Chapter 3: Autoimmune Disorders Involving the Connective Tissue and Immunodeficiency Diseases

The immune system is a tightly regulated network that incorporates both innate and adaptive pathways. The genes regulating the innate system are coded in the germ line. The innate immune system is not antigen specific. The cells and soluble factors of the innate system have pattern recognition receptors (PRRs, such as toll-like receptors) to common motifs on pathogens and altered self-motifs. The motifs on pathogens are called pathogen-associated molecular patterns (PAMPs). Altered self-antigens include danger-associated molecular patterns (DAMPs) as found in heat shock protein, and apoptosis-associated molecular patterns (AAMPs) as found in ds DNA, RNP, and histones. This response is rapid and there is no memory of the encounter.

The receptors on the T and B cells of the adaptive immune system are antigen or epitope specific and clonally variable, and their diversity is derived from gene recombination. The cells retain memory of the encounter and on subsequent engagement with that antigen, the cells exhibit more rapid and robust responses.

The immune network is tightly regulated by cells and cytokines, and a derangement in this immune homeostasis can result in immune response to self-antigens as in autoimmunity (failure of self-tolerance), or failure to recognize pathogens and eliminate them as occurs in immunodeficiency syndromes (failure of immunity). The following 2 groups of disorders are the focus of this chapter: the autoimmune diseases involving the connective tissue and the immunodeficiency diseases.

Diseases in which immune responses to self-antigens occur in the context of a genetic predisposition to disease expression are called autoimmune diseases. Some involve organ-specific pathologic autoimmunity such as Hashimoto thyroiditis and celiac disease, and these are discussed in Chapters 22 and 15, respectively. The autoimmune disorders discussed in this chapter are systemic diseases with predominant involvement of the connective tissue, manifesting clinical features including inflammation of the joints, skin, muscles, and other soft tissues (see Tables 3–1 and 3–2 and Figure 3–1).

The immunodeficiency diseases are subdivided into the relatively rare primary and the more common secondary immunodeficiency diseases. Primary immunodeficiency diseases are a direct consequence of either structural or functional derangement in the immune network. Secondary immune deficiency is the manifestation of a primary infectious disease, such as HIV infection; a malignancy as seen in lymphoma and multiple myeloma; or exposure to a therapeutic regimen such as immunosuppression or radiation.

Systemic Lupus Erythematosus

Description

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, associated with the production of antibodies to a variety of nuclear and cytoplasmic antigens. The hallmark characteristic is the generation of antibodies to ds DNA. These antibodies complex to these self-antigens, and the ensuing immune complexes contribute to the inflammation in many organs, particularly the skin, joints, kidney, and, to a lesser extent, the cardiovascular and nervous systems, lung, and hemopoietic cells.

The disease is more common in women than in men and usually appears in early adulthood, although it is seen in children as well. It not only is more common in African Americans than in Caucasians but also has a more severe clinical phenotype with renal and vasculitic manifestations in African Americans.

The candidate genes associated with SLE include those coding for complement components C1q, C4A, C2, activating and inhibitory FcγR, interferon regulatory factor 5 (IRF5), TNF, MHC class II (DR2 and DR3), and programmed cell death PDCD1, among others.

Table 3–3 summarizes the laboratory evaluation of SLE and Table 3–4 lists the autoantibodies associated with SLE.

Diagnosis

According to the American Rheumatologic Association criteria for diagnosis of SLE, the diagnosis of SLE is made if 4 or more of the following 11 criteria are present at any time during the course of the disease:

Tests utilized in the initial evaluation and subsequent monitoring of patients with SLE are shown in Tables 3–3 and 3–4 and Figure 3–1.

Sjogren Syndrome

Description

Sjogren syndrome (SS) is a systemic connective tissue disease, more common in women than in men. Pathologically, it is an autoimmune exocrinopathy involving the lacrimal glands, salivary glands, and less often the pancreas. The immune inflammation of these glands contributes to the sicca syndrome, with dry eyes (keratoconjunctivitis) and dry mouth (xerostomia) as characteristic clinical features. The disease can be primary or secondary. The primary syndrome is characterized by dry eyes, dry mouth, decreased production of tears as tested by the Schirmer test, and a lip biopsy that demonstrates inflammation of the minor salivary glands. Serologically, patients with primary Sjogren show a positive ANA, positive SS-A (Ro), positive SS-B (La), and positive rheumatoid factor (RF) in the absence of another connective tissue disease. A prospective study of 80 patients with primary SS followed for a median of 7.5 years reported the following frequencies of clinical manifestations: a) keratoconjunctivitis sicca and/or xerostomia occurred in all patients and were the only disease manifestations in 31%; b) extraglandular involvement occurred in 25%; and c) non-Hodgkin lymphoma developed in 2.5%. Secondary SS is clinically similar to the primary disorder, but it is additionally associated with clinical and serologic features of another connective tissue disease, such as rheumatoid arthritis (RA) or scleroderma.

Diagnosis

The diagnostic features are revealed by tests that document the sicca features. The dry eyes are evaluated by the Schirmer test. This test is a measurement of tear flow over a 5-minute period. Filter paper is allowed to hang from the lateral inferior eyelid and the length of the paper that becomes wet is measured. This test is not reliable, as early in the disease there is excessive lacrimation giving a false-negative test. Demonstration of devitalized corneal epithelium due to keratoconjunctivitis is evaluated by rose Bengal or fluorescein stain. The most accurate test is the slit lamp examination of the cornea and conjunctiva. Tests for quantitating salivary secretion are not standardized and also are not specific to SS. Biopsy of the minor salivary gland in the lower lip demonstrating focal lymphocytic infiltration is a useful confirmatory test.

Table 3–5 summarizes the laboratory tests useful in diagnosis of both primary and secondary SS.

Systemic Sclerosis/Scleroderma

Description

Systemic sclerosis is characterized by excessive and widespread deposition of collagen in many organ systems of the body. The hallmark of this pathologic process is the deposition of altered collagen in the extracellular matrix. The disorder is characterized pathologically by 3 features: 1) tissue fibrosis; 2) a proliferative and occlusive vasculopathy of the small blood vessels; and 3) a specific autoimmune response associated with distinctive autoantibody profile.

The immunologic basis is not well understood, but an aberration in TGF-beta-mediated deposition of collagen has been observed. Antibodies to platelet-derived growth factor receptors have been incriminated in the development of fibrosis. Both the triggering event and genetic predisposition are not well defined. Although the common organ involved is the skin, the gastrointestinal tract, kidney, lung, and muscles are also affected as the disease progresses. Renal ischemia leading to hypertension escalates the complications of this disease. Preponderance in females is common.

Clinically there are 4 major subtypes described:

1. Diffuse cutaneous scleroderma with widespread involvement of skin and visceral organs.

2. Limited cutaneous scleroderma, in which the disease is limited to the digital extremities and face. CREST syndrome is a variant of this entity. The name is derived from its features—calcinosis, Raynaud syndrome, esophageal dysmotility, sclerodactyly, and telangiectasia.

3. Localized scleroderma that affects primarily the skin of the forearms, the fingers, and later the systemic organs.

4. Overlap syndromes with features of RA or muscle involvement.

Diagnosis

Ninety percent to 95% of all patients with scleroderma have a positive ANA test. The most common pattern is finely speckled, followed by centromeric and nucleolar patterns. The ANA activity is directed against DNA topoisomerase (also known as Scl-70). A definitive diagnosis is achieved when the characteristic clinical findings are accompanied by a positive ANA test, and often confirmed by an antibody directed to Scl-70 by ELISA.

Tables 3–6.1 and 3–6.2 summarize the laboratory evaluation for systemic sclerosis/scleroderma.

Inflammatory Muscle Diseases

Description

Inflammation of the muscle leading to injury and weakness is the basis of the 3 most common but distinct diseases in this category. They are dermatomyositis (DM), polymyositis (PM), and inclusion body myositis. These diseases are more common in women, and their etiology remains unknown, although immune mechanisms have been incriminated. DM may occur as a specific entity or be associated with scleroderma or mixed connective tissue disease. Rarely, it is a manifestation of a malignancy. Skin manifestations such as a heliotrope rash, the shawl sign, and Gottron papules are common in DM. Like DM, PM may also be associated with another connective tissue disease. In addition, it may be associated with viral, parasitic, or bacterial infections. DM is characterized by immune complex deposition in the vessels and is considered to be in part a complement-mediated vasculopathy. In contrast, PM appears to reflect direct T-cell-mediated muscle injury. Inclusion body myositis is a disease of older individuals and is not associated with malignancy. It is occasionally associated with another connective tissue disease.

Antisynthetase syndrome, characterized by antisynthetase antibodies that are highly specific for DM and PM, is seen in about 30% of patients with DM or PM. These patients typically experience a relatively acute onset of disease, constitutional symptoms such as fever, Raynaud phenomenon, arthritis, and interstitial lung diseases. Their hands exhibit a roughening and cracking of the radial sides of the fingers and the palm, resembling a condition found in people who labor with their hands such as mechanics, and hence called “mechanic's hands.” HLA DR 52 has a strong association (90%) with antisynthetase antibody-positive myositis in people of both European and African descent. The antisynthetase antibodies include antibodies to aminoacyl-tRNA synthetase; antihistidyl-tRNA synthetase, also known as Jo-1; anti-signal recognition particle (SRP) antibodies directed against SRP; and anti-Mi-2 antibodies directed against a helicase involved in transcriptional activation.

Diagnosis

Although there are several common features between DM and PM, a characteristic feature of DM itself is the heliotrope hue around the eyes. Pulmonary interstitial fibrosis is seen in about 10% of cases in both diseases, occurring in the context of antisynthetase syndromes. There are 5 distinctive features described for both of these diseases. At least 3 of the following features are essential to fulfill the clinical diagnostic criteria for each:

1. Proximal and symmetrical muscle weakness

2. History of muscle pain and tenderness on palpation

3. Electromyographic evidence of spontaneous muscle activity and myopathic changes

4. Elevated serum or plasma concentrations of muscle enzymes such as aldolase, creatinine kinase (CK), and AST

5. Muscle biopsy demonstrating cellular inflammation

The laboratory diagnosis begins with documentation of muscle inflammation and injury as shown by elevation of serum or plasma concentrations of muscle enzymes such as aldolase, CK, and AST, together with the expected inflammatory histological features on muscle biopsy. The detection of autoantibodies is found in about one third of the patients, and supports a diagnosis of inflammatory muscle disease. The antibodies are directed at tRNA synthetases. Anti-Jo-1 is such an antibody, with specificity to histidyl-tRNA synthetase. It is found in about 40% of patients with PM, and generally indicates a worse prognosis. It is also more commonly found in patients with pulmonary fibrosis. Jo-1 is more commonly detected in cases of autoimmune myositis than in those with other causes of muscle inflammation. As with many autoimmune diseases, the integration of clinical features with laboratory findings forms the basis of definitive diagnosis. Tables 3–7.1 and 3–7.2 present the laboratory evaluation for inflammatory muscle disorders.

Mixed Connective Tissue Disease

Description

The entity known as mixed connective tissue disease (MCTD) has some of the features of SLE, some of systemic sclerosis, and some of PM. The patients have variable clinical presentations with arthralgias, myalgias, fatigue, and Raynaud phenomenon. These features are superimposed on other findings that can add in over time, including malar rash, sclerodactyly, arthritis of the hands, and Raynaud phenomenon. Pulmonary manifestations occur in over 85% of these patients and include interstitial pneumonitis, pulmonary hypertension, progressive interstitial fibrosis, and, rarely, dysfunction of diaphragm and esophagus. On rare occasion, patients with MCTD develop diffuse proliferative glomerulonephritis, psychosis, or seizures. The appropriate constellation of clinical findings suggests the need for laboratory testing, described in Table 3–8.

Diagnosis

The diagnosis of MCTD is largely made on the basis of the clinical features consistent with multiple autoimmune diseases. It is supported by a high titer of anti-U1 RNP in the serum.

Rheumatoid Arthritis

Description

RA is a systemic autoimmune connective tissue disorder that primarily affects the synovial joints, often starting as a synovitis. It affects 1% to 2% of the adult population worldwide, and is predominantly a disease of young women. Susceptibility and resistance to RA is associated with HLA genotypes. The criteria for diagnosis of RA were revised in 1987 to include clinical features, laboratory values, and radiographic findings. To establish a definitive diagnosis, at least 3 of the following 7 criteria must be present along with morning stiffness for a period of at least 6 weeks:

1. Arthritis in 3 or more small joints

2. Morning stiffness lasting >30 minutes

3. Arthritis of the small joints of the hand

4. Rheumatoid nodules

5. Symmetrical arthritis, often with synovitis

6. A positive test for RF

7. Radiographic changes of the affected joints

Diagnosis

An increased serum titer of RF has been a long-standing marker of RA, until the validation of anti-cyclic citrullinated peptide antibody (anti-CCP). This antibody not only is highly associated with RA but is also a marker for progressive and erosive joint disease. Anti-CCP is approximately 98% specific and 85% sensitive as a serum marker for RA. RF is an IgM autoantibody directed against the Fc region of IgG. While high titers of RF are associated with severe RA, it is not specific for diagnosis of RA, as it is also found in chronic infections and other connective tissue diseases. Table 3–9 summarizes the laboratory tests useful in the evaluation of RA.

Amyloidosis

Description

Amyloidosis and cryoglobulinemia (which follows) are systemic diseases resulting from the deposition in the tissues of insoluble proteins from a soluble circulating precursor. Both represent the consequences of immune dysregulation, and their diagnosis depends on laboratory evaluation and confirmation.

Amyloidosis is a heterogeneous group of diseases resulting from the extracellular deposition of low-molecular-weight fibrils from a soluble circulating precursor giving a “waxy” or “lardaceous” appearance to the infiltrated organs. Ultrastructurally, amyloid deposits are composed of unbranching fibrils 8 to 10 nm in width and with a molecular weight of 5 to 25 kd. At least 25 biochemically distinct forms of human amyloid protein have been identified. The 2 most common forms are primary, with amyloid light chain (AL) derived from light chains of plasma cells, and secondary, with amyloid-associated protein (AA), a nonimmunoglobulin protein. Congo red staining of amyloid deposits demonstrates a characteristic apple-green birefringence on polarized microscopy, while staining with Thioflavin T produces yellow-green fluorescence.

The classification of amyloidosis is based on whether the amyloidosis is associated with a plasma cell dyscrasia such as multiple myeloma or light chain myeloma (primary amyloidosis), or the sequelae of an infectious or inflammatory disease (secondary or reactive amyloidosis). Amyloidosis may also be classified as hereditary or acquired, localized or systemic, or by the type of fibril deposited in tissues, such as transthyretin (TTR) and Alzheimer amyloid precursor protein (APP). A partial list of the chemical classification of human amyloid is given in Table 3–10.1.

The most common form of the disease, representing 75% to 80% of the cases, is primary amyloidosis, as an acquired disorder, with multiorgan systemic involvement. Primary amyloidosis has a male to female preponderance of 2:1. Its incidence increases with age, often starting at age 40 years.

Reactive amyloidosis or type AA amyloidosis is a serious outcome of a group of diseases called autoinflammatory syndromes. This group of diseases represents too much inflammation secondary to dysregulation of the innate immune system, in the absence of high-titer autoantibodies or antigen-specific T cells. The hereditary autoinflammatory syndromes, also known as hereditary periodic fever syndromes, represent a group of genetic disorders characterized by recurrent inflammatory episodes of noninfectious origin, often starting in childhood and persisting lifelong. These syndromes are characterized by a variety of features that include fever, abdominal symptoms, arthralgias, arthritis, lymphadenopathy, and skin manifestations. An exuberant acute phase response with elevated C-reactive protein (CRP), serum amyloid A (SAA), and leukocytosis is associated with the inflammatory clinical presentation. The soluble SAA protein is degraded to the insoluble fibrils composed of AA, which is the hallmark of secondary amyloidosis. The mutated genes in these syndromes all code for proteins that play a role in the regulation of innate immunity.

Diagnosis

The diagnosis of amyloidosis is based on the histological and immunochemical demonstration of amyloid deposits in affected organs and tissues. The preferred tissue for biopsy is obtained by fine needle aspiration of the abdominal fat pad. Its advantages over rectal biopsy are that multiple samples can be obtained for study, and it is less painful and invasive. Since a plasma cell dyscrasia is commonly found in patients with amyloidosis, a serum protein electrophoresis together with a determination of serum free kappa and lambda light chains by nephelometry and a calculation of the kappa/lambda ratio is necessary to exclude a monoclonal gammopathy as the cause of the amyloidosis. Amyloid fibrils may bind to coagulation factor X causing a coagulopathy. Determination of the factor X level is important to explain bleeding tendencies in amyloidosis patients and is useful prior to biopsy of organs and tissues to identify a coagulopathy that would permit excess bleeding at the biopsy site.

To define the extent of the disease and the type of amyloidosis, the patient should be evaluated for renal, cardiac, pulmonary, neurologic, cutaneous, articular, liver, and spleen involvement. Cardiac involvement is extremely common in primary amyloidosis and much less in secondary amyloidosis. Virtually all of the familial amyloidosis manifests with nephropathic, neuropathic, or cardiopathic features. Laboratory evaluation for amyloidosis is summarized in Table 3–10.2.

Cryoglobulinemia

Description

Cryoglobulinemia refers to the presence in the serum of 1 or more immunoglobulins that precipitate at a temperature below 37°C. This precipitation is reversible, as it redissolves on warming to 37°C. The cause of cryoprecipitation remains to be determined.

Cryoglobulins are classified into 3 types. Type I consists of a single monoclonal immunoglobulin that does not have RF activity. It is typically IgM or IgG and less often IgA. Type I, also called simple cryoglobulinemia, is often associated with lymphoproliferative malignancies such as Waldenstrom macroglobulinemia or multiple myeloma. Patients with this disorder may present with features of vasculopathy involving the digits, resulting in gangrene. Type II consists of monoclonal IgM RF mixed with polyclonal IgG or IgA. The most common association for this form of cryoglobulinemia is hepatitis C infection. Type II may rarely be associated with lymphoma. Type III is also a mixed cryoglobulinemia, with polyclonal IgM RF associated with polyclonal IgG or IgA. Type III is found in patients with connective tissue disease and chronic infections. Both type II and III cryoglobulinemia patients may show fixation of complement and be associated with hypocomplementemia. Immune complex vasculitis, arthritis, neuropathy, and renal involvement may be the presenting features in patients with type II or III cryoglobulinemia.

Diagnosis

When present, the cryoglobulins are quantitated using a Wintrobe tube, and the amount of cryoglobulin present is reported as a cryocrit. It is important to remember that it is not the quantity as reported by a cryocrit that is important, but the biological inflammatory properties of the cryoglobulin. This inflammatory potential is reflected by hypocomplementemia, tissue inflammation, and organ injury. With therapy, the cryocrit decreases along with mitigation of inflammatory markers such as CRP, ESR, and complement activation. When a cryoglobulin is identified, the components comprising the cryoprotein are identified by immunodiffusion and immunofixation, using specific antisera directed at the immunoglobulin isotypes and against C3 and C4. Based on the clonality and the constituent isotypes, the cryoglobulin is then categorized as type I, II, or III. Table 3–11 summarizes the laboratory evaluation for cryoglobulinemia.

X-linked Agammaglobulinemia

Description

X-linked agammaglobulinemia (XLA), also known as Bruton agammaglobulinemia, is the prototype humoral immune deficiency. It is a disease restricted to males, and is characterized by a near total absence of B lymphocytes from an arrest in B lymphocyte development. The deficiency of B cells results in pan-hypogammaglobulinemia. Patients with XLA are asymptomatic for the first several months of life. Recurrent infections manifest between 4 and 12 months after birth as the maternal antibodies wane. Lack of the opsonic antibodies results in recurrent bacterial infections due to pyogenic, encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Pseudomonas species. Upper and lower respiratory tract infections are most common, including otitis media, sinusitis, bronchitis, and pneumonia. Skin infections and urinary tract infections also occur. The cause of XLA is due to loss of function mutations of a tyrosine kinase protein known as btk that is essential for B-cell development. The availability of intravenous as well as subcutaneous gammaglobulin replacement therapy has improved outcome as well as longevity for these patients.

Diagnosis

Early diagnosis is essential to prevent infections and complications of infections, such as bronchiectasis, meningitis, bacterial sepsis, septic arthritis, and even osteomyelitis. Recognizing that B cells are CD19 and CD20 positive, a definitive diagnosis can be made at birth by enumerating B cells in cord blood by flow cytometry using monoclonal antibodies to CD19 and CD20. In children less than 6 months of age, measuring serum immunoglobulin concentration is not diagnostically useful due to the presence of transplacentally acquired maternal antibody in the blood. Thus, to establish a diagnosis in the first 6 months, it is necessary to enumerate B cells by flow cytometry. The molecular diagnosis is made by mutational analysis of the btk gene. This is seldom needed in clinical practice as clinical features including lack of tonsils and low numbers of CD19 or CD20 cells can establish the diagnosis. Deficient expression of btk protein can be detected by flow cytometry, a technique that can also be used for carrier detection. Table 3–12 summarizes the laboratory approach to the diagnosis of this disorder.

Common Variable Immunodeficiency

Description

Common variable immunodeficiency (CVID) affects both males and females equally. The phenotypic expression of this disease is characterized by hypogammaglobulinemia, and there are many genetic defects in the B-cell maturation pathway that apparently cause this disorder. The disease usually manifests in adult life. Unlike agammaglobulinemia, in which B cells and tonsils are absent, patients with CVID have tonsils and normal numbers of B cells in blood and lymphoid tissues. Some patients even have mediastinal and abdominal lymphadenopathy. The primary defect in CVID is that the B cells are dysfunctional, and do not differentiate into plasma cells and secrete antibody. The clinical presentation is the consequence of the hypogammaglobulinemia, namely, recurrent pyogenic infections, often of the upper and lower respiratory tracts. Lack of mucosal immunity also results in enteroviral infections and giardiasis. Autoimmune diseases such as immune hemolytic anemia, neutropenia, and pernicious anemia occur. B-cell lymphomas may manifest with time. Studies of B-cell function in CVID have revealed a subset of CVID patients who have normal or low normal IgM, IgG, and IgA but fail to make functional antibody to polysaccharide and protein antigens. Therapy with intravenous as well as subcutaneous gamma globulin has improved the clinical outcome for CVID patients.

Diagnosis

Table 3–13 describes the laboratory tests useful to establish the clinical diagnosis.

Hyper-IgM Syndrome

Description

Hyper-IgM syndrome (HIGM) is characterized by markedly reduced IgG and IgA, with normal to elevated IgM and normal numbers of circulating B cells. The low IgG and IgA is due to an inability of IgM-positive B cells to switch to other isotypes. The increased IgM reflects polyclonal expansion of IgM synthesis in response to infections from encapsulated bacteria. Both X-linked and autosomal recessive forms exist. The molecular causes include the X-linked loss of function mutation of the CD40 ligand (CD154) found on activated T cells, which is needed to engage with CD40 on B cells to promote the isotype switch. Other causes include loss of functional mutations of activation-induced deaminase (AID) and of uracil-DNA glycolase (UNG). These enzymes are involved in class switch recombination and in mending error-prone repair.

Diagnosis

The diagnosis is established by measuring serum IgM, IgG, and IgA along with enumerating CD19 and CD20 cells by flow cytometry. Normal or elevated IgM, with low IgG and IgA, with normal B cells, suggests the diagnosis, which can be confirmed by molecular studies.

Selective IgA Deficiency

Description

Selective IgA deficiency is the most common primary immunodeficiency syndrome. Its prevalence varies from 1 in 500 in Caucasians to 1 in 10,000 to 15,000 in Asians. The clinical picture is variable, and includes asymptomatic individuals and those with allergies, autoimmune disorders, recurrent infections, and gastrointestinal diseases. The defect is due to a B-cell differentiation arrest in the IgG to IgA isotype switch. There are low numbers of IgA-bearing B cells. Anti-IgA antibodies are found in the serum of some patients, and these individuals can experience an anaphylactoid reaction to any blood or blood product containing IgA. These patients are to be given IgA-deficient blood and blood products and washed red blood cells. Patients with pure IgA deficiency and normal IgG subclasses should not receive gammaglobulin replacement therapy as these preparations do not replace IgA and any trace IgA in the gamma globulin preparations can provoke IgA antibodies and subsequent anaphylactoid reactions.

Diagnosis

The diagnosis is made by documenting an IgA level of <5 mg/dL in the presence of normal IgG and IgM. It is important to evaluate for IgG subclasses, as subjects with IgA deficiency and a low IgG2 subclass are prone to recurrent infections. This subset of patients with IgA as well as low IgG2 subclass does benefit from intravenous or subcutaneous gamma globulin therapy. The replacement is designed to correct the IgG2 deficiency, as IgG2 is an important opsonin for polysaccharide antigens.

DiGeorge Syndrome

Description

DiGeorge syndrome is due to deletion of chromosome 22q11.2 and is part of the spectrum described as “CATCH 22” (cardiac anomalies, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia). This deletion leads to failure of the development of third and fourth pharyngeal pouches and consequent abnormalities in the development of the thymus and parathyroid glands. Thymic dysfunction leads to T-cell abnormalities, and also B-cell dysfunction, while parathyroid abnormalities cause hypocalcaemia and tetany. Defects in the third and fourth pharyngeal pouches also result in congenital heart diseases, anomalies of the great vessels, and abnormal facies with low-set ears, fish-like mouth, and cleft palate. Patients with complete DiGeorge syndrome manifest marked defects in T-cell function and are prone to viral infections. Those with partial DiGeorge syndrome have fewer infections but have cardiac and facial abnormalities.

Diagnosis

A child with neonatal tetany and abnormal facies should be evaluated for DiGeorge syndrome by enumerating T and B cells, along with measurement of serum calcium and parathyroid hormone (PTH). The chromosome 22q11.2 deletion is documented by fluorescence in situ hybridization (FISH).

Severe Combined Immunodeficiency (SCID) Syndrome

Description and Diagnosis

As the name implies, SCID syndrome is characterized by profound defects in both cellular and humoral immunity. Affected neonates manifest severe and widespread viral, fungal, and bacterial infections soon after birth. The protection from maternal antibody is minimal, and the child fails to thrive. Respiratory failure often supervenes and is a cause of death. Patients with this disorder were the “bubble babies” decades earlier. Haploidentical, allogeneic bone marrow transplantation has altered the natural history of the disease. The path to recovery is often complicated by graft-versus-host (GVH) disease, and restitution of B-cell function is often incomplete. As a result, SCID patients may need intravenous gamma globulin to increase their antibody repertoire. Hematopoietic stem cell transplant with cytokine modulation to facilitate differentiation has been found to be superior, as there is less GVH disease.

Based on T-cell, B-cell, and NK-cell enumeration, the SCID syndrome is classified according to the position of the block/defect in T-cell and B-cell development. Currently, the spectrum of primary immunodeficiency diseases includes many underlying mutations. One group of these mutations results in different combinations of T-, B-, and NK-cell alterations, to produce SCID and related cellular immunodeficiency diseases (CID). A second group of mutations alters the amount of antibody to produce primary immunodeficiency diseases. Finally, a third group of mutations is linked to syndromes involving autoimmunity and immune dysregulation. Figure 3–2 shows 13 sites where a block in development of a T, B, or NK cell exists. The first 9 are associated with SCID or CID, and the last 4 are linked to antibody deficiency diseases. This classification permits an insight to the molecular mechanisms of the disease and provides a framework for evaluating patients for SCID.

Deficiencies of Complement Proteins

Description

The complement system of proteins and their receptors protect the host against pathogens and non-self-antigens and also abrogate the emergence of autoimmune diseases by scavenging self-antigens such as DNA so that they do not become immunogenic. Deficiencies of the complement system, therefore, result in susceptibility to infections and predispose to autoimmune diseases such as SLE. Deficiency of C3 results in increased susceptibility to infections by encapsulated, pyogenic bacteria. Deficiencies of C5, C6, C7, and C8 result in recurrent or disseminated Neisseria infections. Deficiencies of C1q (which scavenges DNA released from apoptotic cells), C2, and C4 predispose to SLE and other autoimmune diseases. Deficiency of C1 inhibitor causes hereditary angioedema (HAE). In type 1 HAE, there is a deficiency of both the antigenic and functional C1 inhibitor protein. In type 2, the protein is antigenically normal and hence normal serum levels are noted when it is measured by an antigenic assay. However, in type 2 HAE, the protein is functionally abnormal and hence cannot inhibit the kinin, complement, kallikrein, and plasminogen pathways. This results in generation of bradykinin that causes angioedema. Lack of C1 inhibitor causes C4 consumption even in the basal state so that C4 is always low. In HAE patients with angioedema, C2 is also decreased. C3 is normal as this activation occurs in the fluid phase. Acquired C1 INH deficiency leads to a similar clinical phenotype and is called acquired angioedema (AAE). AAE is seen in lymphoproliferative states such as monoclonal B cell diseases that activate C1 leading to consumption of C1 INH via C1qrs activation. In autoimmune diseases, the autoantibody is directed to C1 INH leading to C1 INH–anti-C1 INH immune complexes that activate C1qrs. Activated C1 in the fluid phase contributes to the same sequence of events leading to bradykinin generation and angioedema. The important differentiating factor is that C1q is normal in HAE, but C1q is low in AAE. Factor I deficiency is associated with recurrent infections, and factor H deficiency with hemolytic uremic syndrome and age-related macular degeneration. Deficiency of membrane inhibitors such as decay accelerating factor (DAF or CD55) and homologous restriction factor (HRF or CD59) causes paroxysmal nocturnal hemoglobinuria.

Diagnosis

The traditional method to measure the functional integrity of the complement cascade was to measure the ability of this system to hemolyze antibody-coated sheep red cells in a hemolytic assay. In this test, the result is reported as titer or the concentration of serum that supports 50% hemolysis in the S-shaped titration curve (CH50 test). Serum depleted of complement due to consumption by immune complexes, and serum that is congenitally deficient in complement proteins both yield low CH50 values. This hemolysis assay has been replaced by enzyme assays that detect neoantigens exposed during the activation of terminal complement components. The hemolysis-based screening test for complement abnormalities in the alternative pathway is the AH50 assay. In inherited deficiencies of the complement system, specific assays for the individual complement component must be performed. Further, it must be shown that addition of that component alone will restore the full hemolytic activity. Table 3–14 provides a profile of complement activation that is useful in clinical diagnosis. Figure 3–3 provides a framework for evaluating complement deficiency diseases.