PRIMARY IMMUNODEFICIENCY DISEASES [Detailed presentation is for understanding : Please read your books]

Immunodeficiency Diseases Immunodeficiency diseases [IDD] results from a genetic or developmental or acquired factors resulting in decreased function of the immune system, and is a syndrome mostly characterized by infections A primary disorder [not acquired] in one or more components of the immune system is Primary Immunodeficiency

Components of Immunity Skin and mucosal barriers Innate immune system (Non-specific) Phagocytic cells, NK cells, complement Adaptive immune system (Specific) T and B lymphocytes, antibodies

Production of blood cells from pluripotent stem cells in the bone marrow

Types of T cells Helper T-Cells (also called T4 or CD4+ cells) help other cells destroy infective organisms  Regulatory T-Cells (also called CD4, CD25+ cells) suppress the activity of other lymphocytes so they don't destroy normal tissue      Killer T-Cells (also called cytotoxic T lymphocytes, or CTLs, and are another kind of T8 or CD8+ cell) recognize and destroy abnormal or infected cells          

Function of T helper cells

Helper T cells

NK CELLS Discovered as non-T non-B cells in SCID mice who are able to reject transplant Function by “MISSING SELF” in contrast to T-cells which recognize “NON-SELF”

NK CELLS: RECEPTORS Inhibitory Stimulatory KIR receptors NKp30, 44, 46 NKG2A/ CD94 NKG2C/ CD94 Stimulatory NKp30, 44, 46 NKG2D CD16, CD244 TLR, CD161 Recognize MHC I molecules Inhibit cell lysis by NK cells Up-regulated by infections or cytokines Mediate binding of NK cells release of granzyme and perforins

Primary Immunodeficiency

Primary Immunodeficiency Genetic Defects in various proteins associated with immune cell regulation have been identified There are over 150 Primary immunodeficiency Diseases as identified by these defects

Primary Immunodeficiency Heredity, developmental defect Infancy and childhood Abnormal differentiation and development of hemopoietic stem cells Deficiency of Innate Immunity Leukocyte deficiency Phagocyte deficiency Complement deficiency Deficiency of Adaptive Immunity Humoral immunity deficiency Cellular immunity deficiency Combined immunodeficiency diseases Nonspecific immunodeficiency diseases

Lymphoid follicles Medulla Inter follicular area Cortex B cells T cells Normal Lymph node

Lymph node in immunodeficiency

Normal Hassals Corpuscles Thymus in immunodeficiency Normal Thymus Normal Hassals Corpuscles Thymus in immunodeficiency

Humoral Immunity Deficiency Features: Increased susceptibility to bacteria, enterovirus intestinal parasites Delayed in growth and development Increased incidence of autoimmune disease, malignant tumor Peripheral blood B cells absent or reduced Levels of Ig absent or reduced Pathogenesis: Block of the differentiation and development of B cells Reduced function of Th cells 1 Bruton’s syndrome : X-linked agammaglobulinaemia 2 Selectively IgA deficiency 3 Ig immunodeficiency with increased IgM

Bruton’s syndrome: X-linked agammaglobulinaemia Immunological features: Absence of B cells in blood and IgG Pathogenesis: Block in the differentiation and development of the pre-B cells Genetic features: X-linked recessive inheritance, males Clinical features: Recurrent bacterial infections No Antibody response to vaccination Treatment: Pooled gamma globulin preparations

Selectively IgA deficiency The most common immunodeficiency Immunological features: Lack serum IgA, <50mg/ Decreased level of sIgA Pathogenesis: Failure in terminal differentiation of B cells Clinical features: Recurrent infections in respiratory tract, alimentary canal, urogenital tract Treatment: Breast feeding Few can automatically resume the ability to produce IgA

B cell maturation

Immunoglobulin immunodeficiency with increased IgM Immunological features: Increased level of IgM, decreased levels of other Ig Pathogenesis: Absent of the T cell effector CD40L CD40L can not bind to CD40 of B cellsand therefore do not stimulate B cells to undergo Ab class switching Genetic features: X-linked recessive inheritance Clinical features: Recurrent pyogenic infections Increased level of IgM Decreased levels of IgA,IgG

Cellular Immunity Deficiency Features: Increased susceptibility to intracellular microbesnotable delay in growth and development, death at early age Increased incidence of malignant tumor Deduced numbers of peripheral blood B cells: No reaction to DTH No reaction to HVGR Block in the differentiation and development of the T cells DiGeorge syndrome (Thymic hypoplasia: Third and fourth pharyngeal arch syndrome) Structure and function defect of T cell surface molecules

(Thymic hypoplasia / Third and Fourth Pharyngeal Arch Syndrome) DiGeorge Syndrome (Thymic hypoplasia / Third and Fourth Pharyngeal Arch Syndrome) Immunological features: Absent or hypogenesis of the thymus Pathogenesis: Non heredity Features: Decreased function of the cellular immunity Defect function of the parathyroid gland Clinical features: Recurrent infections of intracellular bacteria No reaction to HVGR Treatment: Fetal thymic transplantation

Structure and Functional Defect of T cell molecules Absent of the TCR:TCR ab Mutant of the CD3 molecules Defect of the NF-AT gene: Reduced ability of the immune response, reduced level of IL-2 Others

Combined immunodeficiency diseases SCID: Severe combined immunodeficiency disease Immunodeficiency diseases with enzymes defect Immunodeficiency diseases with other severe defects

Severe Combined Immunodeficiency Diseases Loss of the humoral immunity and cellular immunity at the same time Autosomal recessive SCID Immunological features: Defect of the common precursors of T and B cells Defects in HLA II molecular SCID Immunological features：Increased susceptibility to virus infection，no CD4+T cells in peripheral blood, decreased function of the B cells X-linked SCID Pathogenesis: Gene mutation of IL-2 receptor g chain reduced numbers of peripheral blood T cells and NKcells

Nonspecific immunodeficiency diseases Deficiency of phagocytes Immunological features：Decreased number and defected function of macrophages Clinical features：Chronic granulomatous disease Pathogenesis：Deficient in NADH/NADPH oxidase in neutrophils， decreased the ability in bacterial killing dependent on oxygen radical Deficiency of complement components Genetic deficiencies of complement components or complement regulatory proteins Hereditary angioneurotic oedema, deficiency of C1INH， Vasodilatation，increased permeability of the blood capillary skin,mucous membrane edema

Secondary immunodeficiency diseases Malnutrition Acquired immunodeficiency syndrome [AIDS] Iatrogenic Post-illness

History Predominant B-Cell defects Onset after maternal antibodies diminish, usually after 5-7 mos, later childhood to adulthood Bacteria: Streptococcos, Staphylococcus, Hemophilus influenza; Campylobacter, enteroviruses, Giardia, Cryptosporidia Recurrent sino-pulmonary infections, chronic gastrointestinal symptoms, malabsorption, arthritis, viral meningoencephalitis Autoimmunity, lymphoreticular malignancy; thymoma, lymphoma Encapsulated bacteria

History Predominant T-Cell Defects Early onset, usually 2-6 mos Bacteria: mycobacteria, mycobacterium avium-intracellulare Viruses: CMV, EBV, varicella Fungi Parasites, Protracted diarrhea, extensive mucocutaneous candidiasis Graft versus Host Disease caused by maternal engrafment, nonirradiated blood Hypocalcemic tetany in infancy T-cells essential in controlling viral, fungal, mycobacterial, protozoal infections. ALSO in providing signals to B-cells to produce antibodies.

History Granulocyte Defects Early onset, delayed separation of cord (>8 weeks), poor wound healing Bacteria: Staphylococcus, Pseudomonas, Serratia, Klebsiella Fungi: Candida, Nocardia, Aspergillus Dermatitis, impetigo, cellulitis, abscesses, suppurative lymphadenitis, periodontitis, osteomyelits Recurrent Catalase producing organisms

History Complement Defects Late components (C5-C9): Neisserial infections: N.meningitidis, septic arthritis from N.gonorrhoeae Early components (C1, C4, and C2): Autoimmune disease C3 deficiency: Overwhelming sepsis, especially with gram negative organisms Lupus-like syndrome

Physical Examination A benign physical exam does not rule out immunodeficiency. Look for: General appearance, weight, overall health Hair, connective tissue Dysmorphic features Gingivitis, dental erosions, signs of sinusitis Tonsillar tissue, adenopathy, splenomegaly Arthritis, ataxia, neurological deficits

Disease Specific Skin Findings Eczema and petechiae : Wiskott-Aldrich Syndrome Telangiectasia : Ataxia-Telangiectasia Oculocutaneous albinism : Chediak-Higashi Dermatomyositis-like rash : XLA Chronic dermatitis : Hyper-IgE Generalized molluscum, extensive warts, candidiasis : T-Cell defects

Laboratory Evaluation Complete Blood Count with differential Total White Cell Count, Neutrophil Count, Lymphocyte Count, Eosinophil Count (age-appropriate values) Lymphopenia = < 3,000 in infants, < 1500 in children and adults Persistently high nuetrophil count occurs in Leukocyte Adhesion Defects Hemolytic anemia, thrombocytopenia, leukopenia occurs in some B-Cell deficiencies

Laboratory Evaluation Quantification of serum immunoglobulins IgG, IgA, IgM is the first-step in evaluation for humoral immunity Subtract albumin from total protein [gives Globulin levels] If ≥ 2 indicates adequate antibody (But we don’t know what types) IgG subclasses do not need to be ordered as screening IgE only if severe atopy, or chronic dermatitis

Laboratory Evaluation Qualitative Evaluation of Antibodies Isohemagglutins : Antibodies to ABO blood-group determinants Antibodies to tetanus and diptheria glycoproteins and pneumococcal polysaccharides If low titers, give booster, then repeat titers 4 weeks later. Children younger than 2 can not be tested for polysaccharide antigen antibody

Laboratory Evaluation T-Cell Immunity Delayed-hypersensitivity skin tests Intradermal injection of antigens; Candida, tetanus, trichophyton. Should produce redness and induration of > 5mm by 48-72 hours. Severe illness, or steroids can cause diminished responses. (anergy) Mitogen testing In vitro proliferative responses to concanvalin A, phytohemagglutinin

Laboratory Evaluation Phagocytic Cell Function Nitroblue Tetrazolium Test Adhesion antigens by flow cytometry (CD11/CD18): checks for adhesion defects Chemiluminescence: Phagocytic killing power

Laboratory Evaluation Complement function Total hemolytic complement (CH50):Tests functional integrity of classic complement pathway. AH50:Tests the functional integrity of alternate pathway The most common reason for an abnormal CH50 is improper handling of specimen

X-linked Agammaglobulinemia Well for first 6-9 months Recurrent infections with pneumococcus, Hemophilus influenzae, Giardia Minimal tonsillar tissue, and no palpable lymph nodes Levels of IgG, IgA, IgM, IgE: <2SD below normal Defect in Btk gene (Bruton tyrosine kinase) : Abnormal B-Cells X-linked agammaglobulinemia (XLA) is characterized by four findings: 1) Onset of recurrent bacterial infections in the first 5 years of life; 2) Serum IgG, IgM and IgA values that are at least 2SD below the normal for age; 3) Absent isohemagglutinins or poor response to vaccines; and 4) Less than 2% CD19+ B cells in the peripheral circulation. It should be noted that the variability of clinical and laboratory findings for XLA is exist. Some XLA cases have been undiagnosed and untreated for more than five decades. 10-20% of XLA have serum IgG values greater than 200mg/dl at the time of diagnosis. The most consistent findings in XLA are the marked reduction in the number of B cells in the peripheral circulation. The primary defect in XLA is the failure of pre-B cells to differentiate into mature B lymphocytes due to a gene mutation of Bruton's tyrosine kinase (Btk) which plays a multifaceted role in signal transduction for normal B cell development. However, approximately 10% of boys with presumed XLA do not have the mutation in Btk and 10% of patients with the early onset of recurrent infections, profound hypogammaglobulinemia and absent B cells, are girls. These observations suggest that there are autosomal recessive disorders clinically indistinguishable from XLA. Intravenous immunoglobulin (IVIG) has been used as a mainstay therapy for XLA and other antibody deficiency disorders or combined immunodeficiency including autosomal recessive agammaglobulinemia, CVID, Hyper-IgM syndrome, SCID, WAS and AT. IVIG therapy may be beneficial for a selective antibody deficiency with IgG1 or IgG2 deficiency and significant recurrent infections. The usual dose of IVIG is 400 mg/kg every 4 weeks and then the dose should be adjusted based on the IgG level after 3-4 infusions (to keep IgG levels above 500mg/dl). Headache, fever, myalgia, chills, rigors, nausea and vomiting are common adverse reactions of IVIG infusion; however, aseptic meningitis has been reported.

Common Variable Immunodeficiency Recurrent sinopulmonary infections with usual pathogens Age of onset 15-35 years Equal male: female Low IgG and poor antibody responses to immunizations Variable levels of IgM and IgA Increased risk for autoimmune diseases and malignancy B-Cells phenotypically normal Common variable immunodeficiency (CVID) is a heterogeneous syndrome, presenting with low IgG levels and no association with drugs or diseases known to cause secondary antibody deficiency. More than 95% of CVID clinically presents with recurrent sinopulmonary infections just like XLA or other hypogammaglobulinemia syndromes. The cause of CVID has not been identified yet. However the intrinsic defects of B cells, diminished T helper cells and dysregulation of cytokines have been described. Most of the patients usually do not become symptomatic until 15-35 years of age. CVID patients have an increased risk of developing autoimmune diseases, lymphatic and gastrointestinal malignancies, malabsorption and granulomatous inflammation. The diagnosis of CVID is based on low IgG levels and poor specific antibody responses to immunizations without an identified cause of the hypogammaglobulinemia. IgM and IgA levels may present in significant amounts or absent. A patient with borderline immunoglobulin levels needs an evaluation of specific antibody responses with immunizations. T cell and B cell enumeration are usually normal; however, decreasing numbers of the cells have been occasionally seen. Some patients may have abnormal T cell function studies such as absent delayed hypersensitivity or depressed responses of mitogen stimulation. Treatment of CVID is identical to XLA. Frequent use of broad-spectrum antibiotics is required. The delayed diagnosis and treatment leads to chronic lung diseases such as bronchiectasis so periodic screening with chest x-rays, high resolution chest CT and pulmonary function tests are needed.

Ataxia-Telangiectasia Recurrent sinopulmonary disease Telangiectasias between 3-6 years Ataxia soon after learning to walk, in wheelchair by 10-12 years Often low or absent IgA Variable depressions of other immunoglobulins Anergy and depressed mitogen studies Risk for lymphoreticular malignancy Ataxia-Telangiectasia (AT) is an autosomal recessive disorder characterized by sinopulmonary infections, telangiectasia, progressive ataxia and hypersensitivity to ionizing radiation. Immunologic studies reveal combine immunodeficiency consisting of selective IgA and IgG2 deficiency, cutaneous anergy and depression of in vitro T cell function study. Supportive treatment is recommended. Other treatments which may be considered include IVIG and bone marrow transplantation.

IgA Deficiency 1:400 to 1:800 Symptoms: GI, GU, RTI infections Many asymptomatic patients Normal IgG and IgM response to pathogens and vaccines Role in diagnosis of Celiac disease May evolve into Combined Variable Immunodeficiency Diseases Be very careful if patient develops Kawasaki… Selective IgA deficiency is the most common primary immunodeficiency disorder with the prevalence between 1 in 400 to 1 in 800. Although many patients are asymptomatic, IgA deficiency predisposes to respiratory, GI and urogenital tract infections, autoimmune diseases, sprue-like syndrome, malignancy, allergy and anaphylaxis reactions to blood products. Moreover, the progression of selective IgA deficiency to CVID or IgG2 subclass deficiency has been reported. The cause of the disease has not been known. Some infectious agents and drugs such as congenital rubella, EBV infection or phenytoin, may cause low IgA levels. The physiologic lag in serum IgA may delay the diagnosis until after the age of 2. The diagnosis can be made if a patient presents with IgA levels less than 7 mg/dL with no other evidence of any immune defects. Unlike XLA, HIM or CVID, selective IgA deficiency has a normal IgM and IgG response to pathogens and vaccines, therefore the routine schedule of immunization is suggested. IVIG replacement is not indicated. Aggressive treatment with broad spectrum antibiotics is recommended for recurrent sinopulmonary infections to avoid permanent pulmonary complications. Some selective IgA deficiency patients may develop antibody to IgA, in which case, there is a risk of anaphylaxis with blood product transfusions.

Severe Combined Immunodeficiency Recurrent infections by three months Can be life-threatening Candida, PCP, cryptosporidiosis, HSV, RSV, rotavirus, adenovirus, enterovirus, Epstein Barr Virus, Cytomegalovirus Absence of lymphoid tissue, lymphopenia, no thymic shadow Anergy, abnormal T-Cell proliferation, +/- B-Cell dysfunction Absence of adaptive immunity Severe combined immune deficiency (SCID) is a life-threatening syndrome of recurrent infections, oral candidiasis, persistent diarrhea, dermatitis, graft versus host disease after blood transfusion and failure to thrive caused by a number of molecular defects that lead to severe compromise in T cell function with or without B cell dysfunctions. The defects in SCID block the differentiation and proliferation of T cells and in some types, of B cells and natural killer (NK) cells. Immunoglobulin and antibody production are severely impaired even when mature B cells are present. NK cells, a component of innate immunity, are variably affected. The majority of the patients present by age 3 months with unusually severe and frequent common infections such as bacterial otitis media and pneumonia or opportunistic infections including Pneumocystis carinii, and cryptosporidiosis. Viral infections such as herpes simplex, RSV, rotavirus, adenovirus, enterovirus, EBV, CMV are also commonly seen. The most common defect of SCID is X-linked SCID (XL-SCID), accounting for 50-60% of cases. Adenosine deaminase (ADA) deficiency, accounting for 15% of SCID, is the second common defect. Other defects are purine nucleoside phosphorylase (PNP) deficiencies, IL-7 receptor alpha chain deficiency, recombination activation gene-1 and gene-2 (RAG1, RAG2) deficiency, CD45 deficiency, CD3 deficiency, MHC class I and II deficiency. SCID is typically diagnosed by clinical features: absence of lymph nodes and tonsils, lymphopenia, absence of a thymic shadow on chest x-ray, abnormal T, B, NK cell enumeration with flow cytometric analysis, abnormal in vivo T cell function studies with skin tests of delayed skin hypersensitivity to tetanus, candida, diphtheria and in vitro lymphocyte function studies by measuring response to phytohemagglutinin (PHA), concanavalin A, pokeweed mitogen, phorbol myristate acetate (PMA) and ionomycin, tetanus and candida. Skin testing for delayed hypersensitivity (which tests type IV cellular immunity function) is a basic way of testing T cell function. Antigens such as tetanus, candida, trichophyton, and mumps are frequently used because nearly everyone should be positive to all of these; however, occasionally normal young children may have a negative response. A positive response to these intradermal antigens indicates intact T cell function. If no response results from all these antigens, the patient may be "anergic". Thus, this panel of antigens is known as an "anergy panel". Bone marrow or other stem cell reconstitution is a first-line, specific therapy for almost all forms of SCID. ADA deficiency has specific therapy as an alternative to the transplantation. Polyethylene glycol-treated (PEG) ADA replacement may be administered with improvement but not complete reconstitution of immune function. Currently gene therapy is successful for XL-SCID. Prophylactic antibiotics, IVIG replacement, meticulous skin and mucosal hygienic care, avoidance of exposure to infectious agents, and irradiation of all blood products prior to transfusion are recommended while awaiting stem cell reconstitution. Many patients with SCID are fully reconstituted without complications with bone marrow and other stem cell reconstitution techniques. Patients who are well nourished, uninfected and younger than 6 months prior to transplantation have the best outcomes. Without stem cell reconstitution, it is rare for a patient with SCID to survive.

Normal Colon Colon in SCID

Di George Anomaly Variable hypoplasia of thymus and parathyroid Hypocalcemia  seizures Susceptability to fungi, viruses, PCP T-Cells variable in number, abnormal mitogen studies Normal to increased B-Cells, normal antibody levels Microdeletion of 22q11.2 Associated heart defects, facial anomalies, esophageal atresia Right-sided aortic arch, ASD, VSD, conotruncal Short philtrum. Mandibular hypoplasia, antimongaloid slant, hypertelorism, low-set notched ears

Leukocyte Adhesion Defect 1:10 million Striking neutrophilia Recurrent bacterial and fungal infections without pus Severe gingivitis, periodontitis, alveolar bone loss Decreased or absent CD18/CD11 by flow Delayed separation of umbilical cord Leukocyte adhesion molecule defect (LAD) syndromes are failures of innate host defenses against bacteria, fungi, and other microorganisms resulting from defective tethering, adhesion, and targeting of myeloid leukocytes (PMN, monocytes) to sites of microbial invasion. Killing of microbes is intact, but since the cells can not be mobilized to the point of inflammation and complement-mediated phagocytosis is impaired, the result is a lack of an inflammatory response. The hallmark of the disease is neutrophilia without PMNs in the infected tissue or pus. Histories of delayed separation of the umbilical cord, recurrent bacterial infections, necrotic skin lesions, severe gingivitis, periodontitis, and alveolar bone loss leading to early loss of deciduous and permanent teeth suggest the diagnosis. A definitive diagnosis with flow cytometric analysis reveals a decreased or absence of CD18 and its associated heterodimers: CD11a,CD11b and CD11c in LAD type I and absence of CD15s in LAD type II. Treatment includes continuous antimicrobial therapy, good oral hygiene, white blood cell transfusions and bone marrow transplantation.

Cyclic Neutropenia Regular, periodic oscillation in the number of peripheral neutrophils Neutropenia every 21+/- 3 days May develop fever, stomatitis, pharyngitis, pneumonia, occasionally sepsis and death May spontaneously abate Cycles become less noticeable with age

Chediak-Higashi Syndrome Partial oculocutaneous albinism Frequent infections of skin, mucous membranes, respiratory tract Gram -, Gram +, and fungi Large inclusions in all nucleated blood cells Accelerated lymphoma-like syndrome; non-neoplastic infiltration of liver, spleen, and lymph nodes associated with recurrent infections and death AR, generallized cellular dysfunction.

Chronic Granulomatous Disease Recurrent abscesses, lymphadenitis, or osteomyelitis at multiple sites Unusual infections with catalase positive organisms: Staphylococcus, Serratia, Aspergillus, Candida, Salmonella Defect in NADPH oxidase enzyme  leading to the inability to produce H2O2 No problem with streprococci Nitroblue Tetrazolium Test Chemiluminescence (DHR test) Chronic granulomatous disease (CGD) is a defect of phagocytic cells with dysfunction of the NADPH oxidase enzyme complex required for the production of reactive oxygen intermediates to destroy microbes. The defect leads to recurrent and uncontrolled catalase-positive organisms including S. aureus, E. coli, Serratia marcescens, Salmonella, Klebsiella spp, Clostridium difficile, Legionella bosmanii, Pseudomonas cepacia, Mycobacterium fortuitum, Chromobacterium, Aspergillus spp, Nocardia spp and Actinomyces spp. The most common infections are lymphadenitis, abscesses of the skin, and of the viscera such as liver. Granuloma formation occurs in CGD because the defect of the intracellular microcidal mechanism causes persistent antigen presentation and induces a sustained cell-mediated response by CD4 T cells, which recruit other inflammatory cells and set up a chronic local inflammation called a granuloma. The diagnosis of CGD can be ascertained by taking advantage of the metabolic defect in the phagocytic cells. A dye called nitro blue tetrazolium (NBT) is pale yellow and transparent. When it is reduced, it becomes insoluble and turns a deep purple color. In normal blood, the NBT is reduced to a dark purple or blue, easily seen in the phagocytic cells. In CGD blood, no dark purple or blue color is seen. Treatment includes short-term treatment of the infections, prophylactic trimethoprim-sulfa, recombinant human interferon-G (enhancing the production of reactive oxygen intermediates) and bone marrow transplantation. This condition is described in further detail in the chapter on neutrophil disorders.

Free Radicals Formation of Free Radicals Synthesis by phagocytes NADPH Oxidase NADPH - 2e- + 2O2 NADP+ + H+ + 2O2-. Respiratory Burst H2O2 +Cl- OH- + HOCl Myeloperoxidase HOCl H+ + OCl-

Nitro-blue Tetrazolium Reduction Test Nitro-blue Tetrazolium Formazan

Myeloperoxidase Deficiency 1:4,000 Most do not have increased infection rate MPO important in producing hypochlorous acid Affected cells use an MPO-independent pathway for killing pathogens Occasionally, disseminated candidiasis No specific treatment needed

Free Radicals Formation of Free Radicals Synthesis by phagocytes NADPH Oxidase NADPH - 2e- + 2O2 NADP+ + H+ + 2O2-. Respiratory Burst H2O2 +Cl- OH- + HOCl Myeloperoxidase HOCl H+ + OCl-

Wiskott-Aldrich Syndrome Atopic dermatitis Microcytic thrombocytopenia  bleeding Recurrent infections with encapsulated bacteria: Pneumococcus Variable antibody levels Often low IgM, high IgA and IgE. Poor antibody finction Low to low-normal T-Cells Wiskott-Aldrich Syndrome Protein: Defect in this protein could result in Abnormal cellular morphology (including platelet shape changes?) Defective cytoskeleton-dependent activation signals in lymphocytes and other leukocytes Abnormal cell-cell adhesions and leukocyte migration WAS is an X-linked recessive disease, caused by a defective gene encoding Wiskott-Aldrich syndrome protein (WASP), which is expressed only in lymphocytes and megakaryocytes. This protein is involved in the reorganization of the actin cytoskeleton in the cells. WAS has a classic presentation with eczema, microcytic thrombocytopenia and recurrent encapsulated infection in a young boy. The initial manifestations often present at birth and consist of petechiae, bruises, bleeding from circumcision or bloody stools. The diagnosis can be made based on the manifestations and immunologic findings including low IgM, high IgA and IgE, poor antibody responses to polysaccharide antigens, moderately reduced number of T cells and variable depression of in vitro T cell function studies. Treatment includes IVIG infusion, irradiated fresh platelet transfusions and splenectomy for bleeding tendency, prophylactic antibiotics after splenectomy, and bone marrow transplantation.

Normal Platelets Small Platelets

Treatment for Primary Immune Deficiencies Bone marrow transplantation Immunoglobulin replacement Enzyme replacement Gene therapy