Refif s. alshawk Lec . 4 & 5

1. Immunodeficiences Refif s. alshawkLec. 4 & 5

2. Autoimmunity – system attacks host cells and tissues • Hypersensitivity- unfavorable immune response • Immunodeficiency – system fails to protect • Primary immunodeficiency • Genetic or developmental defect • Secondary immunodeficiency - acquired

3. Mechanisms of Immunodeficiency Loss or reduction of: • Cell type • Cell numbers • Cell function

4. Deficient humoral immunity usually results in increased susceptibility to infection by encapsulated, pus-forming bacteria and some viruses, • Where as defects in cell-mediated immunity lead to infection by viruses and other intracellular microbes. • Combined deficiencies in both humoral and cell mediated immunity make patients susceptible to infection by all classes of microorganisms. • Immunodeficient patients, especially those with defects in cellular immunity, often present with infections by microbes that are commonly encountered but effectively eliminated by healthy persons; such infections are said to be opportunistic.

5. Defects in innate immunity can result in different categories of microbial infections, depending on the pathway or cell type affected. • Complement deficiencies, for instance, resemble antibody deficiencies in their clinical presentation, • Natural killer (NK) cell deficiencies result mainly in recurrent viral infection.

6. Primary ImmunodeficienciesLymphoid Immunodeficiences • Combined – effects both B and T cells • B-cell Immunodeficiency • Range from absence of B cells, plasma cells, immunoglobulins to absence of only certain classes of Abs • Subject to bacterial infections but do well against viral since T-cell branch is ok • T-cell Immunodeficiency • Can effect both humoral and cell-mediated

7. Progenitor Progenitor

8. Defects in the cell mediated system are associated with: •  increased susceptibility to viral, protozoan, and fungal infections. Intracellular pathogens such as Candida albicans, Mycobacteriaare often implicated, reflecting the importance of T cells in eliminating intracellular pathogens. • also affect the humoral system, because of the requirement for T-H cells in B-cell activation. particularly in the production of specific antibody

10. Defectin T Cell Defect in cells that are critical to the development or activation of T cell (APC) Defects in thymic development (abnormal embryonic changes) Combined partial B & T cell defect Reduced MHC I molecules Reduced MHC II molecules Prevent thymic education of T cell Decrease No. of functional CD8+ & NK Decrease No. of functional CD4+

11. Defect in T cell development Progenitor Progenitor

12. B and T-cell deficiency divided into these categories: A. Selective T-cell deficiency:

13. C. Complete functional B and T cell deficiency: B. Combined partial B and T-cell deficiency:

14. Primary ImmunodeficienciesCombined Immunodeficiencies • Thymus • DiGeorge Syndrome – decreased or absent thymus • Results from deletion of region on chromosome 22 in developing embryo, developmental anomaly • third and fourth pharyngeal pouches during fetal life. • Lowered T cell numbers, results in B cells not producing sufficient Abs • As in other severe T cell deficiencies, patients are susceptible to mycobacterial, viral, and fungal infections.

15. MHC DEFICIENCY class I deficiency(Bare lymphocytes syndrome I or TAP- 1 or 2 deficiency): • defect in their transport associated protein (TAP)gene and hence do not express the class-I MHC molecules and consequently are deficient in CD8+ T cells , CD4+ normal • recurrent viral infection , normal DTH, normal Ab production

16. MHC DEFICIENCY class II deficiency(Bare lymphocytes syndrome II): • Due to defect in the MHC class II transactivator protein gene, which results in a lack of class-II MHC molecule on APC. • Patients have fewer CD4 cells , immunoglobulin levels decreased owing to defective T-cell help • Increased susceptibility to infection

17. Combiend partial B- and T-cell deficiency Ataxia-telangiectasia: • Defect in kinase involved in cell cycle • Associated with a lack of coordination of movement (ataxis) and dilation of small blood vessels of the facial area (telangiectasis). • T-cells and their functions are reduced to various degrees. • B cell numbers and IgM concentrations are normal to low.

18. Primary ImmunodeficiencesCombined Immunodeficiences • Severe Combined Immunodeficiency (SCID) • Low # of circulating lymphocytes • Non-proliferating T cells • Thymus doesn’t develop • Usually fatal early years of life • Infant will have viral and fungal infections • Bacterial don’t show up until later because of placental transfer of Abs from mother • Chronic diarrhea, pneumonia, lesions • Many genetic defects can contribute to SCID • Defects in common γ chain of IL-2 receptor.

19. Defects in B-cell function due to Isotype switching dose not occur Early B cell maturation blocked Terminal differentiation of B cell blocked T-cell to B-cell is defective

20. Defect in B cell development Progenitor Progenitor

21. Examples for humoral immunity defects.

23. Primary ImmunodeficiencesB cell Immunodeficiences • X-linked Agammaglobulinemia • B cell defect • Defect in kinase that keeps B cells in pre-B stage • Low levels of IgG and absence of other classes • Recurrent bacterial infections

24. Primary ImmunodeficiencesCombined Immunodeficiences • X-linked Hyper-IgM Syndrome • Deficiency of IgG, IgE, IgA but elevated levels of IgM • Defect in T cell surface marker CD40L • This is needed for interaction between TH and B cell for class switching for T-dependent antigens • T independent antigens are not effected therefore there is production of IgM

25. CD40 ligand B T h CD40 ligand Cytokines - IL-4, 5, 6

26. Primary ImmunodeficiencesB cell Immunodeficiences • Selective Deficiences of Immunoglobulin Classes • IgA deficiency is most common • Recurrent respiratory and urinary tract infections, intestinal problems • IgG deficiencies are rare • Can often be treated by administering immunoglobulin

27. Defect in phagocytic cells (Myeloid): • (phagocytes, neutrophils,) • Defects are significant because of their key role in innate and adaptive I.R. • affect both ability to kill microb ( Chronic granulomatous disease, Chediak-higashi syndrome ) interactions with other cell (Leukocyte adhesion defect 1)

28. Defect in phagocytic cells Progenitor Progenitor

29. : Defects of phagocytic cells

30. Chronic Granulomatous Disease (CGD) • Defect in enzymes and microcidal molecules (NADPH oxidase; failure to generate superoxide anion & other O2 radicals) • So the microorganisms will be ingested but not killed • Symptoms : recurrent infections with catalase- positive bacteria and fungi specially Staphylococcus aureus

31. Chediak- Higashi Syndrome • Normal levels of enzymes(digestive) • Defect in organelle membrane which inhibits normal fusion of lysosomes • Fail to destroy ingested microbes • Symptoms : Recurrent infection with bacteria (chemotactic and degranulation defects, absent NK activity)

32. Leukocyte Adhesion Defect 1 ( LAD-1) • Absence of CD 18 – common β chain of leukocyte integrin, and become un able to migrate • Symptoms : Recurrent and chronic infection , fail to form pus

33. Disorders of complement system Due to Classical pathway Both pathway Deficiencies in complement regulatory proteins

34. Defects of complement.

35. Defect in classical pathway • Deficiencies of the classical pathway C1q, C1r, C1s, C4, or C2 • Result in a propensity to develop immune complex diseases such as SLE because it required for the dissolution of immune complexes • Increasing the risk of immune complex diseases SLE and increased infections with pyogenic bacteria

36. Deficiencies in complement regulatory proteins • The most important deficiency of the complement system is C1 inhibitor which is responsible for dissociation of activated C1 by binding to C1r2 C1s2 • Deficiency result in Hereditary angioedema (HAE) • The low level of C1 inhibitor in the plasma leads to increased activation of pathways that release bradykinin, the chemical responsible for the increased vascular permeability, and the pain seen in individuals. • Patients have recurrent Episodes of swelling at mucosal surfaces

37. Secondary or Acquired Immunodeficiencies • Agent-induced immunodeficiency: e.g. infections including HIV • Metabolic disorders and trauma • Splenectomy • Drugs such as corticosteroids, cyclosporin A, radiation and chemotherapy • Aging

38. Human Immunodeficiency Virus • Is a member of genus retrovirus (RNA virus) belonging to Lentiviridae • Characterized by long incubation period and slow course of disease • HIV-1 (Common in US) and HIV-2 (in Africa) • AIDS patients have low CD4+ T cells • Virus prevalent in homosexual, i.v. drug users, transfusion, infants born to infected mothers (prenatally, during birth and lactationally) • Opportunistic infections with Candida albicans, Pnuemocystiscarinii, Mycobacterium avium, etc. • Patients with HIV have high incidence of cancers such as Kaposi sarcoma and lymphomas

39. Kaposi Sarcoma

40. HIV strains are:(T-tropic strains) because it infect T cell and the receptor called CXCR4.(M-tropic strains) with receptor called CCR5 functions for the monocyte or macrophage.

42. Pathogenesis of HIV Infection and AIDS • HIV disease begins with acute infection, which is only partly controlled by the host immune response, and advances to chronic progressive infection of peripheral lymphoid tissues . • The virus typically enters through mucosal epithelia. The subsequent events in the infection can be divided into several phases.

43. Acute phase characterized by infection of memory CD4+ T cells in mucosal lymphoid tissues and death of many infected cells. Because the mucosal tissues are the largest reservoir of T cells in the body and the major site of residence of memory T cells, this local loss is reflected in considerable depletion of lymphocytes. In fact, within 2 weeks of infection, a large fraction of CD4+ T cells may be destroyed.

44. The transition from the acute phase to the chronic phase of infection is accompanied by dissemination of the virus, viremia, and the development of host immune responses. • acute HIV syndrome includes a variety of nonspecific signs and symptoms typical of many viral infections.

45. Chronic Phase lymph nodes and the spleen are sites of continuous HIV replication and cell destruction. During this period of the disease, the immune system remains competent at handling most infections with opportunistic microbes, and few or no clinical manifestations of the HIV infection are present. Therefore, this phase of HIV disease is called the clinical latency period 

46. Early in the course of the disease, the individual may continue to make new CD4+ T cells, and therefore these cells can be replaced almost as quickly as they are destroyed. • Eventually, over a period of years, the continuous cycle of virus infection, T cell death, and new infection leads to a detectable loss of CD4+ T cells from the lymphoid tissues and the circulation.

49. Death Opportunistic infections <200CD4+ T cells/mm3

50. Mechanisms of Immune Evasion by HIV • HIV has an extremely high mutation rate and evade detection by antibodies or T cells generated in response to viral proteins. • HIV-infected cells may evade CTLs through down regulation of class I MHC molecule expression. • Other mechanisms of inhibiting cell mediated immunity these include a preferential inhibition of TH1 cytokines, activation of regulatory T cells, and suppression of dendritic cell functions.