTP causes a proliferation defect in both T and B lymphocytes. CTPS1 mutations have been identified in several infants from Northwestern England. The disease is characterized by severe bacterial and viral infections since early in life, and an increased risk of EBV-driven non-Hodgkin lymphoma. There are no extra-immune manifestations. Variable degrees of lymphopenia (especially of CD4⁺ cells), increased proportion of effector memory T cells and reduced in vitro proliferation to mitogens and antigens have been reported. Immunoglobulin levels may be normal, but specific antibody titers are reduced, and there is a low number of memory B cells.¹²⁷

MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I DEFICIENCY

Definition

MHC class I deficiency is characterized by reduced expression of MHC class I molecules at the cell surface. The disease is inherited as an autosomal recessive trait, and may be caused by defects in the TAP1,¹²⁸ TAP2,¹²⁹ or Tapasin¹³⁰ genes. These defects interfere with intracellular transport of peptide antigens and their loading onto MHC class I molecules, and cell-surface expression of the complex.

Clinical and Laboratory Features

MHC class I deficiency manifests with recurrent respiratory infections in childhood, and chronic inflammatory lung disease and skin lesions, mimicking Wegener granulomatosis in patients with transporter-associated with antigen-processing (TAP)-1 and TAP-2 deficiencies.^131,132 Chronic lung disease is a prominent cause of death. Glomerulonephritis and herpes zoster infections have been reported in Tapasin deficiency.¹³⁰

The number of circulating CD8⁺ T cells is reduced, because positive selection of CD8⁺ lymphocytes in the thymus depends on the recognition of MHC class I molecules. In vitro T-cell function is normal, which facilitates differential diagnosis with ZAP-70 deficiency in patients who have significantly reduced CD8⁺ cells. The NK cytolytic activity is usually significantly reduced (see Table 80–2). Serum immunoglobulin levels are variable.

Treatment

Prophylactic measures, similar to those used in cystic fibrosis, may be beneficial. Treatment of the granulomatous lesions is based on use of topical antiseptics; immunosuppressive drugs may worsen symptoms and should be avoided.

MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II DEFICIENCY

Definition

MHC class II deficiency is defined by the lack of MHC class II expression and autosomal recessive inheritance. There is a higher prevalence in populations of North African origin. MHC class II deficiency is caused by mutations of transcription factors that bind to the proximal promoters of the MHC class II gene. Four different gene defects are known and include mutations of the CIITA, RFXANK, RFX5, and RFXAP genes.¹³³

Clinical and Laboratory Features

Typically, patients present early in life with increased susceptibility to bacterial, viral, and opportunistic infections. Severe lung infections, chronic diarrhea, and sclerosing cholangitis, often secondary to Cryptosporidium or CMV infection, are frequently observed. Less-severe presentations and survival into adulthood have been reported.¹³³

The number of circulating CD4⁺ T cells is markedly reduced, reflecting an impairment of positive selection in the thymus. Delayed-type hypersensitivity responses are absent, but in vitro proliferative responses to mitogens are preserved. Hypogammaglobulinemia is common and poor antibody response to immunization antigens is consistently observed (see Table 80–2).¹³³ The diagnosis is based on demonstrating lack of MHC class II expression on monocytes, B lymphocytes and in vitro activated T cells. Differential diagnoses include HIV infection and idiopathic CD4 lymphopenia; however, in these conditions expression of MHC class II molecules is preserved.

Treatment and Course

MHC class II deficiency has a poor prognosis. If untreated, most patients die in infancy or childhood. Respiratory infections are the predominant cause of death. Liver failure is observed in patients who develop sclerosing cholangitis. Antibiotic prophylaxis and immunoglobulin replacement therapy, with adequate nutritional support, are required. HSCT is the only curative approach, but survival rate is lower than in other forms of CID and graft-versus-host disease is common, especially in patients with preexisting viral infections.¹³³

DEFECTS OF STORE-OPERATED Ca²⁺ ENTRY

Calcium mobilization is a key event in the activation process of lymphocytes and nonimmune cells. Two molecules, calcium release-activated calcium channel protein 1 (ORAI1) and stromal interaction molecule 1 (STIM1), mediate the function of Ca²⁺ entry channels. ORAI1 is a ubiquitously expressed protein that constitutes the pore-forming subunits of the Ca²⁺ release-activated channels located in the cell membrane. STIM1 senses the Ca²⁺ concentration in the endoplasmic reticulum and activates Ca²⁺ release-activated channels. Mutations of both the ORAI1 and STIM1 genes in humans result in an autosomal recessive immunodeficiency with increased susceptibility to severe infections, especially from herpesviruses infections, associated with nonprogressive myopathy and ectodermal dysplasia. Manifestations of immune dysregulation (autoimmune cytopenias, hepatosplenomegaly) are common, especially in STIM1 deficiency.^134,135 Although T-cell development is unaffected, in vitro proliferation of circulating T cells to mitogens and to a combination of phorbol ester and ionomycin is drastically reduced, and the Ca²⁺ influx following T-cell activation is absent. Lack of natural killer T (NKT) cells and functional defects of NK lymphocytes have been reported. In spite of hypergammaglobulinemia, specific antibody responses are typically absent. Allogeneic HSCT has been used in some patients to correct the defect.¹³⁵

DEFECTS OF MAGNESIUM TRANSPORTER 1

Mg²⁺ is an important second messenger in the immune system. Mutations of the X-linked magnesium transporter 1 (MAGT1) gene, that encodes for a protein that permits transport of Mg²⁺ across the cell membrane, cause immunodeficiency with increased susceptibility to bacterial and viral infections, and a high risk of EBV-driven lymphoproliferative disease.¹³⁶ Patients have CD4 lymphopenia, defective lymphocyte proliferation in vitro and impaired NK cytolytic function.¹³⁷

DEDICATOR OF CYTOKINESIS 8 DEFICIENCY

Dedicator of cytokinesis 8 (DOCK8) is an atypical guanosine triphosphatase (GTPase) that regulates cytoskeleton reorganization and intracellular signaling. Although it is broadly expressed, it plays a critical role in T, B, and NK lymphocytes. DOCK8 deficiency is inherited as an autosomal recessive trait, and is characterized by recurrent and severe bacterial, fungal, and viral infections, eczema and other manifestations of immune dysregulation, including autoimmune cytopenias. Cutaneous viral infections (warts, molluscum contagiosum, herpes simplex) are especially common, but systemic viral disease (varicella, CMV, EBV) has been also reported. Cutaneous infections frequently evolve into squamous cell carcinoma. Vascular thrombosis in the central nervous system has been described in several patients.^138,139 Multiple immunologic abnormalities have been reported,^{138,139,140,141,142} including a variable degree of lymphopenia that affects especially naïve T cells, increased proportion of CD8⁺ T_EMRA cells, decreased in vitro proliferation to CD3 stimulation, impaired generation of Th17 cells, and defects of NK cytolytic function. Immunoglobulin levels are variable, but IgM serum levels are often low. B-cell response to TLR9 stimulation is defective, and specific antibody responses are blunted. Large, intragenic deletion of the gene has been frequently reported in affected patients,¹³⁹ and lack of DOCK8 protein expression can be demonstrated by flow cytometry.¹⁴³ The disease has a poor prognosis, but can be cured by allogeneic HSCT.¹⁴⁴ Good results have been reported in the treatment of severe herpetic infections with interferon (IFN)-α (see also “The Hyperimmunoglobulin E Syndromes” below).¹⁴⁵

COMBINED IMMUNODEFICIENCY WITH MULTIPLE INTESTINAL ATRESIA

Multiple intestinal atresia is a congenital disease characterized by atresias that may affect the gastrointestinal tract, from stomach to anus.^{146,147,148,149} In many cases, CID is associated, with reduced number of T (and in some patients, B) lymphocytes, impaired in vitro proliferation to mitogens, and profound hypogammaglobulinemia. A high risk of sepsis because of Gram-negative bacteria has been reported, but viral, fungal, and opportunistic infections are also common. The disease is inherited as an autosomal recessive trait and is caused by mutations of the tetratricopeptide repeat domain 7A (TTC7A) gene,^146,147 which plays an important role in intestinal and immune homeostasis by maintaining cell polarity and regulation of cell survival, proliferation, adhesion, and migration.^148,149 In the thymus, TTC7A is expressed both by thymic epithelial cells and by thymocytes.^147,148 Multiple surgeries are often required to establish canalization of the gastrointestinal tract. Total parenteral nutrition often leads to severe liver disease, and combined small bowel and liver transplantation may be needed.¹⁵⁰ Most patients die early in life. Partial immune reconstitution has been reported in a few cases following HSCT.¹⁴⁷

VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY

Venoocclusive disease with immunodeficiency (VODI) is a congenital disorder characterized by liver abnormalities and immunodeficiency, with onset in the first months of life.¹⁵¹ Liver abnormalities include venoocclusive disease, fibrosis, hepatomegaly, and hepatic failure. Patients are prone to recurrent infections, sustained by viruses, bacteria, and opportunistic pathogens (P. jirovecii, Candida, CMV). Thrombocytopenia is frequent. Infections may precede development of liver abnormalities. Immunologic defects include low number of memory T and B lymphocytes, defective B-cell differentiation in vitro into antibody-secreting cells, and hypogammaglobulinemia.¹⁵¹ The disease is more common in the Lebanese population. It is inherited as an autosomal recessive trait and is caused by mutations of the SP110 gene,¹⁵² which encodes for a nuclear body protein that acts as a transcription factor driving expression of genes with a retinoic acid response element. Treatment is based on immunoglobulin replacement therapy, prophylactic antibiotics, prompt treatment of infections, and ursodiol; however, the prognosis remains dismal. HSCT is the only curative approach, but the outcome is often problematic because of liver toxicity as a result of conditioning regimen.¹⁵³

DIGEORGE SYNDROME (22q 11.2 DELETION SYNDROME)

Definition

The DiGeorge syndrome (DGS) is a developmental disorder caused by abnormal cephalic neural crest cell migration and differentiation in the third and fourth pharyngeal arches during early embryonic development.¹⁵⁴ The vast majority of patients with DGS have partial monosomy of human chromosome 22q11.2. However, a significant fraction (10 to 45 percent) of patients with DGS do not have a chromosome 22q11.2 deletion and some 2 percent have small deletions in chromosome 10p.

Clinical and Laboratory Features

The clinical phenotype of DGS consists of the triad congenital cardiac defects, hypocalcemia as a result of parathyroid insufficiency, and immune deficiency as a consequence of aplasia or hypoplasia of the thymus.¹⁵⁴ However, there is significant phenotypic variability. Cardiac defects (especially interrupted aortic arch type B and truncus arteriosus) occur in 50 to 80 percent of patients with 22q11.2 deletion. Hypocalcemia is observed in 50 to 60 percent, and may cause neonatal seizures. Facial dysmorphisms include micrognathia, hypertelorism, antimongoloid slant of the eyes, and ear malformations. A third of DGS patients have velopharyngeal incompetence, leading to feeding difficulties and speech delay; 10 percent have a cleft palate. As young adults, many develop social, behavioral, and psychiatric problems.

There is also significant variability of the severity of immunologic phenotype. Most patients have residual thymic tissue and hence mild to moderate T-cell lymphopenia (see Table 80–2). Approximately 1 percent of DGS patients lack T cells completely, resembling SCID (complete DGS). In some cases, generation of oligoclonal T cells that infiltrate target tissues is associated with generalized skin rash and lymphadenopathy, resembling Omenn syndrome. This phenotype is known as atypical complete DGS.¹⁵⁵ As in other cellular immunodeficiencies, patients with DGS have a high incidence of autoimmune diseases such as cytopenia and thyroiditis. A retrospective analysis of TCR excision circle (TREC) levels at birth in patients with DGS has shown that approximately 20 percent of them had low TRECs; these infants had lower CD8⁺ T-cell count and were more prone to viral infections than DGS infants with normal TREC levels at birth.¹⁵⁶

Treatment

Cardiovascular anomalies require prompt attention and hypocalcemia appropriate medical treatment. Depending on the extent of the immune deficiency, patients may require antibiotic prophylaxis or IVIG therapy. However, patients with complete DGS (including complete atypical phenotype) require more aggressive treatment. Allogenic thymic transplantation may restore T-cell development and function in approximately 75 percent of these patients.¹⁵⁵ Unmanipulated marrow from matched donors can also lead to immune reconstitution by providing mature T lymphocytes contained in the graft.¹⁵⁷

COLOBOMA, HEART DEFECTS, ATRESIA OF THE CHOANAE, RETARDED GROWTH, GENITAL HYPOPLASIA AND EAR ANOMALIES SYNDROME

A syndrome with a severe T-cell defect, CHARGE is caused by heterozygous de novo mutations in the CHD7 gene.¹⁵⁸ Circulating T lymphocytes are decreased in most CHARGE patients and respond poorly to mitogens.

CONGENITAL ALOPECIA AND ABSENCE OF THYMUS

Mutations of the FOXN1 gene, encoding for a transcription factor that plays a critical role in development of thymic epithelial cells, causes thymic aplasia, associated with congenital alopecia, nail dystrophy, and a severe neural tube defect.¹⁵⁹ This phenotype is the equivalent of the mouse nude/SCID phenotype. Successful outcome has been reported after thymic transplantation.¹⁶⁰

The concept of a link between immune dysregulation and autoimmunity has been strengthened by the discovery of distinct single-gene defects resulting in unusual susceptibility to autoimmune diseases. The three representative syndromes in this category include (1) IPEX, (2) autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED), and (3) the autoimmune lymphoproliferative syndrome (ALPS).

IMMUNE DYSREGULATION, POLYENDOCRINOPATHY, ENTEROPATHY, X-LINKED SYNDROME

Clinical Findings

The most prominent IPEX symptoms include early onset diarrhea secondary to autoimmune enteropathy, eczematous dermatitis, multiple endocrinopathies including early onset insulin-dependent type 1 diabetes mellitus, thyroiditis, and, rarely, adrenal insufficiency. Autoimmune hemolytic anemia, thrombocytopenia, and neutropenia are common complications. Eczema is the most frequent pathology of the skin, but erythematous, psoriasiform dermatitis, and alopecia universalis have been reported. Autoimmune hepatitis is present in 20 percent of IPEX patients. Lymphadenopathy and hepatosplenomegaly are less common.¹⁰⁸ Loss of small bowel villi and lymphocytic infiltrates in the intestinal mucosa, the pancreas, thyroid, lung, and liver are commonly observed. Immunologic abnormalities include elevated serum IgA and IgE concentrations and the absence of CD4⁺CD25⁺ FOXP3⁺ regulatory T cells.

IPEX is caused by mutations in the FOXP3 gene located in the centromeric region of the X chromosome.¹⁶¹ The transcription factor FOXP3 binds to more than 700 promotors and acts as a transcriptional repressor of the IL-2, IL-4, and IFN-γ promoters by interfering with the cytokine regulator, NFAT (nuclear factor of activated T cells).¹⁶² FOXP3 plays a crucial role in the generation of T-regulatory cells (Tregs) in the thymus.

Treatment

Immunosuppressive drugs such as cyclosporine, tacrolimus, sirolimus, and glucocorticoids provide temporary remission. Allogeneic HSCT can cure this disease.¹⁶³

IMMUNE DYSREGULATION, POLYENDOCRINOPATHY, ENTEROPATHY, X-LINKED–LIKE SYNDROMES

An IPEX-like phenotype has been associated with mutations in a number of genes, including CD25, STAT5B, STAT1 (gain-of-function mutations) STAT3 (gain-of-function) and ITCH/AIP4.

Cd25 Deficiency

CD25 (IL-2 receptor α chain) was found to be deficient in three infants from two unrelated families. Clinical features resemble those of both IPEX and SCID. CD25-deficient infants presented with severe chronic diarrhea, villous atrophy and autoimmune hepatitis at an early age.^164,165 Early onset insulin-dependent diabetes was observed in one patient; all presented with eczema and developed autoantibodies, hepatosplenomegaly, lymphadenopathy, and lymphocytic infiltrates in the lung, gut, and liver.¹⁶⁵ However, CD25-deficient patients suffered from infectious complications more commonly observed in patients with SCID, including recurrent CMV pneumonitis, persistent thrush, and EBV infection. One patient was treated successfully with HSCT.¹⁶⁴

STAT5B Deficiency

The transcription factor STAT5B is activated/phosphorylated in response to growth hormone and the cytokines IL-2, IL-7, IL-15 and IFN-γ, and promotes the transcription of nonimmune and immune genes. STAT5B plays a crucial role in the transcription of insulin-like growth factor 1 (IGF-1), which is required for in utero and postnatal growth. In addition, STAT5B is required for the transcription of IL-2Rα, a crucial component of the IL-2 receptor necessary for induction of FOXP3, which programs the development of Tregs in the thymus. The clinical phenotype of homozygous STAT5B deficiency reflects these molecular observations. Affected patients suffer from intrauterine and postnatal growth failure from lack of IGF-1 resulting in growth hormone insensitivity.¹⁶⁶ Moderate T and NK cell lymphopenia may be the cause of susceptibility to viral infections.¹⁶⁷ Importantly, STAT5B-deficient patients have reduced numbers of Tregs with low FOXP3 expression, and decreased suppressor function.¹⁶⁸ As a result of abnormal Treg homeostasis, STAT5B-deficient patients have immune dysfunction and multiple autoimmune problems, including arthritis, lymphocytic interstitial pneumonia, severe eczema, autoimmune thyroiditis, and idiopathic thrombocytopenic purpura.¹⁶⁹

STAT1 Gain-of-Function Mutations

Heterozygous mutations in STAT1 were recently identified in patients with chronic mucocutaneous candidiasis.¹⁷⁰ These mutations were within the coiled-coil and DNA-binding domains, leading to hyperphosphorylation of STAT1 in response to cytokines such as IFN-γ. Screening of a cohort of patients with IPEX-like symptoms who also had mucocutaneous fungal infections revealed heterozygous STAT1 gain of function mutations. The clinical characteristics included enteropathy with villous atrophy, type I diabetes, thyroiditis, eczema, short stature, vascular aneurysms and viral infections. FOXP3⁺ Treg numbers were within the normal range, and showed normal suppressive function.¹⁷¹ It has been hypothesized that effector cells may be less responsive to suppression as a result of excessive STAT1 activity.

STAT3 Gain-of-Function Mutations

A Finnish-British consortium discovered heterozygous gain-of-function mutations in several patients with short stature, polyendocrinopathy including type 1 diabetes starting at a very young age (in utero or before 3 weeks of age). The clinical phenotype included the presence of multiple autoantibodies, celiac disease or autoimmune enteropathy, eczema, thyroiditis, arthritis, autoimmune cytopenias and large granular lymphocytic (LGL) leukemia in one in five patients.¹⁷² Except for eczema, none of the patients with STAT3 gain-of-function mutations had the clinical features of autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES) as a result of heterozygous dominant negative STAT3 mutations, although the mutations, all missense, were located in the same domains (DNA binding, SH3 [Src homology 3], and transactivation) as those observed in AD-HIES. When studied for STAT3 activity using a luciferase reporter assay gain-of-function mutations showed an increase, whereas those with heterozygous loss of function mutations causing AD-HIES had decreased activity.

Cytotoxic T-Lymphocyte Antigen-4 Haploinsufficiency

Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is an inhibitory receptor expressed by T lymphocytes including Tregs, and by B cells. While CD28 transmits a stimulatory signal to lymphocytes, CTLA-4 provides an inhibitory signal.¹⁷³ CTLA-4 can also affect signaling in B cells by competing with CD28 for CD80/86 binding.

In a recent report, heterozygous mutations in the CTLA4 gene were observed in members of four unrelated families suffering from multiple autoimmune diseases, recurrent infections, and lymphocytic infiltrates in a number of target organs.¹⁷⁴ Affected patients developed hypogammaglobulinemia, CD4 lymphopenia, progressive loss of circulating B cells and defective/dysregulated Treg cells. Reduced CTLA-4 expression in T cells, B cells, and Tregs, and increased T- and B-cell apoptosis are characteristic findings and may contribute to the clinical phenotype.

ITCH E3 Ubiquitin Protein Ligase Deficiency

The clinical features of ITCH E3 ubiquitin protein ligase (ITCH) deficiency caused by mutations in E3 ubiquitin ligase (ITCH/AIP4) include dysmorphic facial features, failure to thrive and developmental delay. In addition, immune dysregulation that is characterized by chronic interstitial pneumonitis, thyroiditis, type I diabetes, enteropathy, and hepatitis were common.¹⁷⁵ This is a rare syndrome observed in a single large Amish kindred with 10 affected family members. ITCH can affect T-cell anergy in mice because of defective FOXP3 expression.¹⁷⁶

AUTOIMMUNE POLYENDOCRINOPATHY, CANDIDIASIS, AND ECTODERMAL DYSTROPHY SYNDROME

APECED is a rare autosomal recessive disorder, also known as autoimmune polyglandular syndrome (APS) type I. The incidence is high in certain isolated populations, for example, Finns, Iranian Jews, and Sardinians. Most patients with APECED present with chronic mucocutaneous candidiasis and endocrinopathies predominantly involving the parathyroid and adrenal glands, less frequently the thyroid and the pancreas. The syndrome is often associated with ectodermal manifestations such as dystrophic dental enamel and fingernails.¹⁷⁷ APECED results from mutations in the AIRE gene. AIRE expression is limited to medullary thymic epithelial cells which express MHC class II and the costimulatory molecule CD80. These cells are endowed with the remarkable ability to “promiscuously” express a wide variety of tissue-restricted antigens derived from nearly all organs in the body.¹⁷⁸ Expression of these organ specific proteins allows for the negative selection of autoreactive T cells or the generation of immunoregulatory FOXP3⁺ T cells in the thymus. A lack of AIRE function causes decreased expression of tissue-restricted antigens in the thymus, resulting in the escape of autoreactive T-cell clones into the periphery.¹⁷⁹ Autoantibodies against type 1 interferons,¹⁸⁰ and against IL-17A, IL-17F and/or IL-22,¹⁸¹ were detected at high titers in most patients. Treatment for APECED is largely supportive.

AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME

Definition, Clinical Features, and Pathogenesis

ALPS is caused by defective apoptosis of lymphocytes, resulting in nonmalignant lymphadenopathy, hepatosplenomegaly, and autoimmune disorders, which most commonly include Coombs-positive autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. The incidence of lymphoma is estimated to be 9 percent in the National Institutes of Health cohort of 79 probands¹⁸² and consist of both Hodgkin and non-Hodgkin lymphoma. Both lymph nodes and spleen show pronounced hyperplasia and contain a CD3⁺ lymphocyte population of which a large proportion consists of TCRαβ⁺ CD4^–CD8^– cells. This phenomenon is also observed in blood lymphocytes from ALPS patients in which the proportion of double-negative T cells is typically between 5 and 20 percent (range: 1.5 to 68 percent).¹⁸² Many of these cells express MHC class II and secrete high levels of IL-4, IL-5, and IL-10.

The FAS-mediated apoptosis pathway is important for the downregulation of antigen-induced immune responses and the elimination of autoreactive lymphocytes. ALPS patients have mutations in genes required for “programmed cell death.” The most common defect involves heterozygous (dominant) mutations in the gene encoding the T-cell surface molecule FAS, also known as CD95 or TNFRSF6 (ALPS-FAS, formerly ALPS type Ia); rare patients with compound heterozygous or homozygous FAS-mutations (ALPS-FAS or type 0) have been reported. In some patients, somatic mutations of FAS have been identified in double-negative T cells (ALPS-sFAS or type 1m). A few families have been identified with mutations affecting the FAS ligand (CD95L; TNFSF6) which is responsible for ALPS-FASL or ALPS type Ib. Approximately 3 percent of ALPS patients have mutations in caspase 10 (ALPS-CASP10 or ALPS type II). Ten to 20 percent of patients with the ALPS phenotype do not have mutations in FAS, FASL, or caspases and are classified as ALPS-U or ALPS type III.¹⁸² Because three Fas molecules form a trimeric complex to interact with a FasL trimer, most families with ALPS have AD inheritance (dominant negative effect) with variable penetrance (mutations in caspase 8 and 10 are autosomal recessive).

Treatment

Immunosuppressive therapy including steroids, mycophenolate mofetil (MMF), and rituximab, has been used with variable success to treat autoimmune symptoms.¹⁸² A recent clinical trial with sirolimus achieved complete or near complete resolution of autoimmune cytopenia, colitis, lymphadenopathy, and splenomegaly and all patients had a reduction in double-negative T cells.¹⁸³ Splenectomy is recommended only in patients with excessively large spleens or splenic rupture and requires lifetime antibiotic prophylaxis. The long-term prognosis is guarded, but patients can achieve a normal life span.

WISKOTT-ALDRICH SYNDROME

Definition

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by thrombocytopenia (Chap. 117) and small platelets, eczema, recurrent infections, immunodeficiency, and a high incidence of autoimmune diseases and malignancies.¹⁸⁴ A classic WAS phenotype is generally associated with null-mutations of the gene that encode the WAS protein (WASp). WASp is the key regulator of actin polymerization in hematopoietic cells and has well-defined domains that are involved in cytoplasmic signaling, cell locomotion, and immunologic synapse formation. A milder phenotype, X-linked thrombocytopenia (XLT), is often associated with mutations that result in expression of mutated protein. XLT patients have either no or very mild eczema and few problems, if any, with infections, autoimmunity, and malignancy.¹⁸⁵ Amino acid substitutions within the GTPase-binding domain of WASp interfere with the intramolecular autoinhibitory mechanism, resulting in gain-of-function–impaired actin polymerization, causing X-linked neutropenia (Chap. 65).¹⁸⁶

Clinical and Laboratory Features

By definition, WAS and XLT patients have congenital thrombocytopenia in the range of 20,000 to 60,000/μL and microplatelets, but normal numbers of megakaryocytes. Hemorrhagic problems may be mild, consisting of bruises and petechiae, or serious, including gastrointestinal and central nervous system hemorrhages. Patients with classic WAS are susceptible to bacterial, fungal, and viral infections.

Treatment

Patients may require antibiotic prophylaxis and IVIG replacement therapy. Immunosuppressive therapy may be needed if autoimmune symptoms occur. Splenectomy ameliorates the bleeding tendency by increasing the number of blood platelets. However, splenectomy substantially increases the risk of septicemia, sometimes in spite of antibiotic prophylaxis, and often results in fatal bacterial infections. Because of the poor long-term outcome of WAS, early allogeneic HSCT is the treatment of choice. The outcome is excellent if a matched-related or matched-unrelated donor can be identified, or if a partially matched cord blood unit is available.¹⁸⁷ Haploidentical transplantation is not recommended. Patients with XLT have an excellent prognosis, but may develop complications including serious bleeding, autoimmune diseases, and malignancies.^144,185 Therefore, allogeneic HSCT for XLT may be considered if an appropriate donor is available. Because complete myeloid and lymphoid engraftment is required to correct all aspects of WAS/XLT, standard-conditioning using myeloablative protocols (busulfan, cyclophosphamide, with or without antithymocyte globulin) are required. A European followup study of WAS patients who received HSCT reports a strong association of autoimmunity with mixed chimerism, clearly demonstrating that reduced intensity conditioning is not sufficient.¹⁸⁸

WASp-INTERACTING PROTEIN DEFICIENCY

A syndrome exhibiting symptoms and laboratory abnormalities typical for classic WAS has been observed in a female infant with a homozygous nonsense mutation in WIPF1 that encodes WASp-interacting protein (WIP). The patient presented at 11 days of age with eczema, thrombocytopenia (but normal platelet size) and infections.¹⁸⁹ Both WIP and WASp were absent in patient leukocytes, demonstrating that WIP is required for stabilization of WASp. The patient was successfully transplanted at age 4.5 months.

THE HYPERIMMUNOGLOBULIN E SYNDROMES

Autosomal Dominant Hyperimmunoglobulin E Syndrome

HIES (or Job syndrome) is a rare AD or sporadic multisystem immunodeficiency characterized by eczema, S. aureus-induced skin abscesses, recurrent pneumonia with abscess and pneumatocele formation, Candida infections, and skeletal and connective tissue abnormalities.¹⁹⁰ In 1966, two girls suffering from eczema, recurrent respiratory tract infections, and “cold” staphylococcus skin abscesses were described as having Job syndrome because of the phenotypic similarity to the biblical figure Job, who had been “smitten with sore boils from the soles of his feet unto his crown.”¹⁹¹ Subsequently, patients with similar clinical findings were reported to have very-high serum IgE concentrations¹⁹² and additional characteristic abnormalities were recognized, including distinct facial features, often described as “coarse,” hyperextensive joints, pathologic bone fractures, scoliosis, craniosynostosis, and retained primary teeth.^193,194 Serum IgE levels of greater than 2000 IU/mL have been used as arbitrary diagnostic values, but often are greater than 10,000 IU/mL. Other abnormal laboratory tests include eosinophilia, abnormal B-cell maturation and defective antibody responses to neoantigens,¹⁹⁵ chemotactic defects of neutrophils, and reduced lymphocyte proliferation to specific antigens.

Most patients with HIES were noted to arise sporadically from unaffected, healthy parents. With the advent of improved antibiotic therapy, patients survived into adulthood and had affected children, suggesting AD inheritance.¹⁹³ This observation was validated by the finding that heterozygous mutations of the gene encoding the transcription factor STAT3 are the cause of AD-HIES. All STAT3 mutations identified to date in patients with AD-HIES are either amino acid substitutions or in-frame deletions strongly supporting the concept that coexpression of wild-type and mutant STAT3 protein is required to cause the syndrome. The notable lack of nonsense or frameshift mutations strengthens the notion that AD-HIES is a result of a dominant-negative effect.^196,197,198 The molecular analysis of a large cohort of patients (n = 38) with “classic” HIES and a score of greater than 40 points using the National Institutes of Health clinical scoring system, identified STAT3 mutations in all but one individual. The mutations clustered in three domains of the STAT3 protein known to have distinct functional characteristics, the DNA-binding, and the SH2 and the transactivation domains. This finding suggests that more than one molecular mechanism causes the AD-HIES phenotype. This notion is supported by the observation that mutations in the SH2 domain, but not those in the DNA-binding domain, affect tyrosine phosphorylation of STAT3, whereas mutations in the DNA-binding domain interfere with nuclear import and DNA-binding.¹⁹⁸ Because STAT3 plays a key role in the development of IL-17 producing Th17 cells, AD-HIES patients have a marked decrease in circulating Th17 cells.¹⁹⁹ Given that IL-17 plays an important role in host defense against extracellular bacteria and fungi and upregulates production of β defensins and S100 proteins by neutrophils,²⁰⁰ the absence of Th17 cells may directly affect susceptibility to S. aureus and Candida albicans.

Treatment

To prevent progressive lung destruction, prophylactic antibiotic therapy to decrease the frequency of S. aureus infections is important. Antifungal therapy is indicated to prevent recurrent Candida infections. A surgical approach to treating chronic lung disease should be avoided, if possible. Allogeneic HSCT has been performed in a few patients with variable benefits.^201,202

Autosomal Recessive Hyperimmunoglobulin E Syndromes

In 2004, a cohort of 13 patients from consanguineous families were reported to have marked eosinophilia, elevated serum IgE levels, eczema, skin abscesses, recurrent bacterial, fungal, and viral infections including herpes simplex, therapy-resistant molluscum contagiosum, and recurrent varicella zoster. Lymphopenia and decreased lymphocyte proliferation suggested a significant T-cell defect. In contrast to HIES caused by STAT3 mutations, autosomal recessive hyper-IgE syndrome (AR-HIES) patients frequently present with neurologic complications but do not develop skeletal abnormalities or postpneumonia pneumatoceles. Most have large deletions in the DOCK8 gene, resulting in absent DOCK8 protein.^138,139 (See DOCK8 deficiency in “Other Combined Immunodeficiencies” above.) Because of a high incidence of malignancies and early death, HSCT is recommended.²⁰³ A single adult patient with eczema; moderately elevated serum IgE; a history of bacterial (BCG complications, salmonellosis), fungal, and viral infections, including molluscum contagiosum; and a mild T-cell deficiency was found to have a mutation in tyrosine kinase 2 (TYK2), a receptor-associated cytoplasmatic tyrosine kinase that plays an important role in multiple cytokine signaling of T cells.²⁰⁴

IMMUNOOSSEOUS DYSPLASIAS

Cartilage Hair Hypoplasia

Cartilage hair hypoplasia is an autosomal recessive condition characterized by short-limbed dwarfism and light-colored, hypoplastic hair.²⁰⁵ Patients may also present with marrow cell dysplasia, increased susceptibility to malignancies, Hirschsprung disease, defects of spermatogenesis, and a variable degree of immune deficiency (resembling SCID, Omenn syndrome, partial T-cell deficiency) or may have normal immune function.²⁰⁶ The rare disorder is more common in certain populations, such as the Amish and Finns, and is caused by mutations in the gene encoding for untranslated RNA component of the ribonuclease mitochondrial RNA processing (RMRP) complex, which is involved in cleavage of ribosomal RNA, processing of mitochondrial RNA, and cell-cycle control.²⁰⁷ Decreased numbers of T lymphocytes, especially of CD8+ cells, and impaired in vitro proliferative responses to mitogens have been reported and may be from reduced thymic output, cell-cycle abnormalities, and increased apoptosis.^208,209 Impairment of cellular immunity may cause increased susceptibility to severe varicella or other viral diseases, and administration of live-attenuated viral vaccines should be avoided. Defects of humoral immunity are less frequent, and may contribute to recurrent infections. Autoimmune manifestations (hemolytic anemia, neutropenia, and thrombocytopenia) may also occur. Similar to what has been observed in other disorders of ribosomal biogenesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome), disturbances of hematopoiesis, such as anemia, leukopenia, thrombocytopenia, and marrow dysplasia, are frequent manifestations of cartilage hair hypoplasia. Allogeneic HSCT has been successfully used to correct those forms of cartilage hair hypoplasia presenting with a SCID or Omenn syndrome phenotype.²¹⁰

Schimke Syndrome

Schimke syndrome is an autosomal recessive condition characterized by dwarfism with short neck and trunk because of spondyloepiphyseal dysplasia, progressive renal impairment evolving to renal failure, facial dysmorphisms, lentigines, immunodeficiency (ranging from T-cell lymphopenia to SCID), and increased occurrence of marrow failure and of early onset arteriosclerosis associated with cerebral infarcts.²¹¹ Microcephaly and cognitive, motor, or social abnormalities have been reported in a significant proportion of the patients.²¹² The disease is caused by mutations of the switch/sucrose nonfermentable (SWI/SNF)-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 (SMARCAL1) gene that encodes for a chromatin remodeling protein.²¹¹ Recurrent infections of bacterial, viral, and fungal origin, and opportunistic infections (P. jirovecii pneumonia) are seen in half of the patients. Severe presentations lead to death in the first decade of life, and development of renal failure is common among those who survive. Combined HSCT and renal transplantation has been used to correct immune deficiency and renal problems.²¹³

WHIM SYNDROME

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome²¹⁴ is an AD disorder, caused by heterozygous mutations in the CXCR4 gene that encodes for the receptor for the CXCL12 chemokine, involved in leukocyte trafficking.²¹⁵ The term myelokathexis indicates retention of mature neutrophils in the marrow. WHIM mutations result in truncation or structural abnormalities in the intracytoplasmic tail of CXCR4 that interfere with ligand-induced internalization and ultimately cause increased cellular responsiveness to CXCL12.²¹⁴

Patients with WHIM syndrome may present with early onset recurrent bacterial infections, but the clinical phenotype may vary greatly.²¹⁶ Warts, caused by human papillomavirus (HPV), tend to develop in the second decade of life. Severe neutropenia contrasts with accumulation of mature neutrophils in the marrow. Spontaneous apoptosis of neutrophils has been reported.²¹⁷ Lymphopenia, including low B-cell numbers, is a frequent finding. Hypogammaglobulinemia of variable degree can be observed, and immunizations result in short-lived antibody responses and impaired class switch.²¹⁸ EBV-positive B-cell lymphoma can occur.

Immunoglobulin replacement therapy and antibiotic prophylaxis may reduce the incidence of infections. Recombinant G-CSF has been used to increase the absolute neutrophil count. Warts are resistant to local therapy and need to be monitored for neoplastic transformation.

Chromosomal instability syndromes have in common increased spontaneous or induced DNA breaks, susceptibility to infections secondary to immune deficiency, and an increased risk of malignancies. Disease-specific abnormalities involving growth and development, the central nervous system, and the skin provide useful diagnostic clues. The classic chromosomal instability syndromes include ataxia-telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome (BS), and AT-like disorder (ATLD). The genes responsible for these syndromes protect human genome integrity by contributing to the complex task of double-strand break repair. Together with the proteins associated with Fanconi anemia, the gene products of the chromosomal instability syndromes form or regulate a large protein complex that is active in the surveillance and maintenance of genomic integrity.²¹⁹ The triad of immunodeficiency, neoplasia, and infertility is the direct consequence of defective double-strand break repair, and involves nonhomologous end-joining or homologous rejoining. Because nonhomologous end-joining is crucial for the generation of TCR diversity and polyclonal immunoglobulins, any interruption of this process will predictably result in defective adaptive immunity. Tumor development and infertility may be a direct consequence of defective DNA repair during miotic recombination of lymphocytes, other somatic cells, or germ cells, respectively.

ATAXIA-TELANGIECTASIA

AT is a multisystem disorder, characterized by immunodeficiency, progressive neurologic impairment, and ocular and cutaneous telangiectasia.²²⁰

The immune deficiency in AT is highly variable, involving both cellular and humoral immunity. Respiratory infections are common and often result in chronic lung disease. Opportunistic infections are rare. The majority of AT patients have low or absent IgA and IgE, often combined with IgG₂ and IgG₄ deficiency.²²¹ Specific antibody responses may be depressed or normal. The number of circulating lymphocytes is often reduced, and proliferation in response to mitogens is variably depressed. Spontaneous cytogenetic abnormalities include chromosomal breaks, translocations, rearrangements, and inversions; these defects increase following in vitro exposure to radiation. The thymus is often small, showing marked paucity of thymocytes and absence of Hassall corpuscles. The most consistent laboratory abnormality, an elevation of serum α-fetoprotein, is diagnostic in adults and children older than age 8 months as it is not observed in the other chromosomal instability syndromes.

Cancer is the second most common cause of death, after infections.²²⁰ Most malignancies are non-Hodgkin lymphomas (40 percent), leukemias (25 percent), and solid tumors (25 percent); 10 percent are Hodgkin lymphoma. In contrast to other immune deficiency syndromes with increased incidence of malignancies, the leukemias and lymphomas observed in AT are predominantly of T-cell origin. The solid tumors in AT patients include adenocarcinoma, dysgerminoma, gonadoblastoma, and medulloblastoma.

Cerebellar ataxia is the earliest clinical manifestation of AT and becomes evident when a child begins to walk at the end of the first year of life. The ataxic gait persists, and most patients never develop normal speech. Eventually, involuntary movements become a major handicap and the child may require a wheelchair by the end of the first decade of life. Cortical cerebellar degeneration involves primarily Purkinje and granular cells; progressive changes to the central nervous system also occur.

A variety of other features have been reported. Growth retardation is present in 30 percent of the patients. Female hypogonadism is common and associated with hypoplasia of the ovaries. Hypogonadism is also observed in male AT patients.

The AT gene (AT mutated [ATM]) encodes a large transcript that predicts a protein of 3056 amino acids.²²² ATM is a predominantly nuclear protein with a strong serine-threonine kinase activity. Its major function is to rapidly respond to the induction of double-stranded breaks in DNA. The activation of ATM leads to phosphorylation of an extensive array of target proteins, each of which plays a key role in a unique damage response pathway. Specifically, ATM is involved in cell-cycle checkpoint control and delays the passage of cells through the various phases of the cell cycle, allowing time for DNA damage repair. Additionally, ATM is functionally linked to telomere maintenance, a process crucial to aging and cancer.²²³ The more than 400 unique mutations of ATM described to date are distributed throughout the gene with a majority predicted to cause premature termination resulting in unstable truncated proteins.

AT patients should avoid X-radiation and chemotherapeutic agents. Treatment is symptomatic and includes prophylactic antibiotics for those with recurrent pulmonary infections and IVIG for those with antibody deficiency.

ATAXIA-TELANGIECTASIA–LIKE DISORDER

ATLD²²⁴ has many features of AT and is the result of mutations in the Mre11 protein, which is part of the DNA-repair complex (Mre11/Rad50/Nbs1).²²⁵ Affected patients have progressive ataxia, but show less-severe neurodegeneration and may be ambulatory until their early twenties. They do not develop telangiectasia and α-fetoprotein levels are normal. However, similar to AT, ATLD patients have increased spontaneous chromosomal abnormalities in blood lymphocytes and show increased radiation sensitivity.

NIJMEGEN BREAKAGE SYNDROME

NBS is characterized by short stature, microcephaly, a bird-like face, immunodeficiency, chromosomal instability, increased radiosensitivity, and a high incidence of malignancies.²²⁶ Although NBS shares many characteristics with AT and ATLD, it can be distinguished from these disorders by an absence of neurodegeneration, impressive microcephaly with mild to moderate mental retardation, and absence of telangiectasia.

Most NBS patients develop respiratory tract infections, including recurrent pneumonia that may result in bronchiectasis and premature death from respiratory failure. Both humoral and cellular immunity are defective and include hypogammaglobulinemia, except for normal or elevated IgM, abnormal antibody responses to protein and polysaccharide antigens, suggesting a defect in CSR, reduced numbers of T lymphocytes, and abnormal lymphoproliferation to mitogens and specific antigens.²²⁶

NBS lymphocytes show the typical features of chromosomal instability syndromes characterized by increased chromatid and chromosome breaks, rearrangement/translocations of chromosome 7 and 14, telomere fusions, radioresistant DNA synthesis, and hypersensitivity to ionizing radiation and radiomimetic agents.²²⁶

The extensive immunodeficiency and the chromosomal instability explain the high incidence of lymphoid malignancies, including non-Hodgkin lymphoma (both of B- and T-cell origin), lymphoblastic leukemia/lymphoma, and, less frequently, Hodgkin lymphoma and acute myeloblastic leukemia. Solid tumors are less frequent and include medulloblastoma and rhabdomyosarcoma. Because of hypersensitivity to radiation and radiomimetic/alkylating agents, tumor therapy is limited. Magnetic resonance imaging and ultrasound examinations are the preferred imaging techniques, rather than x-ray and CT scan. Prophylactic therapy with antibiotics and IVIG is indicated in patients with recurrent infections. Several patients have been successfully treated with allogeneic HSCT.²²⁷

BLOOM SYNDROME

BS is characterized by short stature, hypersensitivity to sunlight, increased susceptibility to infections, and a predisposition to early development of a variety of cancers.²¹⁹ Susceptibility to bacterial infections, affecting mainly the upper and lower respiratory tract, is associated with hypogammaglobulinemia and variable T-cell deficiency. Most affected patients have decreased fertility and some may develop early onset type II diabetes mellitus. By age 25 years, approximately half of the patients with BS will have developed one or more malignancies. Leukemia and non-Hodgkin lymphoma predominate during the first two decades; later, carcinoma affecting the colon, skin, and breast are common. The diagnosis of BS can be confirmed by demonstrating excessive numbers of sister-chromatid exchanges, increased chromatid gaps and breaks, and the presence of quadriradial configuration composed of two homologous chromosomes. The causative gene, BLM, encodes a 1417-amino-acid protein with homology to the RecQ family of helicases. This family of helicases includes the Werner syndrome, RecQ helicase-like (WRN) protein, which is mutated in Werner syndrome. BLM is a member of a group of proteins that associate with BRCA1 to form a large complex that co-localizes to large nuclear foci if cells are treated with agents that interfere with DNA synthesis. As part of this complex, BLM plays a role in sensing DNA damage and contributes to the maintenance and genomic integrity during the process of DNA replication and repair. More than 60 unique mutations in the BLM gene have been identified. The most common mutation is a 6-bp deletion/7-bp insertion in exon 10, which is the homozygous mutation causing BS in Ashkenazi Jews.

BS patients with significant antibody deficiency may benefit from antibiotic prophylaxis and IVIG therapy. Because of increased radiation sensitivity, exposure to any form of irradiation should be restricted.

RARE SYNDROMES WITH CHROMOSOMAL INSTABILITY

NBS-like phenotypes have been linked to mutations in LIG4, RAD50, and nonhomologous end-joining factor 1 (NHEJ1).²¹⁹ Other syndromes with chromosomal instability include Werner syndrome, Riddle syndrome and immunodeficiency with centromere instability and facial anomalies (ICF) syndrome.

Defense against viruses is primarily dependent on cell-mediated cytotoxicity. Cytotoxic T lymphocytes (CTLs) and NK cells are capable of killing virus-infected target cells using pore-forming perforin and cytolytic granzymes A and B. Different genetic defects can affect various steps in the formation, intracellular transport, and delivery of cytolytic granules,^228,229 and result in different defects of cell-mediated cytotoxicity, that include various forms of familial hemophagocytic lymphohistiocytosis (FHL), Chédiak-Higashi syndrome, Griscelli syndrome type II, and Hermansky-Pudlak syndrome type II. Overall, these disorders are characterized by increased susceptibility to severe viral infections that in some cases is associated with defects of hair and skin pigmentation, and neurologic problems. Dysregulation in CTL and NK homeostasis, with increased production of inflammatory cytokines and accumulation of activated lymphocytes, characterizes the two genetic variants of X-linked lymphoproliferative syndrome (XLP1 and XLP2).

FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS

FHL includes a group of genetically heterogeneous conditions that are characterized by the uncontrolled proliferation of activated lymphocytes and histiocytes that secrete large amounts of proinflammatory cytokines. This results in life-threatening manifestations, characterized by fever, hepatosplenomegaly, marrow infiltration and pancytopenia, and severe neurologic manifestations (Chap. 71).

There are at least five different forms of FHL, four of which have been defined at the molecular level. FHL2 is caused by mutations of the PRF1 gene, which encodes perforin.²³⁰ FHL3 is caused by mutations in UNC13D, also known as Munc13–4.²³¹ FHL4 is caused by defects of the STX11 gene, that encodes syntaxin 11,²³² whereas FHL5 is a result of mutations of the STXBP2 gene, that encodes for Munc18–2, a protein that interacts with STX11.²³³ Each of these defects interferes with a specific step of the cytolytic machinery, and ultimately causes inefficient pathogen clearance, uncontrolled activation of CTLs, and release of IFN-γ and other inflammatory cytokines, resulting in recruitment and activation of macrophages, and inhibition of hematopoiesis.

Clinical and Laboratory Features

In approximately 85 percent of the cases, FHL becomes clinically evident within the first year of life,²³⁴ but late presentations may occur in patients with hypomorphic mutations.^235,236,237 High fever, severe hepatosplenomegaly, lymphadenopathy, hemorrhagic manifestations as a result of thrombocytopenia, and edema are common. Neurologic symptoms, including seizures and decreased level of consciousness, may lead to long-term disability.²³⁸

The FHL diagnostic guidelines were updated in 2007.²³⁹ Anemia and thrombocytopenia are early signs followed by increased serum levels of triglycerides, bilirubin, liver enzymes, ferritin, and coagulation abnormalities. Hemophagocytosis can be observed in the marrow, lymph nodes, and cerebrospinal fluid, which often shows abundant mononuclear cells and increased proteins, even in the absence of overt neurologic symptoms. Immunologic findings include persistently impaired cytolytic activity of NK cells and elevated levels of inflammatory cytokines (IFN-γ, IL-1, IL-6, TNF-γ) in the blood. Monitoring circulating soluble CD25 (IL-2Rα) is also useful as a measure of increased cellular activation.

Flow-cytometry enables analysis of perforin expression, which is absent except for hypomorphic mutations, and may thus facilitate diagnosis of FHL2. The diagnosis of FHL forms that are characterized by reduced NK cell degranulation (such as UNC13D and STX11 defects) may be facilitated by the analysis of membrane expression of the lysosomal marker CD107a.²⁴⁰

Treatment and Prognosis

Without treatment, FHL is usually rapidly fatal. Treatment of active disease should focus on controlling or eliminating possible triggers (infections in particular), blocking T-cell activation, and stopping the hyperinflammatory cytokine response. To this purpose, antimicrobials, etoposide, immune suppression (antithymocyte globulin), cyclosporine, and dexamethasone are commonly used.^239,241 Alemtuzumab has shown some efficacy in controlling etoposide-resistant forms.²⁴² However, relapses are common in FHL. Patients should be monitored carefully for reactivation of the disease, especially in the central nervous system. Administration of anti–IFN-γ monoclonal antibody has given interesting results in animal model of the disease,²⁴³ and is currently being tested in a clinical trial. Permanent cure for FHL can be only provided by allogeneic HSCT. A higher success rate is obtained when HLA-matched related or unrelated donors are available. Use of myeloablative conditioning regimen is associated with high transplantation-related mortality. Considering that partial chimerism is enough to achieve disease control,²⁴⁴ reduced intensity conditioning is being increasingly used, with promising results.²⁴⁵ Outcome of HSCT is worse if the disease is not in remission at the time of transplantation.

X-LINKED LYMPHOPROLIFERATIVE DISEASE

Definition and History

In 1975, Purtilo described a family in which numerous males in multiple generations presented with fulminant infectious mononucleosis, lymphoma, or hypogammaglobulinemia after primary EBV infection.²⁴⁶ XLP1 is caused by mutations in the SH2D1A gene^247,248 that encodes an adaptor protein (SLAM [signaling lymphocyte activation molecule]-associated protein [SAP]) involved in T- and NK-cell signaling.²⁴⁹ Thus, defects of SAP drastically affect both T- and NK-mediated cytotoxicity.^250,251,252 SAP also plays an important role in germinal center formation and antibody production by modulating development and function of follicular helper T cells.²⁵³ Finally, SAP is required for the development of iNKT cells, which are immunoregulatory cells that are involved in the responses to pathogens and cancer cells.²⁵⁴ In the absence of SAP, EBV and other virus infections result in dysregulated immune responses, because of persistent antigenic stimulation that leads to hyperactive cytotoxic T lymphocytes and macrophages, with increased production of IFN-γ.

However, not all males with X-linked lymphoproliferative syndrome (XLP) features have mutations in SH2D1A and mutations in another X-chromosome–associated gene (XIAP; X-linked inhibitor of apoptosis, also known as BIRC4) have been identified,²⁵⁵ resulting in XLP2.

Clinical and Laboratory Features

Although lymphoproliferative disease is observed in both XLP1 and XLP2, there are some important differences in the disease phenotype. Most often, XLP1 becomes clinically manifest following EBV infection in childhood, although later presentations are possible. Fulminant infectious mononucleosis has been observed in 50 to 60 percent of cases, and EBV-related lymphoma in 30 percent of the cases. Most lymphomas are of B-cell origin, and approximately half are of the Burkitt type. Persistent dysgammaglobulinemia, with low IgG and low to increased levels of IgM, is common among survivors. Other clinical manifestations of XLP1 include vasculitis, marrow aplasia secondary to hemophagocytic lymphohistiocytosis, and lymphoid granulomatosis.

Although less frequently encountered, other viral infections (CMV, other herpes viruses) may unmask the clinical phenotype of XLP1.²⁵⁶

Fulminant infectious mononucleosis is marked by a rapid increase of liver enzymes, followed by impaired coagulation, hepatic encephalopathy, and signs of hemophagocytic lymphohistiocytosis (HLH), associated with a high EBV viral load in the blood and other tissues. B-cell lymphomas carry monoclonal immunoglobulin gene rearrangements. Patients who develop dysgammaglobulinemia show impaired antibody responses. Antibody levels to the EBV nuclear antigen usually remain undetectable, even in patients who survive the acute EBV infection. In contrast, antibodies to the EBV viral capsid antigen can be low to elevated. During clinical manifestations of XLP, the proportion of CD8⁺ T cells carrying activation markers is increased and the number of memory (CD27⁺), and specifically switched memory (CD27⁺IgD^–) B cells, is reduced. NK cell cytotoxicity is usually normal, when measured in a conventional K562 killing assay. However, NK cytolytic activity is markedly reduced in XLP1, when costimulation through CD244 is provided.²⁵⁰ Flow cytometry can be used to detect a lack of SAP protein expression in circulating T and NK lymphocytes in patients with XLP1.²⁵⁷

XLP2 often manifests with HLH, and EBV is a common trigger.²⁵⁸ However, some important differences exist in the phenotype of XLP2 versus XLP1. In particular, recurrent splenomegaly often associated with cytopenia and fever is preferentially observed in XLP2, and may represent an attenuated manifestation of HLH. By contrast, lymphoma, a common complication of XLP1, is not frequently observed in XLP2. Importantly, severe inflammatory bowel disease (IBD) has been reported in a significant proportion of patients with XLP2,^258,259 and in some cases may represent the dominant clinical phenotype.²⁵⁹ Moreover, XLP2 may also manifest as delayed-onset Crohn disease.²⁶⁰ The occurrence of IBD in XLP2 may reflect the notion that the RING domain of XIAP is required for NOD2 signaling.²⁶¹

A flow-cytometry-based assay can be used to facilitate differential diagnosis of XLP1 and XLP2.²⁶²

Treatment and Prognosis

If untreated, approximately 70 percent of XLP1 patients die within 10 years of onset. The mortality rate is particularly high (96 percent) in patients who present with fulminant infectious mononucleosis.²⁶³ Allogeneic HSCT is the treatment of choice, yielding the best results when the transplant is performed early in life, prior to EBV infection. However, transplantation using reduced-intensity conditioning may permit correction of the disease in EBV-positive patients with severe organ toxicity.²⁶⁴ The use of anti-CD20 monoclonal antibody can reduce viral load and improve the clinical status, and anti–TNF-α therapy or etoposide may be beneficial in patients with active EBV infection and severe systemic inflammatory response.^265,266,267 Administration of immunoglobulin may reduce the risk of infections, but does not prevent or attenuate the symptoms of primary EBV infection.

Similar survival rates have been reported in XLP2 and in XLP1.²⁵⁸ However, this figure does not take into account forms of XLP2 that may present with features other than HLH, and IBD in particular. Sulfasalazine, glucocorticoids, 5-amino salicylic acid, and anti-TNF medications have been used in the treatment of IBD in patients with XLP2, however the only curative approach is allogeneic HSCT. Use of myeloablative conditioning is associated with high mortality and toxicity rate, but good results have been reported with reduced intensity conditioning.²⁶⁸

CYTOTOXICITY DEFECTS ASSOCIATED WITH PIGMENTARY DILUTION DISORDERS

Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome is an autosomal recessive disorder characterized by immune dysregulation with impaired cellular cytotoxicity, partial oculocutaneous albinism, platelet functional abnormalities, and neurologic involvement.²⁶⁹ The disease is caused by mutations in the lysosomal trafficking regulator (LYST) gene.²⁷⁰ LYST plays an important role in sorting of lysosomal proteins, and in docking and fusion of lysosomal vesicles.²²⁸

Patients are susceptible to recurrent pyogenic and viral infections. Bruises are common and reflect deficiency of the platelet specific granules responsible for secondary aggregation (Chap. 120). Both bacterial and viral infections may trigger the life-threatening “accelerated phase” of the disease, characterized by high fever, hepatosplenomegaly, coagulation abnormalities, increase of liver enzymes and bilirubin (with possible jaundice), edema, and neurologic symptoms, with seizures, ataxia, cranial nerve palsies, and peripheral neuropathy.²⁶⁹

Abnormally large granules in lymphocytes, neutrophils, platelets, melanocytes, and neurons represent a morphologic hallmark of the disease. Light microscopy examination of hair reveals large and evenly distributed granules of melanin. Reduced NK cytotoxic activity and prolonged bleeding time are typical findings.

Treatment requires control of infections, and immunosuppressive intervention during the accelerated phase. Allogeneic HSCT, best performed during remission, is the only permanent cure of the immunohematologic problems.²⁷¹ However, HSCT does not seem to prevent progressive neurologic involvement.²⁷²

Griscelli Syndrome Type 2

Griscelli syndrome type 2 (GS2) is an autosomal recessive syndrome characterized by immunodeficiency and hypopigmentation, and a variable degree of neurologic involvement.²⁶⁹ The presence of immune deficiency distinguishes GS2 from Griscelli syndrome type 1 (GS1; marked by the association of partial albinism and neurologic involvement) and Griscelli syndrome type 3 (GS3; with isolated hypopigmentation). GS2 is caused by mutations of the RAB27A gene,²⁷³ which encodes for a GTPase involved in intracellular transport of granules.

GS2 patients are highly susceptible to recurrent pyogenic infections and to episodes of “accelerated phase” of the disease, with typical features of HLH. Prominent hypopigmentation is a result of large clumps of melanin in the hair shafts. NK cytotoxicity is defective and CD107 expression at the cell membrane of NK lymphocytes is impaired upon coculture with target cells. Treatment is based on allogeneic HSCT, and promising results have been reported with reduced intensity conditioning.²⁷⁴

Hermansky-Pudlak Syndrome Type 2

This autosomal recessive disease is characterized by oculocutaneous albinism, bleeding tendency, recurrent infections, and moderate to severe neutropenia (Chap. 120).²⁶⁹ Bone anomalies (with dysplastic acetabula), facial dysmorphisms and development of pulmonary fibrosis are also part of the clinical phenotype. Hermansky-Pudlak type 2 is caused by mutations of the AP3B1 gene that encode for the β₁ subunit of the AP-3 endosomal protein, which is required for sorting of lysosomal membrane proteins to the granules.²⁷⁵ Missorting of tyrosinase in melanocytes accounts for oculocutaneous albinism. Reduced platelet-dense granules and impaired platelet degranulation are responsible for increased susceptibility to bleeding. Absence of AP-3 leads to low intracellular content of neutrophil elastase in myeloid progenitors causing neutropenia. Even though CTL and NK cell cytolytic activity is defective,²⁷⁶ the risk of progression to HLH is lower than in Chediak-Higashi syndrome or GS2.²⁷⁷ Consequently, preemptive use of HSCT is not justified.

Hermansky-Pudlak syndrome type 9 is caused by mutations of the pallidin (PLDN) gene, and is characterized by recurrent infections, partial albinism and nystagmus.²⁷⁸ NK cell cytolytic activity is impaired.²⁷⁹

Although classical forms of PIDD are characterized by susceptibility to a broad range of pathogens, several disorders have been identified with selective susceptibility to certain microorganisms. Some of these diseases (e.g., mendelian susceptibility to herpes simplex virus encephalitis [HSE] or to pyogenic infections, especially S. pneumoniae) are the result of defects of innate immunity, in particular TLR signaling. Others (mendelian susceptibility to mycobacterial disease) involve defects of the IL-12/IFN-γ axis at the interface of innate and adaptive immunity. Susceptibility to recurrent meningitis caused by Neisseria meningitidis is discussed in “Genetically Determined Deficiencies of the Complement System” below.

IMMUNODEFICIENCIES WITH IMPAIRED SIGNALING THROUGH TOLL-LIKE RECEPTORS

TLRs are transmembrane proteins (Chap. 17) expressed on a variety of cell types that recognize pathogen-associated molecular patterns, such as lipopolysaccharide derived from Gram-negative bacteria, lipopeptide, double-stranded RNA that is generated during viral replication, viral single-stranded RNA, viral cytosine phosphate guanine DNA moieties, and flagellin. Although most TLRs are expressed at the cell surface, TLRs 7, 8, and 9 are expressed on the membrane of endosomal vesicles.²⁸⁰

The recognition of pathogen-associated molecular patterns by TLRs induces characteristic intracellular signaling.²⁸⁰ The classical pathway of TLR activation involves the adaptor molecules MyD88 (myeloid differentiation factor 88) and toll–IL-1R domain-containing adaptor protein (TIRAP), and the intracellular kinases IL-1R–associated kinase (IRAK)-4 and IRAK-1, ultimately resulting in the nuclear transfer of NF-κB and the production of inflammatory cytokines (IL-1, IL-6, TNF-α, IL-12). TLRs 3, 7, 8, and 9 activate an alternative pathway that involves other adaptor molecules, such as TRIF, TRAF3, and the UNC-93B protein, and ultimately results in the induction of type 1 interferons (IFN-α/β). Deficiencies of IRAK-4, MyD88, TLR3, and UNC-93B have been identified in humans, and are associated with two distinct phenotypes.

Toll-Like Receptor Signaling Defects with Increased Susceptibility to Herpes Simplex Virus Encephalitis

Selective susceptibility to HSE is associated with monogenic disorders that affect TLR3,^281,282 or components of the TLR3 signaling pathway, including UNC-93B,²⁸³ TRAF3,²⁸⁴ TRIF,²⁸⁵ and TBK1.²⁸⁶ The disease reflects a CNS-intrinsic defect of neurons and oligodendrocytes to produce type 1 IFN in response to herpes simplex virus (HSV).²⁸⁷

Because TLR3 recognizes double-stranded RNA and is normally expressed in CNS-resident cells, mutations of TLR3 or other components of the TLR3-dependent signaling pathway impair the response of these cells to actively replicating HSV-1. Because cellular responsiveness to type 1 IFN is intact in both UNC-93B–deficient and TLR3-deficient patients, the use of IFN-α along with acyclovir should be considered to treat HSE in these patients.^281,287

HSE may also be a result of null mutations of STAT1, a transcription factor that is activated upon interaction of type 1 IFN with their receptors, and is critical for the induction of IFN-responsive genes. However, these patients are also prone to other severe viral infections. Furthermore, because STAT1 is also involved in the response to IFN-γ, patients with null STAT1 mutations are also at risk for mycobacterial disease.²⁸⁸

Other Immunodeficiencies with Increased Susceptibility to Viral Infections

Mutations of STAT2, leading to impaired response to IFN-α and IFN-β predispose to severe viral infections, including disseminated vaccine-strain measles.²⁸⁹

Skin warts caused by HPV infection are the hallmark of epidermodysplasia verruciformis. This disease is caused by mutations of the EVER1 and EVER2 genes.²⁹⁰ There is an increased risk of squamous cell carcinoma.

Toll-Like Receptor Signaling Defects with Increased Susceptibility to Pyogenic Infections

IRAK-4 and MyD88 deficiencies are characterized by recurrent and invasive pyogenic bacterial infections, particularly from S. pneumoniae and S. aureus.^123,291,292 These infections are common especially during the first years of life (when lethality rate can be as high as 50 percent), but their frequency tends to decline with age.²⁹³ Fever and systemic inflammatory responses are absent or unusually modest, reflecting poor induction of inflammatory cytokines and reduced response through the IL-1R.

Use of antimicrobic prophylaxis is important to prevent invasive pyogenic infections, especially in childhood. Substitution therapy with immunoglobulins may be beneficial in patients with impaired antibody responses.

Defects Involving Other Pattern-Recognition Signaling Pathways with Increased Susceptibility to Fungal Infections

Several inborn errors of immunity have unraveled key mechanisms of defense against Candida. Chronic mucocutaneous candidiasis (CMC) is a common complication affecting patients with APECED; it results from a mutation in the transcription factor AIRE.¹⁷⁷ CMC also affects those with AD-HIES; in this case, it is a result of mutations in the transcription factor STAT3.¹⁹⁰ Autoantibodies to IL-17 are a common feature of APECED,^181,294 and Th17 differentiation is impaired in HIES because of STAT3 mutations. The Th17 cytokines IL-17A, IL-17F, and IL-22 induce the synthesis of chemokines that recruit neutrophils, and promote production of antimicrobial peptides from epithelial cells, thereby playing a key role in mucocutaneous resistance to Candida spp. Heterozygous, dominant negative mutations in IL17F gene, and biallelic loss-of-function mutations in the IL-17RA gene (encoding for the α chain of IL-17 receptor) have been linked with CMC.²⁹⁵ Furthermore, mutations of the ACT1 gene²⁹⁶ (that encodes for an adaptor molecule that interacts with IL-17R) and gain-of-function STAT1 mutations impairing Th17 immunity¹⁷⁰ are associated with CMC.

Mutations of the CARD9 gene have been identified in patients with CMC or disseminated candidiasis, including infection of the brain.²⁹⁷ CARD9 is recruited by Dectin-1, a transmembrane pattern-recognition receptor that senses the β-glucan component of fungal cell walls, and together with other cytoplasmic proteins, forms an intracellular signaling complex that leads to the nuclear import of NF-κB and the induction of key cytokines including IL-1, IL-6, IL-23, and the generation of IL-17 cells, which are required to control antifungal immune responses. However, invasive fungal infections in CARD9 deficiency are not restricted to Candida, but also include other species, such as Exophiala, an environmental black yeast with low virulence.²⁹⁸ Granulocyte macrophage-colony stimulating factor (GM-CSF) therapy resulting in complete clinical remission has been reported in one CARD9-deficient patient with relapsing albicans meningoencephalitis.²⁹⁹

MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE

The IL-12/IFN-γ axis is essential for controlling mycobacterial infections. Following phagocytosis of mycobacteria, macrophages secrete IL-12, a heterodimer composed of IL-12p40 and IL-12p70. IL-12 binds to the heterodimeric IL-12R (composed of IL12Rβ₁ and IL-12Rβ₂ chains) expressed by Th1 and NK cells. This results in activation of the JAK-STAT4 pathway, and ultimately in the production of IFN-γ, which binds to its receptor (comprising IFN-γR1 and IFN-γR2 chains) on the surface of macrophages, triggering a signaling cascade that involves the transcription factor STAT1 and induction of IFN-γ-responsive genes that are essential to contain the infection and kill the mycobacteria. A variety of defects along this pathway have been shown to account for mendelian susceptibility to mycobacterial disease (MSMD) in humans.³⁰⁰ The basis for increased susceptibility to mycobacterial disease in patients with NEMO deficiency was discussed in “X-Linked Anhydrotic Ectodermal Dysplasia with Immunodeficiency Caused by Mutations in Nuclear Factor-κB Essential Modulator” above.

IL-12p40 Deficiency

Affected patients are at increased risk of childhood infections because of BCG and Salmonella; Candida infections have also been reported. Recurrence of Salmonella infection is common.³⁰¹ IL-12p40 can associate with IL-12p70 to form the IL-12 heterodimer, or with IL-23p19 subunit to form IL-23. Consequently, patients with IL-12p40 deficiency have defects in both IL-12 and in IL-23–dependent immunity, with the latter causing a Th17 deficiency. The clinical course is variable, with some genetically affected siblings being asymptomatic, but approximately 32 percent of symptomatic IL-12p40–deficient patients die prematurely of infections.³⁰¹ Treatment with antimicrobial drugs and IFN-γ has been tried with variable results.

IL-12Rβ₁ Deficiency

Autosomal recessive IL-12Rβ₁ deficiency is characterized by infections with mycobacteria of low virulence and Salmonella species.³⁰² However, infections with Mycobacterium tuberculosis, Cryptococcus, and disseminated coccidioidomycosis have also been reported.^302,303,304 Unlike salmonellosis, mycobacterial infections tend not to recur and the overall prognosis is good. In most cases, IL-12Rβ₁ expression on the cell surface is absent, and in vitro IFN-γ production in response to IL-12 is abrogated. Treatment with appropriate antibiotics and IFN-γ is effective.

IFN-γR1 and IFN-γR2 Deficiencies

The genetic and biochemical pathophysiology of IFN-γR1 and IFN-γR2 deficiencies are remarkably complex. Autosomal recessive forms are most often associated with mutations that abrogate cell surface expression of IFN-γR1 or result in the expression of receptors that do not bind IFN-γ. Partial autosomal recessive deficiency is the result of hypomorphic mutations, with residual IFN-γ binding and signaling.³⁰⁵ Dominant partial forms reflect the presence of heterozygous mutations in the cytoplasmic tail of IFN-γR1, allowing the expression of mutant molecules on the cell surface (often in increased density because of defective receptor shedding) which are unable to mediate signal transduction.³⁰⁶

The severity of the clinical features reflects the nature of the biochemical defect.³⁰⁷ Patients with complete deficiency develop severe infections with environmental mycobacteria infections early in life, with lack of granuloma formation. Osteomyelitis caused by BCG or by environmental mycobacteria has been reported in several patients with dominant partial IFN-γR1 deficiency.

Treatment of partial deficiency should be based on careful identification and typing of the mycobacterial strains and appropriate antimicrobial therapy; addition of IFN-γ may be useful in patients with AD mutations in IFN-γR1 who are able to express reduced amounts of normal IFN-γR1 on the cell surface. Recessive forms are resistant to medical treatment. Although allogeneic HSCT may be curative, a high rate of graft failure has been observed³⁰⁸ as a consequence of the inhibitory effect of high levels of circulating IFN-γ.³⁰⁹

GATA2

The syndrome of monocytopenia, B-cell and NK-cell lymphopenia associated with mycobacterial, fungal and viral infections, also called MonoMAC syndrome or familial myelodysplasia/leukemia with lymphedema (Emberger) syndrome was first described in 2010.³¹⁰ One year later, heterozygous mutations in GATA2 resulting in haploinsufficiency were identified as the molecular defect causing MonoMAC³¹¹ and Emberger syndrome.^312,313

GATA2 plays a role in the early development of lymphatics and their valves,³¹⁴ explaining the connection with Emberger syndrome. The transcription of GATA2 occurs in early and undifferentiated hematopoietic cells, but also in somatic cells. Because of its progression to myelodysplastic syndrome or acute myeloid leukemia, mortality can be as high as 28 percent.³¹⁰ HSCT has successfully reversed clinical symptoms.³¹⁵

STAT1 Deficiency

Complete STAT1 deficiency causes increased susceptibility to viral infections and to mycobacterial disease with a severe clinical course and early death.²⁸⁸

Dominant partial STAT1 deficiency is caused by a heterozygous mutation that allows formation of the IFN-α/β-dependent ISGF3 transcription factor, but abrogates expression of the γ-activating factor, which is composed of STAT1 homodimers. Affected individuals have either a mild clinical course, characterized by selective susceptibility to mycobacterial infections, or are asymptomatic.³¹⁶

Partial autosomal recessive STAT1 deficiency is associated with impaired, but not abrogated, IFN-α/β and IFN-γ signaling, and occurrence of severe, but curable, intracellular bacterial and viral infections.³¹⁷

Heterozygous STAT1 gain-of-function mutations result in susceptibility to mycobacterial infections, candidiasis, and IPEX-like phenotype (see “Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked–Like Syndromes” above).¹⁷¹

Other Genetic Disorders with Mendelian Susceptibility to Mycobacterial Disease

Interferon-regulated factor 8 (IRF8) is a transcription factor that regulates the differentiation of granulocytes and macrophages, and the development of DCs. IRF8 mutations in humans cause MSMD.³¹⁸ Two variants of the disease have been described: an autosomal recessive form characterized by extreme leukocytosis (up to 98 × 10⁹/L cells), marked expansion of lymphocytes and granulocytes, and absence of monocytes, myeloid DCs, and plasmacytoid DCs; and an AD variant, in which monocytes and DCs are present, but there is selective loss of IL-12–producing CD1c⁺ DCs. The clinical phenotype of autosomal recessive IRF8 deficiency is more severe, with early onset, failure to thrive, and disseminated BCG. HSCT is curative. The AD variant of the disease is characterized by disseminated but curable BCG infection.

The interferon stimulated gene 15 (ISG15) protein is an IFN-α/β-inducible, ubiquitin-like protein involved in ISGylation, but can be also secreted by granulocytes and act upon T and NK lymphocytes, inducing IFN-γ production. Inherited ISG15 deficiency causes severe MSMD, with disseminated BCG infection, which is responsive to antimycobacterial treatment.³¹⁹

The complement (C) system³²⁰ consists of the classical and alternative pathways and the membrane attack complex, and is composed of a series of plasma proteins that play an important role in host defense, inflammation, clearance of immune complexes and apoptotic cells, and induction of a normal humoral immune response (Chap. 19). Mutations in the classical pathway (C1q, C1r/C1s, C4, C2, and C3) result in pyogenic infections and autoimmune diseases. Mutations affecting the alternative pathway (factors B, D, properidin) result in meningococcal and pneumococcal sepsis. Mutations in the terminal components (C5–C9) are associated with an increased susceptibility to Neisseria species, especially meningococcal sepsis and meningitis. C1 inhibitor deficiency, an AD disorder, is the cause of hereditary angioedema. All other complement-component deficiencies have an autosomal recessive mode of inheritance with the exception of properidin deficiency, which is X-linked.

The most important screening tests for complement deficiencies are those using the assessment of the hemolytic function of both the classic and alternative pathways, CH50 and AH50, respectively. If both tests are normal, a complement deficiency is unlikely. If CH50 is absent and AH50 normal, a defect of C1, C4, or C2 is likely. Normal CH50 but absent AH50 suggests a defect of properdin or factor D. If both tests are abnormal, the defect most likely affects C3 to C8. Deficiency of C9 results usually in a CH50 value that is approximately half of normal. To pinpoint the specific complement component deficiency, immunochemical tests using component specific antibodies or functional assays using in vitro reconstitution of the hemolytic function are recommended. Mutations and single nucleotide polymorphisms (SNPs) in the complement regulatory proteins factor H and factor I are implicated in atypical hemolytic uremic syndrome and age-related macular degeneration.^320,321 Treatment of complement-component deficiencies depends on the defect and may include frequent immunizations using the appropriate vaccines, antibiotic prophylaxis, and workup for sepsis if the clinical symptoms suggest bacterial infections. Autoimmune disorders are treated symptomatically, using the same immunosuppressive agents and antiinflammatory medications as those used in the general population. Management of angioedema has been revolutionized by C1 esterase inhibitor concentrate (Cinryze, Berinert), which is most effective for the treatment of acute attacks and by the kallikrein inhibitor Kalbitor (Dyax) and the bradykinin receptor antagonist Firazyr (Shire).