IMMUNO - DEFICIENCIES

1. IMMUNO- DEFICIENCIES

2. IMMUNODEFICIENCIES No sufficient level of protective immunity is reached due to inherited(primary) or acquired (secondary) defects of the immune system. CLINICAL PRESENTATION: Serious overwhelming reccurent life-threatening infections of predominantly respiratory, GI or skin system. Defects in phagocytosis or immunoglobulin synthesis: pyogenic bacterial infections Defects in specific cell-mediated immunity: viral, fungal or opportunistic infections

3. IMMUNODEFICIENCIES IMMUNODEFICIENCIES • PRIMARY • IMMUNODEFICIENCIES • inherited • presentation • in early infancy • SECONDARY • IMMUNODEFICIENCIES • acquired • presentation • during • adulthood

4. PRIMARY IMMUNODEFICIENCIES: ·rare events ·heterogenous group ·with known molecular basis ·both innate and acquired immunity could be affected

5. DISTRIBUTION OF PRIMARY IMMUNODEFICIENCIES complement phagocytosis combined and T cell deficiencies defect in production of antibodies

6. INNATE IMMUNITY: PHAGOCYTOSIS: - defects in adhesion (LAD II, I) - defects in chemotaxis - defects in ingestion - defects in killing O2 independent (defensins) O2 dependent (NADPH oxidase) COMPLEMENT SYSTEM: both classical and alternative pathways could be impaired

7. PRIMARY IMMUNODEFICIENCIES: INNATE IMMUNITY PHAGOCYTOSIS COMPLEMENT SYSTEM ADHESION LAD II, I SY. KILLING early components of classical and alternative pathways deficiency deficiency of soluble regulatory factors O2-INDEPENDENT defensins deficiency CHEMOTAXIS lazy leukocytes sy. O2-DEPENDENT NADPH oxidase defect (CGD) myeloperoxidase defect membrane regulatory molecules deficiency (protectin) INGESTION LACK OF OPSONINS DEFECTS IN CYTOSKELETON

8. SPECIFIC IMMUNITY: A) PRIMARY HUMORAL IMMUNODEFICIENCIES B-cell development and immunoglobulin synthesis is affected. X-linked agammaglobulinemia (Bruton’s) ·mutation in btk gene encoding cellular kinase ·absence of B-cells ·absence of immunoglobulins Selective Ig class deficiency: ·IgA deficiency is the commonest

9. Hyper IgM syndrome: ·high level of IgM ·low levels of other classes of immunoglobulins ·absence of CD40L on T-cells ·inability to switch isotype Ig synthesis

10. Common Variable ImmunoDeficiency (CVID): ·manifestation in early adulthood ·HLA association (HLA-DR3) ·association with immunopathological diseases ·recurent severe bacterial pneumonia ·hypogammaglobulinemia is a common feature ·probably caused by defects in T, B cell cooperation

11. B) PRIMARY CELL-MEDIATED DEFICIENCIES: ·absence or malformation of thymus ·lethal viral, fungal or opportunistic infections ·thymic aplasia ·DiGeorge abnormality

12. C) PRIMARY COMBINED HUMORAL • AND CELLULAR DEFICIENCIES: • ·both cellular and humoral components • of the immune system are affected • ·severe combined immunodeficiency (SCID) is developed • ·there are several molecular mechanisms • of SCID development • ADENOSIN DEAMINASE DEFICIENCY (ADA): • ·abnormal purine metabolism • ·toxic products are accumulated in T and B cells • ·T and B cells are killed • ·replacement therapy • ·first example of gene therapy

13.  SUBUNIT OF IL-2 RECEPTOR DEFICIENCY: · subunit is shared by at least receptors for IL-2, IL-4, IL-7, IL-9, IL-13, IL-15 ·absence of  subunit leads to substantial defects in signaling DEFICIENCIES OF HLA-I OR HLA-II MOLECULES DEFICIENCY OF ZAP-70 KINASE DEFICIENCY OF RAG-1, 2 ENZYMES

14. MISCELLANEOUS PRIMARY IMMUNODEFICIENCIES: ·any signaling surface or intracellular molecule of leukocytes could be affected by the genetic defects with resulting immunodeficiency ·examples are receptor for interferon , IL-12R, production of interferon , IL-12, intracellular signaling molecules such as Jak-1 kinase

15. PRIMARY IMMUNODEFICIENCIES (ID) selective deficiency of Igs SPECIFIC IMMUNITY agammaglobulinemia hyper IgM syndrome HUMORAL ID B lympho, Ig CVID ADA deficiency Jak-1 deficiency RAG 1,2 deficiency COMBINED ID (SCID) ZAP-70 deficiency  subunit IL-2R deficiency HLA I, II deficiency CELLULAR ID T lympho CD3 subunits deficiency thymic aplasia INFR deficiency DiGeorge anomaly ataxia teleangiectasia Wiscott- Aldrich sy.

16. PRIMARY IMMUNODEFICIENCIES (ID) CLINICAL NOTES: ·molecular evidence of defects enabled prenatal testing ·immunoglobulin replacement therapy by intravenous immunoglobulins (IVIG) ·bone marrow transplantation ·gene therapy

17. SECONDARYIMMUNODEFICIENCIES (ID) • ·very heterogenous group of immunodeficiencies according to their origin • acquired presentation during adulthood • ·origin is sometimes not known • CLINICAL PRESENTATION: • ·chronic infections of respiratory, GI and skin systems • LABORATORY PARAMETERS: • ·diminished or absent skin test reactions • ·hypogammaglobulinemia • ·low level of T-cells and helper T-cells • ·low level of lymphocyte proliferation in vitro

18. SECONDARY IMMUNODEFICIENCIES ASSOCIATED WITH MALIGNANCY: ·most frequent ·most profound in the hematological malignancies ·hypogammaglobulinemia ·defects in phagocytosis ·defects in T-cell imunity SECONDARY IMMUNODEFICIENCIES INDUCED BY DRUGS: ·chemotherapeutics ·antiinflammatory drugs (corticosteroids) ·antibacterial drugs ·abused drugs (coccaine, marihuana)

19. SECONDARY IMMUNODEFICIENCIES ASSOCIATED WITH MALNUTRITION: ·caloric malnutrition ·protein malnutrition ·vitamins and trace elements malnutrition ·vegetarian habit SECONDARY IMMUNODEFICIENCIES ASSOCIATED WITH TRAUMA: ·injury is associated with inflammatory response ·iatrogenic injuries in medicine

20. SECONDARY IMMUNODEFICIENCIES CAUSED BY INFECTIOUS AGENTS: • ·viral infections • (herpes simplex, EBV, CMV, rubella, measles, etc.) • can cause immune depression • ·this immune depression is self-limiting • in majority of patients • ·HIV infection and AIDS • ·development of life-threatening • Systemic Inflammatory Response Syndrome (SIRS) • induced by infection caused by LPS positive • bacteria (septic shock) • ·followed by immune system exhaustion • (immune depression)