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PRIMARY IMMUNODEFICIENCIES ARPAD LANYI PhD IMMUNODEFICIENCIES • INHERITED (PRIMARY) • Loss of function mutation of genes of the immune system • Enhanced susceptibility to infections • Particular types of pathogens depending on the gene defect • Did not show up until 1950 - antibiotics • ACQUIRED • Due to infectious diseases • AIDS • Other virus infections • Malnutrition • Artificial immunosuppression • Drugs • Radioactive irradiation PRIMARY IMMUNODEFICIENCIES MOST ARE RECESSIVE MUTATION OF SINGLE GENES • Recessive traits • Autosomal genes • Disease in homozygous children • Heterozygous children are carriers • X-linked genes • Single gene defect causes disease in males • Single gene defect in females renders the affected woman carrier NUMEROUS IMMUNODEFICIENCY LOCI RESIDE ON THE X CHROMOSOME CGD: Chronic Granulomatous Disease WAS: Wiscott-Aldrich Syndrome SCID: Severe Combined Immunodeficiency XLA: X-linked Agammaglobulinemia XLP: X-linked Lymphoproliferative Disease XLHM: X-linked Hyper-IgM Syndrome PRIMARY IMMUNODEFICIENCIES MOST ARE RECESSIVE MUTATION OF SINGLE GENES • Recessive traits • Autosomal genes • Disease in homozygous children • Heterozygous children are carriers • X-linked genes • Single gene defect causes disease in males • Single gene defect in females renders the affected woman carrier • Dominant traits have been eliminated from the population Mutation in the IFNγ receptor results in binding without intracellular signaling - dominant Disseminated infection by the BCG strain of Mycobacterium used for vaccination THE IMPACT OF RECESSIVE AND DOMINANT MUTATIONS IN THE IFN-γ RECEPTOR ON MONOCYTE ACTIVATION TYPES OF INHERITED IMMUNODEFICIENCIES INNATE IMMUNITY • PHAGOCYTIC SYSTEM • Enhanced susceptibility to bacterial infections • LAD1: CD18 (CR3, CR4, LFA1) • CGD • NADPH oxidase • G6PD • Myeloperoxidase • Vesicular fusion • COMPLEMENT SYSTEM • Some infections, primarily with encapsulated organisms and Neisseriae • Immunocomplex deposition • • • • • • Soluble and membrane factors C1 – C4 Alternative pathway C3 Terminal components Complement inhibitors TYPES OF INHERITED IMMUNODEFICIENCIES ADAPTIVE IMMUNITY • ANTIBODY DEFICIENCY • Recurrent sinopulmonary and GI infections beginning after 3-4 mo. • B cell development • T CELL DEFICIENCY • SCID, opportunistic infections manifest early in infancy • T cell development • RAG-1, RAG-2 • IL-7/Jak3 • Artemis • RAG-1 RAG-2 • DNA-PK • Artemis • ADA • DNA-PK • XLA • ADA • IgA deficiency • BLS • Hyper IgM • B – T cell collaborations • CD40 ligand, XLHIM IMMUNODEFICIENCIES AFFECTING INNATE IMMUNITY DEFECTS IN PHAGOCYTE FUNCTION ENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS DEFECTS IN PHAGOCYTE FUNCTION LEUKOCYTE ADHESION DEFICIENCY (LAD1) CD18 DEFICIENCY (ITGB2;21q22.3) Common β-subunit of CR3, CR4 and LFA-1. DEFECTS IN PHAGOCYTE FUNCTION LEUKOCYTE ADHESION DEFICIENCY (LAD1) CD18 DEFICIENCY (ITGB2;21q22.3) Common β-subunit of CR3, CR4 and LFA-1. Blocked phagocyte migration from blood to infection site. Inhibited uptake and degradation of opsonized bacteria. Persistant infection with extracellular bacteria, pyogenic infections. (No opportunistic infections.) Defect in wound healing, omphalitis, pneumonia, gingivitis, peritonitis. Lethal within the first decade of life without bone marrow transplantation. Omphalitis in LAD I patient DEFECTS IN PHAGOCYTE FUNCTION CHRONIC GRANULOMATOUS DISEASE – CGD (1 million in the US) Mutation of NADPH oxidase – any of the 4 subunits (most common: gp91 – X-linked) • No superoxid O2- radical antibacterial activity is compromised • Chronic intracellular bacterial or fungal infections – granuloma formation • Aspergillus pneumonia, suppurative arthritis, osteomyelitis, superficial skin infections (cellulitis, impetigo). CHRONIC GRANULOMATOUS DISEASE – CGD DEFECTS IN PHAGOCYTE FUNCTION CHRONIC GRANULOMATOUS DISEASE – CGD (1 million in the US) Mutation of NADPH oxidase – any of the 4 subunits (most common: gp91 – X-linked) • No superoxid O2- radical antibacterial activity is compromised • Chronic intracellular bacterial or fungal infections – granuloma formation • Aspergillus pneumonia, suppurative arthritis, osteomyelitis, superficial skin infections (cellulitis, impetigo). • IFN-gamma improves resistance. Mechanism?? • Diagnosis: NBT + PMA treatment of neutrophils. Lack of blue colour in CGD. Healthy CGD Carrier DEFECTS IN PHAGOCYTE FUNCTION CHRONIC GRANULOMATOUS DISEASE – CGD (1 million in the US) Mutation of NADPH oxidase – any of the 4 subunits (most common: gp91 – X-linked) • No superoxid O2- radical antibacterial activity is compromised • Chronic intracellular bacterial or fungal infections – granuloma formation • Aspergillus pneumonia, suppurative arthritis, osteomyelitis, superficial skin infections (cellulitis, impetigo). • IFN-gamma improves resistance. Mechanism?? • Diagnosis: NBT + PMA treatment of neutrophils. Lack of blue colour in CGD. Defect of glucose-6-phosphate dehydrogenase • Less severe phenotype • X-linked • Reduced NADPH level • Predisposes to hemolysis • Malaria Myeloperoxidase deficiency (Chr 17) • Less severe phenotype • Myeloperoxidase produces cytotoxic hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl−) • Respiratory burst with a normal nitro blue tetrazolium (NBT) test • Disseminated candidiasis DEFECTS IN PHAGOCYTE FUNCTION CHÉDIAK-HIGASHI SYNDROME • Affected gene: chs1 (1q42-43) • Defect in vesicle fusion mechanism. Failure of phagolysosome formation, phagocytosed material is not delivered to lysosomes. Persistent and recurrent bacterial infections. Infections most commonly involve the skin, the lungs, and the respiratory tract and are usually due to Staphylococcus aureus, Streptococcus pyogenes, and Pneumococcus species. Severe immunodeficiency, NK cell, CTL defect, neutropenia Oculocutaneous albinism: hypopigmentation: skin, hair, eyes, photophobia. Accelerated phase: lymphoma-like syndrome, early childhood, life threatening COMPLEMENT DEFINIENCIES IMPAIRED ANTIBODY EFFECTOR FUNCTIONS ACCUMULATION OF IMMUNE COMPLEXES COMPLEMENT DEFICIENCIES CLASSICAL PATHWAY ALTERNATIVE PATHWAY EARLY COMPONENTS AUTOIMMUNITY EARLY COMPONENTS Factor B: No case described Accumulation of immune complexes Factor D: Tissue demage Rare, increased risk of infections Inflammation Properdin: SLE, RA INFECTIONS Inadequate humoral response Decreased production of the opsonin C3b Sinopulmonary infections Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis C2 deficiency is the most common (1 in 10,000) C3 C5 C6 C7 C8 C9 The only X-linked complement protein Increased susceptibility to bacterial infections of the Neisseria family (fulminant meningococcal disease) TERMINAL COMPONENTS Invasive meningococcal disease Disseminated gonococcal infection COMPLEMENT DEFICIENCIES C3: CENTRAL POSITION Defective synthesis, expression or secretion of C3: AUTOIMMUNE/INFECTIONS OR BOTH Autoimmune disorders: SLE-like, glomerulonephritis C3 C5 C6 C7 C8 C9 Recurrent, severe, invasive infections Gram+/GramS. pneumoniae, S. pyogenes, S. aureus N. meningitidis, H. influenzae Impaired responses to immunization Secondary C3 deficiency: Impairment in the regulatory proteins factor I or factor H COMPLEMENT INHIBITOR DEFICIENCIES DEFICIENCIES OF C3 CONVERTASE INHIBITORS Factor H: Factor I: C3bBb inhibitor Cleavage of C4b, C3b Co-factor of factor I Uncontrolled amplification of C3 cleavage results in acquired C3-deficiency Higher susceptibility to S. pneumoniae and N. meningitidis infections Immune complex deposition-mediated diseases (SLE, glomerulonephritis) aHUS: atypic hemolytic uremic syndrome: systemic thrombotic microangiopathy, heart attack, renal failure, and death. Mutations in factor H and factor I are associated with HUS. Mutation of membrane co-factor protein CD46 (MCP) is also associated with HUS. stroke, COMPLEMENT INHIBITOR DEFICIENCIES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) Acquired clonal mutation of pig-a gene (X-chromosome) in myeloid progenitors No GPI-enchored proteins in the cell membrane of affected cells (rbc, plt, wbc) A CD55 (DAF) és CD59 (MIRL) complement regulatory proteins are GPI-enchored proteins COMPLEMENT INHIBITOR DEFICIENCIES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) Normal, CD55+CD59+ red blood cells can resist complement-mediated lysis Doi:10.3324/haematol.2009.017848 COMPLEMENT INHIBITOR DEFICIENCIES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) Absence of CD55/CD59 leads to MAC-mediated intravascular hemolysis Doi:10.3324/haematol.2009.017848 COMPLEMENT INHIBITOR DEFICIENCIES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) INTRAVASCULAR HEMOLYSIS Release of hemoglobin Release of erythrocyte arginase Large amounts of Hb deplete haptoglobin Conversion of L-arginine, the substrate for NO synthesis, to ornithine Free Hb irreversibly binds to nitric oxide (NO) NO SCAVENGING PLATELET AGGREGATION THROMBOSIS Magnetic resonance angiography in a patient with PNH and superior sagittal sinus thrombosis with collateral vessel formation. Case of dermal vein thromboses in a patient known to have PNH. Anita Hill et al. Blood 2013;121:4985-4996 COLOUR OF URINE SAMPLES TAKEN FROM PNH PATIENT AT DIFFERENT TIMES COMPLEMENT INHIBITOR DEFICIENCIES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) TREATMENT General: Blood transfusion Bone marrow transplantation Pharmacological: Immunosuppression – Prednisolone Iron supplements Thromboprophylaxis: Anticoagulants (warfarin) Eculizumab ECULIZUMAB: ANTI-C5 HUMANISED MONOCLONAL ANTIBODY With C5 blocked, PNH red blood cells are protected from hemolysis, but once opsonized by C3 RBCs become prey to macrophages. Chronic treatment increases the risk of infections with Neisseria meningitidis. It does not appear to change the risk of myelodysplastic syndrome, acute myelogenous leukemia, or aplastic anemia. Doi:10.3324/haematol.2009.017848 HEREDITARY ANGIONEUROTIC EDEMA (HANE) C1 inhibitor deficiency; Autosomal dominant (1 in 30000) Uncontrolled production of vasoactive peptides Enhanced permeability of postcapillar venules Non-inflammatory swellings of skin and mucosal membranes due to leakage of fluid from blood vessels into connective tissue. Subcutaneous tissues: face, hands, arms, legs, genitals Abdominal organs: stomach, intestines, bladder, and urethra; vomiting, diarrhea, serious abdominal spasms Larynx swelling – suffocation, may cause death C1inh deficiency predisposes to autoimmune diseases (SLE) due to its consumptive effect on complement factors 3, 4. Treatment: Anabolic steroid (Winstrol) iv. C1INH, FFP (fresh frozen plasma) Kallikrein inhibitor Bradykinin receptor antagonists Inhibition by C1INH in many steps Child with symptoms of HANE IMMUNODEFICIENCIES AFFECTING ADAPTIVE IMMUNITY B-CELL IMMUNODEFICIENCIES SYMPTOMS OF B-CELL DEFICIENCIES MANIFEST REALTIVELY LATE DUE TO THE PRESENCE OF MATERNAL ANTIBODIES Approx. 70% of all IDs. Increased sensitivity to: Encapsulated bacteria, Streptococcus pneumoniae, Haemophylus influenzae, Enteroviruses, parasites ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA X-LINKED AGAMMAGLOBULINEMIA, XLA (Bruton’s agammablobulinemia), 1:200,000 Genetic defect: • Mutation in the Bruton’s tyrosine kinase, essential for B-cell activation and development. • NO B-CELLS IN THE PERIPHERY – block at pre B-cell stage. • Male XY HEALTHY – XY DISEASE • Carrier female XX HEALTHY – non-random inactivation of X in B-cells DIAGNOSIS OF THE LACK OF B-CELLS BY FLOW CYTOMETRY Normal XLA ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA X-LINKED AGAMMAGLOBULINEMIA, XLA (Bruton’s agammablobulinemia), 1:200,000 Symptoms: • First few months of life is relatively normal (maternal Ig). • Tonsils are small, lymph nodes are barely palpable. • Increased susceptibility to bacteria and enteroviruses (likely due to IgA defficiency). • Encapsulated bacteria resisting ingestion by phagocytes unless they are coated with antibody and complement. • Recurrent infection of sinuses and of the middle ear. Pneumonia. • Pyogenic bacteria – permanent tissue demage caused by enzyme release from bacteria and phagocytes – bronchiectasis, chronic lung disease • Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus • Oral polio vaccine disseminate and cause poliomyelitis. • T-cell responses to intracellular bacteria is normal (mycobacteria). ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA X-LINKED AGAMMAGLOBULINEMIA, XLA (Bruton’s agammablobulinemia), 1:200,000 Treatment: • Monthly injections of Gamma globulin (IVIG OR SC). ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA NON BRUTON’S AGAMMAGLOBULINEMIA AUTOSOMAL µ heavy chain (IGHM) λ5 (IGLL1) lgα (CD79A) lgß (CD79B) DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T-CELL HELP X-LINKED HYPER IgM SYNDROME (XLHIM) Genetic defect: • Defect of the CD40L gene (Xq26). Symptoms: • No specific antibody response to T-dependent antigens. • low IgG, IgA, IgE • No macrophage/B-cell/DC activation by T-cells – CD40 – CD40L DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T-CELL HELP X-LINKED HYPER IgM SYNDROME (XLHIM) Genetic defect: • Defect of the CD40L gene (Xq26). Symptoms: • No specific antibody response to T-dependent antigens. • low IgG, IgA, IgE • No macrophage/B-cell/DC activation by T-cells – CD40 – CD40L • No germinal center formation. LACK OF GERMINAL CENTERS IN LYMPH NODES OF X-LINKED HYPER-IGM SYNDROME PATIENTS DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T-CELL HELP X-LINKED HYPER IgM SYNDROME (XLHIM) Genetic defect: • Defect of the CD40L gene (Xq26). Symptoms: • No specific antibody response to T-dependent antigens. • low IgG, IgA, IgE • No macrophage/B-cell/DC activation by T-cells – CD40 – CD40L • No germinal center formation. • No leukocytosis but neutropenia. • Susceptibility to pyogenic bacteria/opportunistic infection. • Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus • Pneumocystis carnii infection. Not seen in XLA. Treatment: • Antibiotics • IVIG • Injection of GM-CSF (neutropenia) AUTOSOMAL HYPER IgM SYNDROME • Intrinsic B-cell defect, activation induced deaiminase (AID) deficiency. Cytidine uridine conversion. • The enyme is involved in affinity maturation and Ig. class switch. • Limphoid hyperplasia. • Lack of opportunistic infections. doi:10.1038/nri1489 SELECTIVE IgA DEFICIENCY IgA: protection against infections of the mucous membranes Occurance: 1:160-1:800 (Europe, less in Asia). May be asymptomatic, but often associated with chronic or recurrent disease of the respiratory system. Giardia infection with chronic diarrhea is frequent. Higher frequency of allergies. Tenfold risk of coeliac disease. Autoimmune disease, autoimmune cytopenia. 40% of patients develop anti-IgA antibodies. Chest radiograph of a 50-year-old man with immunoglobulin A deficiency and severe bilateral pneumonia COMMON VARIABLE IMMUNODEFICIENCY,CVID A GENETICALLY AND CLINICALLY HETEROGENEOUS GROUP OF DISEASES CHARECTERIZED BY LOW ANTIBODY LEVELS AND RECURRENT INFECTIONS Symptoms: 1:25000 •Low IgG and IgA/IgM levels. •Frequent respiratory infections. •Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, •Pure response to vaccination. •Autoimmune manifestations: cytopenia, RA, psoriasis •Lymphocytic infiltration: lymphadenopathy, splenomegaly, hepatomegaly •Granulomas in lung and in the GI system. •GI problems: lactose intolerance, lymphoid hyperplasia/diffuse lymphoid infiltration, loss of villi and infection, especially with Giardia lamblia, diarrhea •Hematological malignancies, Non-Hodgkin's lymphoma Therapy: IVIG •Only 10 % has a family history. •Only 10% with a known genetic defect. Transmembrane activator and CAML (calcium modulator and cyclophilin ligand) interactor (TACI) SIGNALING PATHWAYS EMANATING FROM TRANSMEMBRANE ACTIVATOR AND CAML INTERACTOR (TACI) DOI:10.1111/j.1749-6632.2011.06266.x T-CELL IMMUNODEFICIENCIES SEVERE COMBINED IMMUNODEFICIENCY,SCID DEFECT IN T-CELL FUNCTIONS T-cells are involved in all aspects of adaptive immunity • Neither T-cell-dependent antibody response nor cellular immunity are functional. • Persistent and recurrent infections with a broader range of pathogens than patients with B-cell deficiences. SEVER COMBINED IMMUNODEFICIENCIES The SCID phenotype can be caused by various gene defects X-LINKED SEVERE COMBINED IMMUNODEFICIENCY • The common γ-chain of interleukin receptors is mutated, IL-7 receptor. • Part of IL-2, 4 ,7, 9, 15, 21 receptor • T-, B+, NK- (non functional B-cells) • Over 50% of SCID cases. • Small body weight, failure to thrive, diarrhea, sepsis, otitis media. • Opportunistic infections (Candidiasis, Pneumocystis carnii pneumonia). David Vetter, 12 years in a bubble AUTOSOMAL SCID • Mutation of Jak3 kinase – IL-7 receptor-mediated signaling – T-B+NK- (IL-15-NK, non-functional B-cells) (less than 10%) • IL-7Rα deficiency – T-B+NK+ 11% of SCID cases. • Defect in the catabolism of purin bases – Adenosine deaminase (ADA) mutation – T- B- NK dATP accumulation - inhibition of ribonucleotide reductase 15% of SCID cases. Underdeveloped thymus Neurological problems: hearing and visual impairment, mental retardation, low muscle tone and movement disorders AUTOSOMAL SCID • Mutation of RAG enzymes – T-B-NK+ • Mutation of DNA-PK/Artemis – T- B-NK+ • Omenn syndrome – T+B-/low, hypomorphic mutation of RAG1/2 (or Artemis) – T-cell counts are normal to elevated – Restricted TCR repertoire – Activated Th2 phenotype – Eosinophilia, elevated IgE level – Recurrent infections, mainly opportunistic – Autoimmunity: T-cell infiltration: GI tract, skin, hepatosplenomegaly, lymphadenopathy – Exfoliative dermatitis (erythroderma) – Failure to thrive, RAPIDLY FATAL AUTOSOMAL SCID • Bare lymphocyte syndrome – BLS I TAP1/2 deficiency – low abundance of MHC I Selective loss of CD8+ T-cells – BLS II Lack of MHC II – CD4+ T-cells fail to develop Compromises all aspects of adaptive immunity DOI: 10.1152/nips.01462.2003 TREATMENT • Gene therapy. • Bone marrow transplantation (BMT), preferably from a histocompatible sibling. • Often SCID babies need to be stabilized first before BM-transplant as they have severe infections when brought to the clinic. • Survival of HEALTHY SCID babies after BMT is over 95%! • Testing before diseases develops??? EARLY DIAGNOSIS CAN SAVE MANY LIVES !!!! EARLY DIAGNOSIS OF SCID PATIENTS TREC-ASSAY At TCR recombination T-cell receptor excision circle (TREC) is produced as a result of excision of the δ segments from the TCRA locus. TRECs can be detected with QPCR. Early diagnosis practically no false positives. WISKOTT-ALDRICH SYNDROME (WAS) A disease of defective reorganization of the actin cytoskeleton Genetic defect: – Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes. X-linked. Symtomps: – Thrombocytopenia, small platelet size (decreased production of platelets in bone increased destruction in spleen). marrow, WAS VERSUS NORMAL PLATELETS WISKOTT-ALDRICH SYNDROME (WAS) A disease of defective reorganization of the actin cytoskeleton Genetic defect: – Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes. X-linked. Symtomps: – Thrombocytopenia, small platelet size (decreased production of platelets in bone increased destruction in spleen). marrow, – Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells, macrophages and target cells is defective. CAPPING OF TCR IS DEFECTIVE IN WASP NEGATIVE T-CELLS WT,ctrl. WT,α-CD3 WASP-/ctrl. WASP-/-, α-CD3 WISKOTT-ALDRICH SYNDROME (WAS) A disease of defective reorganization of the actin cytoskeleton Genetic defect: – Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes. X-linked. Symtomps: – Thrombocytopenia, small platelet size (decreased production of platelets in bone increased destruction in spleen). marrow, – Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells, macrophages and target cells is defective. – Normal lymphocyte surface is covered with abundant microvilli, which are sparse or absent from the patient's lymphocytes. – The marginal zone which contains B lymphocytes and specialized macrophages is severely reduced in size. SEVERE REDUCTION OF THE MARGINAL ZONE IN THE SPLEEN FROM WISKOTT–ALDRICH SYNDROME PATIENTS The germinal centers (GC) are surrounded by the mantle (M) and by the marginal zone (MZ), which contains B lymphocytes and specialized macrophages. In patients with WAS, the MZ is severely reduced in size. WISKOTT-ALDRICH SYNDROME (WAS) A disease of defective reorganization of the actin cytoskeleton Genetic defect: – Mutation in the WAS protein (WASP) expressed in white blood cells and megakaryocytes. X-linked. Symtomps: – Thrombocytopenia, small platelet size (decreased production of platelets in bone increased destruction in spleen). marrow, – Rearrangement of cytoskeleton upon T-cell activation in the polarized contact with B-cells, macrophages and target cells is defective. – Normal lymphocyte surface is covered with abundant microvilli, which are sparse or absent from the patient's lymphocytes. – The marginal zone which contains B lymphocytes and specialized macrophages is severely reduced in size. – No antibodies to carbohydrate antigens (role for T-cells?). – Low IgM high IgA, IgE serum levels. – Eczema. – B-cell lymphomas. – Pyogenic and opportunistic bacterial infections. – Severe infection with varichella (chicken pox) and herpes simplex (impaired CD8+ T-cell response). Treatment: Bone marrow transplantation CONGENITAL GENE DEFECTS DISRUPT LYMPHOCYTE DEVELOPMENT AT VARIOUS STAGES Non-Bruton’s/ Bruton’s agammaglobulinemia (µ, λ5, lgα, lgß, btk) proB CLP preB I preB II Autosomal hyper IgM syndrome (AID) Selective IgA deficiency Imm. B ADA RAG, DNA-PK, Artemis deficiency deficiencies, SCID SCID proT preT Cγ-chain, IL-7Rα, Jak3 deficiencies, SCID DP Mat. B CVID? SP Imm. T BLS (TAP, RFX,CIITA) Mat. T Beff XLHIM CD40L Teff WAS THE END