IMMUNODEFICIENCIES

1. IMMUNODEFICIENCIES Dr. Gülderen Yanıkkaya Demirel

2. WHAT YOU WILL LEARN • Description of immunodeficiency • Types of immunodeficiency • Examples of diseases

3. What is Immunodeficiency? • A failing of one or more of the body’s defensive mechanisms resulting in morbidity or mortality. • Any part of the immune system can be deficient cells, proteins, signalling mechanisms……. • The body is susceptible to infection by organisms that meet with little or no resistance. • Or, in certain cases, other homeostatic systems in the body will be disrupted by the defect. • Severity is variable. • May be Primary or Secondary.

4. IMMUNODEFICIENCIES • Primary (inherited) • Secondary (to some other) • Physiological

5. Immunodeficiency (Defect in one or more components of immune system) Types: • Primary: Mutation in genes controlling immune system (e.g. Recurrent, severe infection in children) • Secondary: Acquired as a consequence of other diseases or environmental factors (e.g. infection, malignancy, aging, starvation, medication, drugs)

6. Clinical features associated with immunodeficiency • Feature frequency present and highly suspicious: • Chronic infection • Recurrent infection (more than expected) • Unusual microbial agents • Incomplete clearing of infection • Incomplete response to treatment

7. Clinical features associated with immunodeficiency • Feature moderately suspicious Diarrhea (chronic) Growth failure Recurrent abscesses Recurrent osteomyelitis • Feature associated with specific immunodeficiency disorder Telangiectasia Partial albinism

8. CLASSIFICATION of PRIMARY IMMUNDEFICIENCIES • Combined T cell and B cell immunodeficiencies • Predominantly antibody deficiencies • Other well defined immunodeficiency syndromes • Diseases of immune dysregulation • Congenital defects of phagocyte number, function or both • Defects in innate immunity • Autoinflammatory disorders • Complement deficiencies

9. Primary Immunodeficiencies Stem Cell Reticular Dysgenesis Lymphoid Progenitor Myeloid Progenitor Severe combined Immunodeficiency SCID Congenital Agranulocytosis Pre-B Monocyte Pre-T Neutrophil x-linked agglobulinemia xLA Mature B Thymus Leukocyte Adhesion Deficiency DiGeorge Syndrome D Chronic Granulomatous Disease (x or D) Mature T Plasma Cell Memory B WAS Common Variable Hypogglobulinemia / x-linked hyperIgM syndrome/Selective Ig deficiency WAS=Wiskott- Aldrich Syndrome x Bare Lymphocyte Syndrome

10. Phagocyte Deficiencies: Chronic granulomatous disease (CGD) Leukocyte adhesion deficiency (LAD I) Chediak- Higashi syndrome IL-12 / IFN pathway deficiencies Chronic or cyclic neutropenia

11. Leucocyte Adhesion Defect (LAD)

13. Defects in T cell-B cell interactions Btk=Bruton tyrosine kinase Defect (XLA) IL-2Rg defect IL-2Rg IL-2, 4, 7, 9, 15 B J Btk XHM CD40 CD40L JAK3 defect Ag JAK-3 Ag RAG 1/2 RAG1/2 MHC II TCR Ig Bare Lymphocyte Syndrome (MHC II- ve) CD4 T cell B cell RAG=Recombinase activating gene defect (SCID) JAK=Janus kinase

14. Adaptive Immunity Deficiency • T cell deficiency • Susceptible to intracellular bacterial infection • Susceptible to viral, parasitic and fungal infection • B cell deficiency • Susceptible to extracellular bacterial infection • Severe Combined Immunodeficiency Disease (SCID) • T and B cell functions defective • Usually fatal • Transplacental/milk transmission of Abs • TCR gene rearrangement lacking • Myeloid and erythroid components intact

20. Ig Levels vs Age

21. Overview of B-Cell Development

22. Hyper IgM syndrome

23. Serum levels of immunoglobulin in Hyper IgM syndrome IgG↓ IgM ↑↑ IgA↓ IgE↓

24. Hyper IgM syndrome • Defect in CD40 ligand CD40 ligand T cell CD40 B cell Ig Class switch

25. Selective IgA Deficiency • Selective IgA deficiency is the most common ID disorder. The prevalence is about 1:700. • Pathogenesis : block in B cell differentiation is due to intrinsic B cell defect or abnormal T cell help such as production of cytokine (TGF-B,IL-5) or in B cell responses to these cytokines.

26. IgA Deficiency • Clinical feature: Recurrent sinopulmonary infection, gastrointestinal disorders, allergy, cancer and autoimmune disease. • IgA Deficiency and genetic factors: association with HLA-A2, B8 and DW3 or A1 and B8. • IgA Deficiency and drug. • Serum IgA<5mg/dl but normal IgM and IgG • Immunopathogenesis :arrest in the B cell differentiation.

27. Selective IgG subclass deficiency • Total serum IgG levels are normal • One or more subclasses are below normal. • IgG3 deficiency is the most common subclass in adults. • IgG2 deficiency associated with IgA deficiency in children. • Pathogenesis: abnormal B cell differentiation. • Some individual have recurrent bacterial infection.

30. Nude Athymic mouse

31. Secondary or Acquired Immunodeficiencies • Agent-induced immunodeficiency: e.g. infections, metaboic disturbance, trauma, corticosteroids, cyclosporin A, radiation, chemotherapy • Acquired Hypogammaglobulinemia (Low levels of Ig; recurrent infections; treat with Ig)

32. Secondary Immunodeficiency - Infection - Renal failure, or protein losing enteropathy • Leukaemia or Lymphoma • Myeloma • Extremes of age - Certain Drug Therapies

34. MALNUTRITION • Most common cause of secondary immune deficiency. • Protein-calori malnutrition can lead to abnormalities of T cells, B cells and phagocytes • Atrophic and fibrotic thymus • Reduced lymphocyte proliferation in response to antigens.

36. INITIAL SCREENING for ID’s • Blood Count • Quantitative Immunoglobulins • Antibody responses to previous vaccines • Isoagglutinin (Anti-A and Anti-B) titers • Total hemolytic complement • Infection Evaluation (ESR, appropriate cultures, X-rays)

37. Human Immunodeficiency Virus • Discovered in 1983 • Luc Montagnier and Robert Gallo • Retrovirus • HIV-1 and HIV-2 • Patients with low CD4+ T cells • Homosexual; promiscuous heterosexual, i.v. drug users; transfusion; infants born to infected mothers • Opportunistic infections with Pnuemocystis carinii, Candida albicans, Mycobacterium avium, etc. • Kaposi sarcoma

38. Kaposi Sarcoma

39. Acquired Immunodeficiency Syndrome (AIDS) Structure of HIV-1 gp120 env gp41 Protease Envelope Reverse Trascriptase pol Integrase Matrix (p17) gag Capsid (p24) Genome

40. HIV Infection Coreceptors: Chemokine receptors T cell-tropic (Syncitium-inducing) gp120 CXCR4: SDF1 (Stromal cell derived factor) CD4 ssRNA Macrophage-tropic (Nonsyncitium inducing) Provirus CCR5: RANTES (regulated on activation, normal T cell expressed and Secreted), MIP1a, MIP1b (Macrophage Inflammatory Protein) Reverse transcriptase dsDNA

41. Serological Profile Kuby, 2007

42. Host Factors influencing course • Transmission of HIV • Sexual contact • Breast feeding • Transfusion • During birth • Sharing needles • Resistance to HIV in individuals • CCR5D32 • Some HLA types (HLA-A2 are resistant; HLA-B35 are susceptible)

43. Virus-induced effects on immune cells • Th Cells • Initially control viral load • Destruction of infected Th cells by CTL • Cytopathic virus • Anergy of surviving Th cells • CTL • gp120 specific CTL • Virus mutation induces resistance to CTL • Lack of Th affects CTL activation • Resistance to CTL by downregulation of class I MHC on target cells • Ab • Develops after 3 weeks • Virus Agic variability • Non-neutralizing. Thus, ineffective

45. Immunomodulation • HAART + IL-2 (To reconstitute the immune system) • Chemokine receptor inhibitors • Vaccines: Proteins, DNA, subunit and recombinant virus (SIV-HIV chimeric virus ) Problems • HIV-1 inf. -> AIDS in the presence of Abs • Low immunogenicity • Destruction of CD4+ T cells by vaccine • Integration of virus in host genome • Instability of HIV-1 genome • High rate of virus replication (109 viruses/day) • Live attenuated or heat killed organism (vaccinia virus carrier for HIV proteins) • Route of exposure (Rectal or vaginal challenge) • Lack of animal models and in vitro testing system

46. Summary • Primary immunodeficiencies are inherited • They can affect hematopoietic stem cells, lymphoid or myeloid cells. • Secondary immunodeficiencies are due to infections, aging, cancer or chemical exposure • HIV affects immune system by eliminating CD4+ T cells • Vaccine development has been hindered by lack of an experimental model, antigenic variation, etc.