Dr. Nelson, Diseases of the Immune System - D2

Congenital Immunodeficiency Disorders

Make flash cards of these

Case 1

Any time that a patient has a systemic infection: Two Questions! Are you immunosuppressed? What is your travel history? Example: 27 yo, otherwise healthy, presents with cough and fever. CXR shows diffuse Pneumocystis infection. This is HIV until proven otherwise. "Its always rare disease day!"

Mayo Clinic Connective Tissue Cascade

Associate the Disease with the antibody. (make flash cards)

15. Using just a few sentences, define autoimmune disease and state the key underlying immune defect.

Autoimmune diseases are immune-mediated inflammatory diseases in which tissue and cell injury are due to immune reactions to self antigens (autoimmunity). The diseases may be mediated by autoantibodies, immune complexes, or by T lymphocytes (or by combinations of these three mechanisms). Please note that the presence of autoantibodies does not always indicate the presence of autoimmune disease, as innocuous autoantibodies can be found in healthy individuals. Autoimmunity results from the loss of self-tolerance. Self tolerance refers to the phenomenon of unresponsiveness to an individual's own antigens as a result of exposure of lymphocytes to that antigen.

17. In one sentence, describe the typical clinical course of untreated autoimmune disease.

Autoimmune diseases, once initiated, tend to be progressive. While there may be sporadic relapses and remissions, there is usually inexorable tissue damage if untreated.

16. State the two key factors that combined together lead to autoimmune disease. Describe some of the ways that infections can cause autoimmunity.

Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes. Ways that infections cause autoimmunity: Loss of self-tolerance Abnormal display of self antigens Inflammation or an initial innate immune response may lead to activation of lymphocytes. Infections may up-regulate the expression of co-stimulators on APC's

31. State the laboratory tests you would order to assess B-cell function, T-cell function, phagocytic function, and complement.

Basic, initial laboratory tests to assess immune function: Complete white blood count with differential (CBC with diff): to assess for decrease in lymphocytes (lymphopenia) and/or decrease in neutrophils (neutropenia). Blood chemistries (comprehensive metabolic panel): to assess for diabetes, kidney or liver disease Urinalysis: to assess for renal disease Sedimentation rate, CRP: to assess for inflammatory state (infection, autoimmune disease) Tests to evaluate for specific infections

23. Describe the underlying pathogenesis of systemic sclerosis (scleroderma), and describe the typical clinical and pathologic findings as seen in the skin, GI tract, lungs, and musculoskeletal system. Compare and contrast diffuse vs. limited scleroderma, and define the CREST syndrome.

Chronic disease characterized by chronic inflammation, presumably autoimmune in nature, with widespread damage to small blood vessels and progressive interstitial and perivascular fibrosis of the skin and multiple organs. The disease occurs in adults, with a 3:1 F:M ratio. The skin is most commonly affected, but the GI tract, kidneys, heart, muscles, and lungs are also frequently involved. The disease is clinically heterogeneous, and several subtypes have been described: Diffuse scleroderma: widespread skin involvement at onset, with rapid progression and early visceral involvement. Limited scleroderma: skin involvement is confined to the fingers, forearms, and face, with late visceral involvement (more indolent form). Some patients with the limited form develop the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia). The cause is unknown, but may be related to an abnormal, autoimmune response by CD4+ T lymphocytes to an unknown antigen(s) with release of cytokines that activate inflammatory cells and fibroblasts. Inappropriate humoral immunity (in the form of autoantibodies) is also involved. Small vessel (microvascular) damage is also consistently present, along with ischemic damage. Progressive fibrosis is also seen. The pathologic findings are secondary to ischemic damage and fibrosis in the affected organs. Patients may have antibodies to Scl-70 (DNA topoisomerase 1); patients with CREST syndrome may have anti-centromere antibodies. Clinical and pathologic findings include: Raynaud's phenomenon (most common initial complaint). Skin: sclerotic atrophy and sclerosis, beginning in the distal fingers (sclerodactyly) and extending proximally; these changes can also involve the face; extensive dystrophic calcification in the subcutaneous fat can also be present. GI tract: involved in 90% of patients; esophageal fibrosis results in dysmotility, with dysphagia and reflux; small bowel involvement can result in loss of villi and dysmotility with malabsorption, cramps, and diarrhea. Lungs: interstitial fibrosis (respiratory failure is the most common cause of death). Musculoskeletal system: non-destructive arthritis; 10% of patients can develop an inflammatory myositis indistinguishable from polymyositis. Kidneys: vascular thickening; patients may develop hypertension.

24. Compare and contrast the pathogenesis, clinical presentation, and pathologic findings of dermatomyositis and polymyositis.

Dermatomyositis: autoimmune disease with immunologic injury and damage to small blood vessels and capillaries in the skeletal muscle, along with skin involvement and characteristic skin rash. Muscle biopsy shows lymphocytic inflammation around small blood vessels and in the perimysial connective tissue, along with perifascicular myocyte atrophy secondary to ischemia. Necrotic muscle fibers with regeneration can also be seen. Activated B and T cells and antibodies with complement activation are involved in the capillary damage. Certain autoantibodies are associated with specific clinical features (anti-Mi2, anti-Jo1, anti-P155/P140, do not memorize!). Clinical manifestations typically involve muscle weakness and skin rash. Classic rash is a violaceous discoloration of upper eyelids associated with periorbital edema, accompanied by a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules). Muscle weakness typically affects proximal muscles first and is symmetric, often accompanied by myalgias (muscle pain). Extramuscular manifestations may be present such as interstitial lung disease, dysphagia secondary to involvement of oropharyngeal and esophageal muscles, and myocarditis; 15-25% of patients with dermatomyositis have an underlying malignancy (screen newly diagnosed patients for malignancy!). Juvenile form of the disease exists, more often is accompanied by abdominal pain and involvement of the gastrointestinal tract. Patients will have elevated creatine kinase; treat with immunosuppressive agents. Polymyositis: Muscle and systemic involvement is similar to that seen in dermatomyositis, except for the lack of skin involvement. This disorder is also seen mainly in adults. Autoantibodies similar to that seen in dermatomyositis may be present, such as anti-Jo1, which is directed against histidyl t-RNA synthetase. Pathogenesis is believed to be caused by immunologic injury to muscle by activated CD8+ cytotoxic T cells. Muscle biopsy shows lymphocytic inflammation surrounding and invading muscle fibers, without the perifascicular atrophy seen in dermatomyositis. Necrotic and regenerating muscle fibers are found throughout the fascicle. No vascular injury is seen. Patients will have elevated creatine kinase; treat with immunosuppressive agents.

27. Describe the difference between primary and secondary immunodeficiencies. In what patient population does one typically encounter primary immunodeficiencies?

Immunodeficiency states can be categorized as primary (congenital, i.e. genetically determined) or secondary (due to complications of cancer, infection, malnutrition, immunosuppression, irradiation, or chemotherapy).

18. Describe the underlying pathologic mechanism of systemic lupus erythematosis (SLE).

Nearly diagnostic for SLE: Antibodies for dbDNA and Smith antigen. ANA: positive Type III Hypersensitivity SLE is an autoimmune disease involving multiple organs, characterized by the formation of multiple autoantibodies, particularly anti-nuclear antibodies (ANA's), in which injury is caused mainly by deposition of immune complexes and binding of antibodies to various cells and tissues. Onset of disease may be acute or chronic; however, it is typically a chronic, remitting and relapsing, often febrile illness characterized principally by injury to the skin, joints, kidney, and serosal membranes, although virtually any organ system can be affected. SLE is relatively common, with a prevalence of 1 in 2500 in certain populations. This disorder has been discussed by Dr. Ana Fernandez in the musculoskeletal course. Here we will only discuss some key pathologic points. The production of autoantibodies is a hallmark of SLE. These autoantibodies play a major role in the pathogenesis of the disorder, and measurement of these autoantibodies have value in the diagnosis and management of patients with SLE. Patients have a variety of anti-nuclear antibodies (ANA's), which can be detected by immunoassay (known as the ANA test) as well as with indirect immunofluorescence. The pattern of nuclear fluorescence suggests the type of anti-nuclear antibody present. The immunofluorescence test for ANA's has largely been replaced by immunoassay tests for specific nuclear antigens. In SLE, antibodies for double stranded DNA and Smith (Sm) antigen are virtually diagnostic for SLE. Most of the systemic lesions of SLE are caused by immune complex deposition (type III hypersensitivity). In addition to anti-nuclear antibodies, patients with SLE can have antibodies directed against red cells, platelets, and white cells. These autoantibodies opsonize these cells and promote their phagocytosis and lysis, resulting in cytopenias (anemia, thrombocytopenia, leukopenia). These autoimmune cytopenias are examples of antibody mediated (type II) hypersensitivity. Patients with SLE may also have autoantibodies that react with proteins complexed with phosopholipids. These anti-phospholipid antibodies are present in 30-40% of patients. Anti-phospholipid antibodies may produce a false positive syphilis test, and can prolong the partial thromboplastin time (lupus anticoagulant). Despite having in vitro anticoagulant activity, anti-phospholipid antibodies are associated with complications of a hypercoagulable state, and patients can get venous and arterial thrombosis, resulting in spontaneous miscarriages and cerebral ischemia (this is called secondary anti-phospholipid antibody syndrome, as it is occurring in association with SLE, another autoimmune disease). The fundamental defect in SLE is the failure of mechanisms to maintain self-tolerance. It is believed that the pathogenesis is related to the presence of susceptibility genes, coupled with environmental triggers (e.g. exposure to UV light, estrogen, certain medications). The environmental triggers lead to apoptosis and an increased burden of nuclear antigens in a genetically susceptible individual. The loss of self-tolerance and persistence of nuclear antigens leads to the formation of antigen-antibody complexes, which are deposited in the tissues, leading to injury (primarily an immune complex-mediated disease, type III hypersensitivity). The pathologic features of SLE are widespread and quite variable!

19. State the potential complication of the presence of anti-phospholipid antibodies in SLE.

Patients with SLE may also have autoantibodies that react with proteins complexed with phosopholipids. These anti-phospholipid antibodies are present in 30-40% of patients. Anti-phospholipid antibodies may produce a false positive syphilis test, and can prolong the partial thromboplastin time (lupus anticoagulant). Despite having in vitro anticoagulant activity, anti-phospholipid antibodies are associated with complications of a hypercoagulable state, and patients can get venous and arterial thrombosis, resulting in spontaneous miscarriages and cerebral ischemia (this is called secondary anti-phospholipid antibody syndrome, as it is occurring in association with SLE, another autoimmune disease).

21. Describe the underlying pathologic mechanism in rheumatoid arthritis. Describe the pathologic findings seen in the involved joints and in rheumatoid nodules.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder that may affect many tissues and organs, but primarily attacks the joints, producing a nonsuppurative proliferative and inflammatory synovitis that often progresses to destruction of the articular cartilage and ankylosis (stiffening or immobillity) of the joints. Pathogenesis is uncertain, but RA is thought to be triggered by exposure to an arthritogenic (arthritis causing) antigen in a genetically predisposed individual that results in a breakdown of immunological self-tolerance and a chronic inflammatory reaction. The initial arthritis thus leads to a continuing autoimmune reaction, with activation of CD4+ helper T-cells, and the release of inflammatory mediators and cytokines that ultimately destroy the joint. In addition to a T cell response, there is also a B cell response, producing autoantibodies. Genetic susceptibility is a major contributor to the disease, with specific HLA alleles and other genes linked to the risk of developing RA (e.g. HLA-DRB1, PTPN22). The environmental arthritogen(s) are unknown, but many of the autoantibodies produced are specific for citrullinated peptides (CCPs). These peptides are formed when there is post-translational conversion of arginine to citrulline. CCPs are produced during inflammation, so insults such as infection and smoking may promote citrullination of self proteins, triggering the autoimmune reactions in genetically susceptible individuals. Presence of antibodies to cyclic citrullinated proteins (CCPs) can be used as a diagnostic test for rheumatoid arthritis.

29. List the causes of secondary immunodeficiency. State which type of infection patients without a spleen are at risk for and why.

Secondary immunodeficiencies are immunodeficiencies secondary to another underlying disorder. Secondary immunodeficiencies are much more common than primary (congenital) immunodeficiencies. Some of the more common examples are listed on the next few slides. Causes of secondary immune deficiency: Immunosuppressive therapy (medications): Cytotoxic therapy for malignancy Treatment of autoimmune disease Bone marrow ablation prior to transplantation Treatment or prophylaxis of graft vs. host disease Treatment of rejection following solid organ transplant Microbial infection (e.g. HIV/AIDS (acquired immunodeficiency syndrome) Infection with the human immunodeficiency virus (HIV) results in marked immune suppression, primarily from selective infection and loss of CD4+ T helper lymphocytes (affects cell-mediated immunity). Causes of secondary immune deficiency: Malignancy (disease-related immunosuppression): Hodgkins disease, CLL (e.g. hypogammaglobulinemia in chronic lymphocytic leukemia) Multiple myeloma Malignancy of solid tumors (tumor-derived immunosuppressive factors) Disorders of biochemical homeostasis: Diabetes (multifactorial, including decreased neutrophil function and impaired cytokine production from macrophages) Renal insufficiency/dialysis Hepatic insufficiency/cirrhosis Malnutrition (affects many components of the immune system). Autoimmune disease (e.g. SLE, RA) Severe burn injury Exposure to radiation, toxic chemicals Asplenia/hyposplenism (loss of splenic macrophages post splenectomy can lead to increased risk of bacterial infection with encapsulated organisms, particularly with Streptococcus pneumoniae; as such, these patients receive vaccinations for S. pneumoniae, H. influenzae, and N. meningitidis) Aging

20. Explain why SLE can involve multiple organ systems. Using the clinical charts in the lecture as a guide, describe some of the key pathologic and clinical features seen in SLE when involving the skin, kidney, joints, and hematologic system.

The fundamental defect in SLE is the failure of mechanisms to maintain self-tolerance. It is believed that the pathogenesis is related to the presence of susceptibility genes, coupled with environmental triggers (e.g. exposure to UV light, estrogen, certain medications). The environmental triggers lead to apoptosis and an increased burden of nuclear antigens in a genetically susceptible individual. The loss of self-tolerance and persistence of nuclear antigens leads to the formation of antigen-antibody complexes, which are deposited in the tissues, leading to injury (primarily an immune complex-mediated disease, type III hypersensitivity). The pathologic features of SLE are widespread and quite variable! Pathologic findings: SOAP BRAIN MD S = serositis O = oral ulcers A = arthritis P = photosensitivity, pulmonary fibrosis B = blood cells R = renal, Raynauds A = ANA I = immunologic (anti-Sm, anti-dsDNA) N = neuropsych M = malar rash D = discoid rash

25. Define secondary Sjogren syndrome and Mixed Connective Tissue Disease (MCTD).

There are six main systemic autoimmune (collagen vascular) diseases: Systemic lupus erythematosis (SLE) Rheumatoid arthritis Systemic sclerosis (scleroderma) Polymyositis Dermatomyositis Secondary Sjogren syndrome (Sjogren associated with one of the above). Some patients present with an "overlap" autoimmune disease that has features that are a mixture of the features seen in SLE, systemic sclerosis, and polymyositis. These patients also have antibodies to a ribonucleoprotein particle containing U1 ribonucleoprotein (RNP). Mixed connective tissue disease (MCTD) is defined by the overlap features and the presence of the distinctive anti-U1-RNP antibody. Some investigators regard MCTD as a distinct entity, where as others consider the disease as variants of the above.

26. For all of the autoimmune diseases discussed, state the key autoantibodies that are present (study the Mayo Clinic Connective Tissue Disease Cascade).

There are six main systemic autoimmune (collagen vascular) diseases: Systemic lupus erythematosis (SLE) Rheumatoid arthritis Systemic sclerosis (scleroderma) Polymyositis Dermatomyositis Secondary Sjogren syndrome (Sjogren associated with one of the above). Some patients present with an "overlap" autoimmune disease that has features that are a mixture of the features seen in SLE, systemic sclerosis, and polymyositis. These patients also have antibodies to a ribonucleoprotein particle containing U1 ribonucleoprotein (RNP). Mixed connective tissue disease (MCTD) is defined by the overlap features and the presence of the distinctive anti-U1-RNP antibody. Some investigators regard MCTD as a distinct entity, where as others consider the disease as variants of the above.

22. Describe the underlying pathogenesis of Sjogren syndrome, and describe the typical pathologic and clinical findings. State the type of neoplasm that can be seen in Sjogren syndrome.

Think: Lacrimal and Salivary Glands Lab: antibodies to ribonucleoproteins SS-A and SS-B Chronic disease characterized by dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), resulting from autoimmune, immunologically mediated destruction of the lacrimal glands and salivary glands. It can occur as an isolated disease (primary Sjogren syndrome), or in association with another autoimmune disorder (e.g. rheumatoid arthritis (most common association), SLE, polymyositis, scleroderma, vasculitis, mixed connective tissue disease); in these cases it is called secondary Sjogren syndrome) Disease typically occurs in middle age women. Pathogenesis is unknown, but thought to be related to aberrant T and B cell activation in genetically susceptible individuals (possibly trigger: viral infection of salivary glands). Pathology demonstrates lymphocytic inflammation involving lacrimal and salivary glands, followed by fibrosis and gland atrophy as the disease develops. May also see parotid gland enlargement due to inflammation (Mikulicz disease). Some patients will exhibit extraglandular disease, such as synovitis, diffuse pulmonary fibrosis, and peripheral neuropathy. Patients characteristically have antibodies to ribonucleoproteins SS-A and SS-B (not specific). Diagnosis of Sjogren syndrome involves clinical findings as well as clinical tests of tear production, tear clearance, and conjunctival damage; measurement of the above antibodies and lip biopsy (to assess minor salivary gland inflammation) are also used. There is an increased risk for development of lymphoma (typically a marginal zone lymphoma). About 5% of patients with Sjogren syndrome develop lymphoma.

28. For each of the primary immunodeficiency syndromes discussed in the powerpoints, describe the underlying pathogenic defect (and pertinent genetics if appropriate), as well as the findings of appropriate laboratory tests (e.g. immunoglobulin levels, blood smear for CHS, complement tests). Use the chart in the powerpoint lecture to assist you in this exercise.

X-linked Agammaglobulinemia (Bruton's Agammaglobulinemia): Characterized by the failure of B-cell precursors (pro-B and pre-B cells) to develop into mature B cells. This maturational defect is due to a mutation in an X-linked gene which codes for a cytoplasmic tyrosine kinase required for B cell maturation (Bruton tyrosine kinase (Btk). Affected individuals will have markedly decreased or absent B cells in the peripheral blood, virtually no plasma cells, decreased or absent immunoglobulins, and underdeveloped germinal centers in lymph nodes and Peyer's patches; T cell-mediated reactions are normal Common Variable Immunodeficiency: Heterogenous group of disorders characterized by failure of B cells to differentiate into plasma cells. Thus, these patients have decreased immunoglobulin production (i.e. have hypogammaglobulinemia); in contrast to X-linked agammaglobulinemia, normal numbers of B cells are present in the peripheral blood, but they cannot mature to plasma cells (no plasma cells are seen). The decrease in gammaglobulins often affects all classes, but sometimes only IgG is reduced. B cell lymphoid areas (germinal centers) are hyperplastic. Symptoms are similar to that seen with X-linked agammaglobulinemia (sinopulmonary bacterial infections, serious enterovirus infection (e.g. meningoencephalitis), Giardia). Herpesvirus infections are also common. In contrast to X-linked agammaglobulinemia, both sexes are affected equally and the onset of symptoms is later, in childhood or adolescence, or in some cases, young adults. Treatment is with administration of prophylactic immunoglobulin therapy. Sporadic and inherited forms of the disease occur. Intrinsic B cell defects as well as defects of helper T cell mediated activation of B cells may account for the antibody deficiencies. The diagnosis is based on exclusion of other well-defined causes of decreased antibody production. Isolated IgA Deficiency: Failure of B cells to differentiate into IgA producing plasma cells; as a result, serum and secretory IgA levels are decreased. The molecular defect(s) involved are mostly unknown. Disorder may be familial, or acquired as a result of infection (toxoplasmosis, measles, other viral infections); In the USA, 1 in 600 individuals of European descent are affected, and most are asymptomatic (80%). In those that develop symptoms, mucosal defenses are weakened, so increased sinopulmonary infections and diarrhea (due to Giardia) are seen. Patients with isolated IgA deficiency who also have deficiency of IgG2 and IgG4 subclasses of IgG are particularly prone to developing infections. Patients have a high frequency of respiratory tract allergies, and have increased risk of autoimmune disease, particularly SLE and rheumatoid arthritis (uncertain etiology). Some individuals will develop severe, even fatal anaphylactic reactions to transfused blood products (normal IgA in the blood product acts like a foreign antigen). DiGeorge Syndrome (Thymic Hypoplasia): T cell deficiency due to failure of development of the third and fourth pharyngeal pouches, which normally give rise to the thymus, parathryroid glands, clear cells of the thyroid, and the ultimobranchial body. Individuals with this syndrome have variable loss of T cell-mediated immunity (thymic hypoplasia or lack of the thymus), tetany (lack of parathyroid glands), congenital defects of the heart and great vessels, and facial abnormalities. The disorder is usually not familial, but due to a sporadic deletion of a gene on chromosome 22q11, which is seen in 90% of affected patients (thus DiGeorge syndrome is part of the disorder known as 22q11 deletion syndrome). Patients will have low levels of T lymphocytes in the peripheral blood, and T cell areas in the lymph nodes and spleen are depleted. Deficiency in cell-mediated immunity makes these individuals susceptible to fungal, viral, and Pneumocytis jiroveci infections. Serum immunoglobulin levels may be normal or reduced, depending on the severity of the T cell deficiency. Hyper-IgM Syndrome: Patients are able to make IgM but are deficient in their ability to make IgG, IgA, and IgE antibodies (defect in immunoglobulin class switching, i.e. failure of B cells to switch from IgM to other classes of immunoglobulins). Laboratory studies typically show normal to elevated levels of IgM, no IgA or IgE, and very low levels of IgG. Peripheral blood shows normal number of T (60-70%) and B (10-20%) lymphocytes. Molecular defect(s) affects the ability of CD4+ T helper cells to deliver activating signals to B cells and macrophages, which is necessary for class switching. The T cells need to express CD40 ligand for this to occur. Approximately 70% of individuals have X-linked recessive mutations in the gene encoding CD40 ligand. Other individuals have defects in an enzyme called activation-induced cytidine deaminase, with an autosomal recessive inheritance pattern. Patients present with recurrent pyogenic infections (low levels of opsonizing IgG). Those patients with CD40 ligand mutations are also susceptible to pneumonia caused by the intracellular organism Pneumocystis jiroveci, because of the defect in cell mediated immunity. Patients are also at risk for IgM induced cytopenias (autoimmune hemolytic anemia, autoimmune thrombocytopenia, and neutropenia); patients can also get extensive involvement of the GI tract by polyclonal IgM producing plasma cells. Severe Combined Immunodeficiency (SCID): Represents a group of syndromes all having in common profound defects of both humoral and cell mediated immunity. Without hematopoietic cell transplantation, death occurs within a year. Affected infants present with thrush (oral candidiasis), extensive diaper rash, and failure to thrive. Some infants develop a skin rash shortly after birth due to GVH disease from maternal T cells that have crossed the placenta in utero. Patients are extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, P. jiroveci, Pseudomonas, CMV, varicella, and many other bacteria. Many different genetic lesions can give rise to SCID, and in some instances the genetic defect is not known. The most common form, accounting for 50-60% of cases, is X-linked, and is due to a mutation in the gene encoding the common gamma-chain subunit of cytokine receptors. This results in reduced cytokine signaling, and T cell lymphocyte development is markedly impaired. T cell numbers are decreased, and although B cell numbers are normal, antibody synthesis is severely impaired due to lack of T helper lymphocytes. NK cells are also deficient. Remaining types of SCID are inherited as autosomal recessive disorders. The most common form of autosomal recessive SCID is a deficiency of the enzyme adenosine deaminase (ADA). It is believed that ADA deficiency leads to accumulation of deoxyadenosine and its derivatives which are toxic to rapidly dividing immature lymphocytes (especially T lymphocytes). Treatment of SCID is with hematopoietic cell transplantation. Some patients with X-linked SCID have also been treated with gene therapy, with a retroviral vector used to insert a normal cytokine receptor gamma chain gene into the patients bone marrow stem cells which are then transplanted back into the patient. However, some patients have developed acute T-cell leukemias with this type of therapy. Some patients with ADA deficiency have also been treated with gene therapy. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome): Wiskott-Aldrich syndrome is an X-linked recessive disorder characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection (usually sinopulmonary), resulting in premature death. The disease is caused by mutations in the gene encoding Wiskott-Aldrich syndrome protein (WASP), located on the short arm of the X chromosome. This protein belongs to a family of proteins that are believed to link membrane receptors, including antigen receptors, to actin filaments in cytoskeletal elements. This leads to defects in cell migration and signal transduction. Affected patients experience depletion of T lymphocytes, with variable loss of cell-mediated immunity. Antibody production to polysaccharide antigens is absent, with low levels of serum IgM (thus at risk for infections with encapsulated organisms). IgG levels are usually normal, and IgA and IgE levels are often elevated. Diagnostic genetic tests for WASP mutations are available. In addition to developing recurrent infections, patients are at risk for non-Hodgkin B cell lymphomas. The only effective treatment is hematopoietic cell transplantation. X-linked Lymphoproliferative Syndrome: Disease characterized by inability to eliminate Epstein-Barr virus (EBV), leading to severe and sometimes fatal infectious mononucleosis and B cell lymphomas. Most cases are due to mutations in the gene encoding a molecule called SLAM-associated protein, which is involved in the activation of NK cells and T and B lymphocytes. Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder characterized by recurrent pyogenic infections, partial oculocutaneous albinism, progressive neurologic abnormalities, and mild coagulation defects. The gene responsible for this defect is called CHS1/LYST, and is part of the BEACH family of vesicle trafficking regulatory proteins. This results in defective fusion of phagosomes and lysosomes in phagocytes, resulting in defective phagocyte function and susceptibility to infections. The diagnosis of CHS can be made by examination of a peripheral smear for pathognomonic giant cytoplasmic granules in leukocytes and platelets, and confirmed with genetic testing. Hematopoietic cell transplantation (HCT) is the treatment of choice. Genetic deficiencies of the complement system, as they relate to susceptibility for infections: Hereditary deficiencies have been described for virtually all components and several pathway regulators. Deficiencies of the early classical pathway components (C2, C1, C4) show little or no increase in susceptibility to infections, but there is an increased incidence of an SLE-like autoimmune disease. Deficiency of components of the alternate pathway (properdin and factor D) are rare and are associated with recurrent pyogenic infections. Deficiency of C3 affects both the classical and alternative pathways, and results in susceptibility to serious and recurrent pyogenic infections. C3 deficiency also results in increased incidence of immune complex-mediated glomerulonephritis. Deficiencies of the terminal components (C5, C6, C7, C8, C9) show increased susceptibility for recurrent neisserial (gonococcal and meningococcal) infections. This is due to impaired function of the membrane attack complex involved in the lysis of organisms (Neisseria bacteria have thin walls and are especially sensitive to the lytic actions of complement).