Chapter 68: Immunodeficiency

Immunodeficiency can occur in any of the four major components of the immune system: (1) B cells (antibody), (2) T cells, (3) complement, and (4) phagocytes. In a patient with a history of infections that are unusually frequent, unusually severe, or caused by unusual organisms, the pattern of these infections can indicate which component(s) of the immune system might be defective. Most immunodeficiencies are acquired, and these are frequently caused by immunosuppressive medications, transplantation, and/or diseases that suppress immunity. Although they are less common, congenital immunodeficiencies (Table 68–1) are important to understand because (1) the patterns of infections that are seen teach us how various immune components are supposed to function normally, and (2) recent technological advances have allowed us to better diagnose and treat these diseases, preventing the infectious complications.

T-Cell Deficiencies

Congenital T-cell deficiencies tend to be the most severe and easily recognized immunodeficiency. Because T cells are central to so many aspects of immune responses, including antiviral immunity, maturation of B cells and antibody, and the activation of macrophages, their absence results in a broad range of unusual opportunistic infections (i.e., viruses, bacteria, fungi, and protozoa that are rarely seen in healthy hosts). These diseases often present within the first 6 to 12 months of life when maternal antibody is waning. They are also usually associated with some degree of B-cell deficiency. Severe T-cell deficiency is not compatible with life; without a hematopoietic stem cell transplant, these children rarely live past the age of 2 years, and these transplants are only possible if the diagnosis is made before the onset of severe infectious complications. Newborn screening for T-cell receptor excision circles (TRECs) has greatly increased the early detection of these diseases (see Chapter 59).

1. Wiskott-Aldrich syndrome—Recurrent pyogenic infections, eczema, and low platelets characterize this syndrome. The symptoms typically appear during the first year of life. It is an X-linked disease caused by mutations in the WASp gene, leading to a defect in actin filament assembly that is important for T cells to respond to antigen presentation and for B cells to be activated by signals from the B-cell receptor. These patients are therefore unable to mount an IgM response to the capsular polysaccharides of bacteria, such as pneumococci, whereas IgA and IgE levels can be elevated.

2. Ataxia-telangiectasia—In this disease, ataxia (staggering) and telangiectasia (enlarged small blood vessels of the conjunctivas and skin) occur. About two-thirds of patients have lymphopenia and low immunoglobulins, particularly IgA, which results in recurrent pyogenic upper respiratory infections that appear by 2 years of age. It is an autosomal recessive disease caused by mutations in the genes that encode DNA repair enzymes. In addition to the lymphopenia, these patients frequently develop leukemia, lymphoma, or other cancers.

3. Thymic aplasia (DiGeorge’s syndrome)—In this disease, both the thymus and the parathyroids fail to develop properly as a result of a defect in the third and fourth pharyngeal pouches. (In complete DiGeorge syndrome, the thymus is completely absent, but this is quite rare. More often, the thymus is simply malformed or small.) A common presenting symptom is tetany due to hypocalcemia caused by hypoparathyroidism. Aortic arch malformations and cleft palate can also be seen in these patients. It is usually caused by a spontaneous deletion in chromosome 22 during early development, although rare cases are inherited genetically.

   Severe viral, fungal, or protozoal infections occur in affected infants early in life as a result of absence of the thymus, where T-cell precursors recombine their receptors and mature to become T cells (see Chapter 59). Pneumonia caused by Pneumocystis jiroveci and thrush caused by Candida albicans are two common infections in these patients. Antibody production may be decreased or normal. If decreased, severe pyogenic bacterial infections can occur.

   This disease is unusual in that it is not caused by a defect in the bone marrow precursor cells. The T-cell precursors themselves are normal, and so performing a thymus transplant into these patients can largely correct the defect by allowing the patient’s own T-cell precursors to mature.

4. Cytokine signaling defects—Patients with defects in specific cytokines or their receptors have increased susceptibility to specific organisms. For example, chronic mucocutaneous candidiasis is an infection of the skin and mucous membranes with C. albicans, which, in immunocompetent individuals, is a nonpathogenic member of the normal flora. In rare families with heritable mucocutaneous candidiasis, the overall T-cell and B-cell levels and functions are normal except that there is deficiency specifically of interleukin (IL)-17 or the IL-17 receptor.

   In contrast, defects in IL-12, gamma interferon (IFN-γ), or the receptors for these cytokines, result in recurrent or severe infections with mycobacteria and Salmonella species. IL-12 normally helps to differentiate naïve CD4-positive T cells into Th-1 cells, which make the IFN-γ that is required to activate the macrophages that limit these infections (see Chapter 60). A common presentation of IL-12 or IFN-γ deficiency is a child with disseminated infection with bacillus Calmette-Guérin (BCG), the attenuated Mycobacterium strain in the BCG vaccine that is given in many countries to prevent severe tuberculosis disease.

Deficiency in the gene encoding the transcription factor STAT3 causes defects in IL-23, IL-6, and IL-21 signaling. STAT3 is essential for the differentiation of Th-17 cells but is also important in B-cell class switching and neutrophil activation. This leads to high levels of IgE and impaired neutrophil migration to barrier surfaces, causing recurrent staphylococcal skin infections. These patients can also have eosinophilia, eczema, and skeletal defects. The autosomal dominant form is referred to as Job’s syndrome or hyper-IgE syndrome.

Combined T- & B-Cell Deficiency

An isolated T-lymphocyte deficiency is a life-threatening condition, but even more devastating are deficiencies caused by defects in all lymphocyte development, which causes severe combined immunodeficiency (SCID). In this disease, recurrent infections caused by bacteria, viruses, fungi, and protozoa occur in early infancy (3 months of age) because both B cells and T cells are defective. In some children, the B and T cells are completely absent; in others, the number of cells is normal but they do not function properly. Immunoglobulin levels are very low, and tonsils and lymph nodes are absent. Note that innate immunity is not directly affected, but without adaptive immunity, the innate immune system is unable to clear infections.

Pneumocystis pneumonia is the most common presenting infection in these infants. Infections caused by C. albicans and viruses such as varicella-zoster virus, cytomegalovirus, and respiratory syncytial virus are common and often fatal.

The inherited mutations that can cause a combined T- and B-cell deficiency are generally in genes that are important for lymphocyte development. The X-linked form is the most common, but many autosomal forms also occur.

1. X-linked SCID is caused by a defect in one protein chain of the IL-2 receptor, a chain that is also a part of the receptors for several other cytokines.

   Autosomal forms of SCID include the following mutations:

2. The gene encoding a tyrosine kinase called ZAP-70 that plays a role in signal transduction in T cells.

3. The gene encoding a different kinase called Janus kinase 3, which transmits activation and survival signals from cell surface receptors.

4. The RAG-1 or RAG-2 genes that encode the recombinase enzymes that catalyze the recombination of the DNA required to generate the T-cell antigen receptor and the IgM that acts as the B-cell antigen receptor.

5. Deficiency of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), enzymes that recycle nucleotides for DNA synthesis, which reduces the ability of B-cell and T-cell precursors to divide and survive in the bone marrow.

6. Defective class I or class II major histocompatibility complex (MHC) proteins, causing inability to display antigens to T cells (also called bare lymphocyte syndrome).

Because immunity is so profoundly depressed, children with SCID must be strictly isolated from potentially harmful microorganisms. Live, attenuated viral vaccines should not be given. Hematopoietic stem cell transplantation may restore immunity, and because infants with SCID do not reject allografts, these transplants require minimal immunosuppressive drugs to engraft.

In patients with ADA deficiency, enzyme replacement therapy can boost lymphocyte numbers and reduce the number and severity of infections. Several patients with ADA deficiency have benefited from gene therapy, placing a new functional enzyme in their hematopoietic stem cells.

B-Cell Deficiencies

Congenital deficiencies in the number or function of B cells cause low or absent antibody levels. Like the T-cell and combined deficiencies, patients with these deficiencies are protected from infections by maternal antibody until the age of 6 to 12 months, at which point they begin to have recurrent infections. However, unlike the “opportunistic” infections described earlier, recurrent bacterial infections and impaired responses to vaccines are usually the presenting finding in patients with low antibody levels. Their infections are often in the oropharynx and respiratory tract, including sinusitis, otitis, and pneumonia, as these are the sites protected by antibody. But antibody deficiencies also predispose patients to certain viral infections, infections of the gastrointestinal tract, and bacteremia from encapsulated organisms.

1. X-linked hypogammaglobulinemia (Bruton’s agammaglobulinemia)—Boys with this disease have low levels of all immunoglobulins (IgG, IgA, IgM, IgD, and IgE) and a virtual absence of B cells; female carriers are immunologically normal. Pre-B cells are present, but they fail to differentiate into mature B cells. This failure is caused by a mutation in the gene encoding a tyrosine kinase that is an important signal transduction protein. Clinically, recurrent pyogenic bacterial infections (e.g., otitis media, sinusitis, and pneumonia caused by Streptococcus pneumoniae and Haemophilus influenzae) occur in infants at about 6 months of age, when maternal antibody is no longer present in sufficient amount to be protective.

   Treatment with pooled gamma globulin reduces the number of infections. The pooled gamma globulin preparation contains purified IgG from more than a thousand donors to ensure a broad range of protective antibodies. It is called “intravenous immunoglobulins” (IVIG) and is administered monthly.

2. IgA deficiency—This is the most common antibody class deficiency; IgG and IgM deficiencies are rarer. Patients with a deficiency of IgA can have recurrent sinus and lung infections. However, with time, the infections become less and less frequent, and some individuals with IgA deficiency do not have frequent infections. This is likely because their IgG and IgM levels confer protection that compensates for the loss of IgA. The cause of IgA deficiency may be a failure of heavy chain gene switching. Patients with a deficiency of IgA should not be treated with gamma globulin preparations, because the IgA in the infusion can be immunogenic in these patients, i.e., they can form antibodies against the foreign IgA.

   Patients with selective IgM deficiency or deficiency of one or more of the IgG subclasses also have recurrent sinopulmonary infections caused by pyogenic bacteria such as S. pneumoniae, H. influenzae, or Staphylococcus aureus.

3. Hyper-IgM syndrome—In this syndrome, severe, recurrent pyogenic bacterial infections resembling those seen in X-linked hypogammaglobulinemia begin early in life. Patients have a high concentration of IgM but very little IgG, IgA, and IgE. But unlike the X-linked agammaglobulinemia patients, these patients have normal numbers of B cells. Instead, the deficiency is in the gene encoding CD40 ligand (CD40L), which CD4-positive T cells express on their surface to bind and activate other cells that express CD40. CD40L is one of the main components of T-cell help (see Chapter 60). T follicular helper (Tfh) cells from these patients lack CD40L, and their failure to properly interact with B-cell CD40 results in an inability of the B cell to switch from the production of IgM to the other classes of antibodies. Treatment with pooled gamma globulin results in fewer infections.

4. Common variable immunodeficiency (CVID)—This term actually comprises a heterogeneous group of diseases, most of which are idiopathic. Like other antibody deficiencies, patients with CVID present with low IgG levels and recurrent infections caused by pyogenic bacteria (e.g., sinusitis and pneumonia caused by pyogenic bacteria such as S. pneumoniae and H. influenzae). However, the infections tend to be milder and may even begin to occur later in life, between the ages of 15 and 35 years. (This has led to speculation that some forms of idiopathic CVID are actually acquired rather than congenital.) Like hyper-IgM syndrome (described earlier), the known causes of CVID are often functional defects in helper T cells rather than in B cells. The number of B cells is usually normal, but their ability to synthesize IgG (and other immunoglobulins) is greatly reduced. Intravenous gamma globulin given monthly reduces the number of infections.

Complement Deficiencies

The complement system is an important initiator of many inflammatory processes. It plays a key role in complement-dependent cytotoxicity (CDC) and in immune complex deposition (type III hypersensitivity) reactions seen in many autoimmune and inflammatory disorders.

Chapter 63 describes several conditions in which complement is overactivated, including hereditary angioedema, caused by C1 inhibitor deficiency, and paroxysmal nocturnal hemoglobinuria, caused by a deficiency of the GPI (glycosylphosphatidylinositol) anchor for CD59 protein in the cell membrane. CD59 protects the cell membrane from damage by the membrane attack complex (MAC) of complement. A reduced amount of CD59 results in increased hemolysis by MAC.

In host defense, many components of the complement cascade play overlapping roles with other immune components (e.g., antibody). This means that, although diseases of inherited complement deficiencies do exist, the infectious complications in these patients are relatively rare.

Patients with deficiencies in C1, C3, or C5 or the components recruited later in the cascade, C6, C7, or C8, have an increased susceptibility to bacterial infections. Patients with C3 deficiency are particularly susceptible to sepsis with pyogenic bacteria such as S. aureus. Those with reduced levels of C6, C7, or C8, which form the MAC (see Chapter 63), are especially prone to bacteremia with Neisseria meningitidis or Neisseria gonorrhoeae.

Phagocyte Deficiencies

1. Chronic granulomatous disease (CGD)—Patients with this disease are susceptible to opportunistic infections with certain bacteria and fungi (e.g., S. aureus); enteric gram-negative rods, especially Serratia and Burkholderia; and Aspergillus fumigatus. CGD is due to a defect in the intracellular microbicidal activity of phagocytes as a result of a lack of NADPH oxidase activity (or similar enzymes). Much less hydrogen peroxide and superoxides are produced (i.e., no oxidative burst occurs), and the organisms, although ingested, are not killed as efficiently. Even with this deficiency, a phagocyte can use hydrogen peroxide produced by the microbe itself to generate toxic hypochlorite, but CGD patients have a particular susceptibility to infections with catalase-positive bacteria, such as staphylococci, because the microbial catalase further degrades what little peroxide there is to water and oxygen. (Infections with catalase-negative bacteria, such as streptococci, and viral, mycobacterial, and protozoal infections are of less concern in CGD patients than infections caused by catalase-positive bacteria and fungi.) B-cell and T-cell functions are usually normal. In 60% to 80% of cases, this is an X-linked disease that appears by the age of 2 years. (In the remaining patients, the disease is autosomal.)

   In the laboratory, diagnosis can be confirmed by the nitro blue tetrazolium (NBT) dye reduction test or by the dichlorofluorescein (DCF) test. In the NBT test, normal neutrophils will turn the dye a blue color, whereas the neutrophils of a patient with CGD fail to produce the blue color. In the DCF test, cells that oxidize the DCF are detected by flow cytometry.

   Prompt, aggressive treatment of infection with the appropriate antibiotics is important. Chemoprophylaxis using antibacterials can reduce the number of infections. Gamma interferon treatment significantly reduces the frequency of recurrent infections, probably because it increases phagocytosis by macrophages.

   The name chronic granulomatous disease arises from the widespread granulomas seen in these patients, even in the absence of clinically apparent infection. These granulomas can become large enough to cause obstruction of the stomach, esophagus, or bladder. The cause of these granulomas is unknown.

2. Chédiak-Higashi syndrome—In this autosomal recessive disease, recurrent pyogenic infections, caused primarily by staphylococci and streptococci, occur. This is due to the failure of the lysosomes of neutrophils to fuse with phagosomes. The degradative enzymes in the lysosomes are, therefore, not available to kill the ingested organisms. Large granular inclusions composed of abnormal lysosomes are seen. In addition, the neutrophils do not function correctly during chemotaxis as a result of faulty microtubules. The mutant gene in this disease encodes a cytoplasmic protein involved in protein transport. Peroxide and superoxide formation is normal, as are B-cell and T-cell functions. Treatment involves antimicrobial drugs to prevent infections. There is no useful therapy for the phagocyte defect.

3. Leukocyte adhesion deficiency syndrome—Patients with this syndrome have severe pyogenic infections early in life because they have defective adhesion (LFA-1) proteins on the surface of their phagocytes. This is an autosomal recessive disease in which there is a mutation in the gene encoding the β chain of an integrin that mediates adhesion. As a result, neutrophils adhere poorly to endothelial cell surfaces and cannot exit the blood circulation (see Figure 58–4). Accordingly, although they are immunosuppressed, these patients often have extremely high numbers of leukocytes in the blood.

4. Cyclic neutropenia—In this autosomal dominant disease, patients have a very low neutrophil count (<200/μL) for 3 to 6 days of a 21-day cycle. During the neutropenic stage, patients are susceptible to life-threatening bacterial infections, but when neutrophil counts are normal, patients are not susceptible. Mutations in the gene encoding neutrophil elastase have been identified in these patients, but it is unclear how these contribute to the cyclic nature of the disease. It is hypothesized that irregular production of granulocyte colony-stimulating factor may play a role in the cyclic aspect of the disease.

Pattern-Recognition Receptor Deficiency

Mutations in the genes encoding the pattern recognition receptors (PRRs) on the surface of and within the cells of the innate immune system result in susceptibility to severe infections (Table 68–2). For more information on PRRs, see Chapter 58.

1. Receptors on the surface of innate immune cells—Deficiency of Toll-like receptor-5 (TLR-5) results in a failure to recognize flagellin on bacteria and a marked susceptibility to Legionella infections. This deficiency is quite common. Deficiency of mannose-binding lectin (MBL) is also common. It results in a failure to activate complement through the lectin pathway (see Chapter 63). However, there are redundant pathways of complement activation, and it is not clear that this actually presents a clinically significant immunodeficiency.

2. Receptors within innate immune cells—NOD receptors in the cytoplasm recognize the peptidoglycan of gram-positive and gram-negative bacteria. Various mutations of NOD-2 have been associated with Crohn’s disease, presumably resulting from defects in gut barrier immunity and small amounts of bacteria able to invade the intestinal wall. RIG helicase receptors recognize viral double-stranded RNAs synthesized during replication in the cytoplasm. Deficiency of these receptors results in a reduced interferon response to various viruses (i.e., influenza virus).

Previous chapters have addressed some of the immunosuppressive medications, such as corticosteroids, that can cause acquired immunodeficiency (see Tables 62–2 and 66–3). Cushing syndrome, which can be caused by excessive exposure to exogenous or endogenous corticosteroids, is associated with immunosuppression. As discussed in Chapters 57 and 66, aging and pregnancy are associated with relatively depressed immunity. Finally, certain cancers, particularly the malignancies of hematopoietic cells (e.g., leukemia, lymphoma, and myeloma), can cause immunosuppression when excessive proliferation of the malignant cells “crowds out” the leukocyte progenitor cells in the bone marrow.

Acquired T-Cell Deficiencies

1. Acquired immunodeficiency syndrome—Patients with acquired immunodeficiency syndrome (AIDS) present with opportunistic infections caused by certain bacteria, viruses, fungi, and protozoa (e.g., Mycobacterium avium-intracellulare, herpesviruses, C. albicans, P. jiroveci, and Cryptosporidium). This is due to reduced helper T-cell numbers caused by infection with the retrovirus human immunodeficiency virus (HIV; see Chapter 45). This virus specifically infects and kills cells bearing the CD4 surface protein. The response to specific immunizations is poor; this is attributed to the loss of helper T-cell activity. AIDS patients also have a high incidence of cancers such as lymphomas, which may be the result of a failure of immune surveillance. See Chapter 45 for information on treatment and prevention.

2. Measles—Patients with measles have a transient suppression of delayed hypersensitivity as manifested by a loss of reactivity to purified protein derivative (PPD), which is used in the skin test for latent tuberculosis. Tuberculosis can actually reactivate in these patients. Despite the depressed T-cell function in this disease, immunoglobulins are normal.

Acquired B-Cell Deficiencies

1. Malnutrition—Severe malnutrition can reduce the supply of amino acids and thereby reduce the synthesis of IgG. This predisposes to infection by pyogenic bacteria.

2. Asplenia—Patients occasionally need to have their spleen removed through a surgical splenectomy, either because of a traumatic splenic rupture, a malignancy, or an autoimmune disease such as immune thrombocytopenic purpura. Even patients with spleens can develop “functional asplenia,” as occurs in patients with sickle cell disease who suffer numerous splenic infarcts. Without a functioning spleen, antibody responses to new antigens are generally suppressed, although antibodies to previously encountered antigens are generally intact. This is because the long-lived plasma cells responsible for circulating antibodies usually leave the spleen and reside in the bone marrow. Asplenic patients are predisposed to pneumococcal sepsis and severe babesiosis caused by Babesia microti.

Acquired Complement Deficiencies

1. Liver failure—Liver failure caused by alcoholic cirrhosis or by chronic hepatitis B or hepatitis C can reduce the synthesis of complement proteins by the liver to a level that allows severe pyogenic infections to occur.

2. Malnutrition—Severe malnutrition can reduce the supply of amino acids and thereby reduce the synthesis of complement proteins by the liver. This predisposes to infection by pyogenic bacteria.

Acquired Phagocyte Deficiencies

1. Neutropenia—Patients with neutropenia (low circulating neutrophils) present with severe infections caused by pyogenic bacteria, such as S. aureus and S. pneumoniae and enteric gram-negative rods. This occurs because neutrophils are a major component of the immune barrier in the skin, oropharynx, and gastrointestinal tract. Neutrophil counts below 500/μL predispose to these infections. Common causes of neutropenia include cytotoxic drugs, such as those used in cancer chemotherapy; leukemia, in which the bone marrow is “crowded out” by leukemic cells; and autoimmune destruction of the neutrophils. Ciprofloxacin is used to try to prevent infections in neutropenic patients.