IMMUNODEFICIENCIES AGE AND HEALTH DEPENDENT IMMUNOSUPPRESSIVE DRUGS

1. INHERITED 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 stand out until 1950 - antibiotics ACQUIRED Due to infectious diseases AIDS Other virus infections Malnutrition Artificial immunosuppression Drugs Radioactive irradiation IMMUNODEFICIENCIES AGE AND HEALTH DEPENDENT IMMUNOSUPPRESSIVE DRUGS

2. INHERITED IMMUNODEFICIENCIES • MOST ARE RECESSIVE MUTATION OF SINGLE GENES • Dominant traits have been eliminated from the population • 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 • Mutation in the IFNγ receptor results in binding without intracellular signaling - dominant DISSEMINATED INFECTION BY THE BCG STRAIN OF Mycobacterium USED FOR VACCINATION

3. 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

4. AGE-DEPENDENT DEVELOPMENT OF THE IMMUNE SYSTEMS BEFORE BIRTH AFTER BIRTH IgA milk IgM IgG Maternal IgG IgA Immunodeficiency ADULT AGING months years

5. ANTIBODY DEFICIENCY - recurrent sinopulmonary and GI infections beginning after 3-4 mo. B cell development (XLA, IgA deficiency) B – T cell collaborations CD40 ligand, hyper IgM T CELL DEFICIENCY - SCID, opportunistic infections beginning early in infancy T cell development IL-7/Jak3 Cytoskeleton Thymus epithelial cells DiGeorge syndrome Purin catabolism DNS repar enzyme defect MHC class II synthesis blockade TYPES OF INHERITED IMMUNE DEFICIENCIES

6. TYPES OF INHERITED IMMUNE DEFICIENCIES 2. • PHAGOCYTIC SYSTEM • CD18 (CR3, CR4, LFA1) • NADPH oxidase (CGD) • Vesicular fusion • COMPLEMENT SYSTEM • some infections, primarily with encapsulated organisms and Neisseriae • Soluble and membrane factors • C3 • C1 – C4 • Komplement inhibitors

7. ANTIBODY DEFICIENCY INABILITY TO CLEAR EXTRACELLULAR BACTERIA • X-LINKED AGAMMAGLOBULINEMIA XLA • Bruton’s agammaglobulinemia • Mutation in the Bruton tyrosine kinase (Btk) gene • Expressed in B cell, monocytes • Essential for B cell activation and development • NO B CELLS IN THE PERIPHERY – block at pre-B • Carrier mother XXHEALTHY non-random inactivation of X in B cells • Son XYDISEASE Son XY HEALTHY • Increased susceptibility to bacteria – antibiotics and enteroviruses • Pyogenic bacteria – permanent tissue demage caused by enzyme release from bacteria and phagocytes • Haemophilus, Streptococcus, Staphylococcus, • bronchiectasis, chronic lung disease – monthly injections of Gamma glob. or passive antibody isolated from plasma of healthy donors

8. SELECTIVE IgA DEFICIENCY • 1/800 • - Chronic lung disease, no increased susceptibility to infections • - Tendency to develop respiratory and gastrointestinal allergies and autoimmunity • - Over 40% of patients have anti-IgA antibodies – blood products containing IgA can cause severe allergic response. -Some are related to MHC class III region

9. a a antigen binding V V V V L L mIg molecule Kinases H H Ig-a/Ig-b heterodimer b SHP-1 a Syk Phosphatases Btk PLC Vav Lyn HS1 jelátvitel Adaptors + substrates SLP-65/BLNK THE IgM B-CELL RECEPTOR

10. HYPER IgM SYNDROME CD40L CD40 inflammation macrophage Th1 NO Cytokine production IFNγ T-dependent Ag T B  NO Cytokine production Isotype swith Somatic hypermutation

11. DIMINISHED ANTIBODY PRODUCTION AS A RESULT OF INHERITED DEFECT OF T CELL HELP • HYPER IgM SYNDROME • Defect of the DC40L membrane cytokine gene • X-linked, disease in males • No specific antibody response to T-dependent antigens • low IgG, IgA, IgE • Sensitivity to pyogenic bacteria • No germinal center formation • No macrophage activation by T cells CD40 – CD40L • No inflammation end leukocyte mobilization • No leukocytosis but neutropenia • sores and blisters in the mouth and throat • injection of GM-CSF • Susceptibility to pyogenic bacteria/opportunistic infection • Antibiotics • Monthly gammaglobulin

12. Lack of germinal centers in lymph nodes of X-linked Hyper-IgM syndrome patients

13. MUTATION OR FUNCTIONAL INACTIVATION OF SOLUBLE COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY Classical Lectin Alternative MBL C1Inh C1 B-factor MASP C4 D-faktor C2 Properdin HANE* C3 Neisseria-infection Pyogenic infections I-factor immune complex immune complex H-faktor disease disease C5 Pyogenic infections immune complex C6 disease C7 C8 Neisseria-infection C9 severe pyogenic infections *HANO - hereditary angioneurotic edema Stabilizes alternative C3 convertase

14. DEFECTS IN COMPLEMENT COMPONENTS IMPAIR ANTIBODY RESPONSES ACCUMULATION OF IMMUNE COMPLEXES • DEFICIENCY OF C3 OR ITS ACTIVATION • Susceptibility to pyogenic bacteria – inefficient opsonization • DEFICIENCY OF C5-C9 • Neisseria – NO complement mediated lysis • DEFICIENCY OF EARLY C1-C4 • No C3b and C4b fragments  No CR1-mediated erythrocyte transport of immune complexes • Accumulation of immune complexes in blood, lymph, extracellular fluid  deposition in tissues  tissue demage  macrophage activation  inflammation • DEFICIENCY IN COMPLEMENT INHIBITORY FACTORS • I factor – uncontrolled C3  C3b  C3 depletion  inefficient opsonization • Properdin – reduced deposition of C3  increased susceptibility to Neisseria • Decay Accelerating Factor DAF or CD59 MAC inhibitor – autoimmune-like condition  lysis of autologous erythrocytes  paroxysmal nocturnal hemoglobulinuria • C1 inhibitor – uncontrolled activation of the classical pathway  vasoactive C2  accumulation of fluid in tissues – epiglottal swelling may lead to death by suffocation

15. MUTATION OF MEMBRANE BOUND COMPLEMENT PROTEINS RESULTS IN IMMUNODEFICIENCY MIRL = CD59

16. A FAGOCITA FUNKCIÓK KÁROSODÁAS FOKOZOTT ÉRZÉKENYSÉG A BAKTERIÁLIS FERTŐZÉSEKKEL SZEMBEN • CD18 DEFICIENCIA/LEUKOCITA ADHÉZIÓ • A CR3, CR4 és LFA-1 közös β-alegysége • Gátolt fagocita miráció a vérből a fertőzés helyére • Az opszonizált baktériumok felvétele és lebontása gátolt • Perzisztáló fertőzések extracelluláris baktériumokkal • Gennykeltő baktériumok • A sebgyógyulás károsodása, súlyos íny gyulladás

17. DEFECTS IN PHAGOCYTE FUNCTION ENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS • DEFICIENCY OF CD18/LEUKOCYTE ADHESION (LAD) • 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 • Defect in wound healing, severe inflammation of the gums Lethal within the first decade of life without bone marrow transplant Omphalitis in LAD I patient

18. DEFECTS IN PHAGOCYTE FUNCTION ENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS • CHRONIC GRANULOMATOUS DISEASE – CGD • Mutation of NADPH oxidase – any of the 4 subunits • NO superoxid O2- radical  antibacterial activity is compromised • Chronic bacterial infections – granuloma formation • Aspergilus pneumonia • IFN-gamma improves resistance. Mechanism?? • Defect of glucose-6-phosphate dehydrogenase and myeloperoxidase  less severe phenotype CGD patient with skin infections due to Serratia marcescens

19. DEFECTS IN PHAGOCYTE FUNCTION ENHANCED SUSCEPTIBILITY TO BACTERIAL INFECTIONS • CHÉDIAK-HIGASHI SYNDROME • Abnormal large granules in a variety of cells leading to: • -hypopigmentation/partial albinism hair and eyes • -severe immunodeficiency • Defect in vesicle fusion mechanism • phagocytosed material is not delivered to lysosomes • Persistent and recurrent bacterial infections • Defective gene: CHS1 located on 1q42-43

20. DEFECTS OF MACROPHAGE FUNCTIONS CAUSING IMMUNODEFICIENCIES

21. T CELL IMMUNODEFICIENCIES

22. DEFECT IN T CELL FUNCTIONS T cells are involved in all aspects of adaptive immunity • Persistent and recurrent infections with a broader range of pathogens than patients with B cell deficiences • Neither T cell-dependent antibody response nor cellular immunity are functional SEVERE COMBINED IMMUNODEFICIENCY SCID • Treatment: • Bone marrow transplantation, preferably from a histocompatible sibling • Gene therapy

24. SEVER COMBINED IMMUNODEFICIENCIES The SCID phenotype can be caused by various gene defects • X-SCID – The common γ-chain of interleukin receptors is mutated IL-7 receptor • Autosomal SCID – mutation of Jak3 kinase IL-7 receptor-mediated signaling • Defect in the catabolism of purin bases – autosomal • Adenosine deaminase (ADA) mutation – mental retardation • Purin nucleotide phosphorilase (PNP) • Accumulation of purin metabolites • Highly toxiC for developing T lymphocytes, less toxic for developing B lymphocytes • Mutation of RAG enzymes – autosomal (Omen syndrome T- B- SCID) • No or little somatic gene rearrangement (RAPIDLY FATAL) • No circulating peripheral lymphocytes or very narrow repertoire • Mutation of a DNA repair enzyme – autosomal • DNA-dependent protein kinase (DNA-PK) involved in the cleavage of hairpins in somatic gene rearrangement • Bare lymphocyte syndrome – inhibited MHC synthesis • No CD4+ T cell response • CIITA co-activátor, RFX promoter binding protein or other transcription factor mutation • DiGeorge syndrome • Development of thymic epithelial cells is inhibited – T cell development is inhibited • Mutation of TAP transporter • Selective loss of CD8+ T cell responses – no SCID phenotype • Wiskott-Aldrich syndrome WAS – X-kinked • Thrombocytes and lymphocytes – WAS protein (WASP) • Rearrangement of cytoskeleton upon T cell activation in the polarized contact with B cells, macrophages and target cells

25. SEVER COMBINED IMMUNODEFICIENCIES The SCID phenotype can be caused by various gene defects • Defect in the catabolism of purin bases – autosomal (T- B-) • Adenosine deaminase (ADA) mutation – mental retardation • Purin nucleotide phosphorilase (PNP) • Accumulation of purin metabolites • Highly toxiC for developing T lymphocytes, less toxic for developing B lymphocytes

26. MUTATIONS IN IMMUNODEFICIENCIES AND LYMPHOCYTE DEVELOPMENT BONE MARROW THYMUS LYMPHOID PRECURSOR ADA PNP X-SCID DiGeorge BRUTON MHC II Hyper IgM CVID IgA PERIPHERAL LYMPHOID TISSUES

27. Wiskott-Aldrich syndrome WAS – X-kinked • Thrombocytes and lymphocytes – WAS protein (WASP) abnormally small platelets, B-cells normal pyogenic and opportunistic infections severe infection with varichella (chicken pox) and herpes simplex • Eczema • No antibodies to ccarbohydrate antigens • Rearrangement of cytoskeleton upon T cell activation in the polarized contact with B cells, macrophages and target cells

28. IL-7 RECEPTOR-MEDIATED SIGNALING Jak3 Jak1 Src Stat PI3K Pyk2 Stat bcl-2 Adapters STAM Trophic Transcription Chromatin remodeling Prolipherative VDJ recombinaion c-myc, cyclinD1 IL-7 gamma-c IL-7 receptor α-chain EARLY DIFFERENTIATION OF B AND T LYMPHOCYTES Before gene rearrangements

30. DiGeorge Syndrome • Conotruncal cardiac malformation • Hypoparathyroidism • Thymic hypoplasia leading to variable immunodeficiency • Other features: • Characteristic facies • Deletion in 22q11 in > 80% • Affected gene(s) is a transcription factor in the T-box family called Tbx1

31. Severe Combined Immunodeficiency Syndromes (SCID) • X-linked SCID (c deficiency) • Jak3 kinase deficiency • Adenosine deaminase deficiency • Purine nucleoside phosphorylase deficiency • Bare lymphocyte syndrome • RAG1 and RAG2 deficiency