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IMMUNODEFICIENCIES AIDS

IMMUNODEFICIENCIES AIDS. Primary or Congenital Immunodeficiency. Secondary Immunodeficiency:. Infection Renal failure, or protein losing enteropathy Leukaemia or Lymphoma Extremes of pediatric age: premature, small for date Certain Drug Therapies. Secondary immunodeficiencies.

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IMMUNODEFICIENCIES AIDS

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  1. IMMUNODEFICIENCIESAIDS

  2. Primary orCongenital Immunodeficiency

  3. Secondary Immunodeficiency: • Infection • Renal failure, or protein losing enteropathy • Leukaemia or Lymphoma • Extremes of pediatric age: premature, small for date • Certain Drug Therapies

  4. Secondary immunodeficiencies • Iradiation-induced, drugs (steroids, other cytotoxic drugs) • AIDS (HIV target cells and immune dysfunction [see Virology for other aspects of the viral infection]) • Nutritional deficiency (reduced proteins, calories, biotin, B12, Iron, Vit. A, Zinc; thymic atrophy pathologic result) • Autoimmune Disease ( frequent inflammatory diseases are found in immunodeficient patients) (5) Other (postviral, chronic infection, neoplastic diseases)

  5. Usually patients suffer from chronic infections of opportunistic pathogens High incidence of cancer

  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 frequency present and highly suspicious: • Chronic infection • Recurrent infection (more than expected) • Unusual microbial agents • Incomplete clearing of infection • Incomplete response to treatment

  8. 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

  9. Classification of Immunodeficiencies: • Antibody deficiencies • Cellular deficiencies • Phagocytic disorders • Complement deficiencies

  10. Signaling molecules in TCR ( T Cell Receptor) activation • Key transcriptional factors of immune cells • Molecules and organs for lymphocyte development • Antigen presentation • Phagocyte function • Cytokines and co-stimulation molecules • Immune cell migration and adhesion • Complement • DNA recombination and metabolism

  11. Laboratory tests to assess immune function (1) T cell: Enumeration (flow cytometry), functional assays (mitogen response, MLR, DTH skin tests) (2) B cell: Enumeration, circulating antibody levels (3) Macrophage: Enumeration, functional assays (nitrobluetetrazolium) (4) Complement: Direct measurement of complement components, complement hemolysis assay

  12. Primary B cell immunodeficiencies • (1) X-linked Agammaglobulinemia (Bruton's syndrome); btk deficiency • (2) Common Variable Immunodeficiency (acquired hypogammaglobulinemia) • (3) Selective IgA deficiency (most common immunodeficiency disorder) • (4) Other (minor): • (a) Transient hypogammaglobulinemia of infancy • (b) Selective deficiency of IgG subclasses • (c) Immunodeficiency with hyper IgM

  13. Primary T cell immunodeficiencies Congenital thymicaplasia (DiGeorge's Syndrome or Third and Fourth Pharyngeal Arch Syndrome)

  14. Combined B and T cell immunodeficiencies (symptoms, description of defect, current therapy) • Severe Combined Immunodeficiency (SCID; a group of genetically determined diseases) • X-Linked combined immunodeficiency (accounts for 50-60% of all SCID; defect in cytokine receptors) • Adenosine deaminase deficiency (an autosomal recessive SCID; accounts for ~20% of all SCID) • (c) Other mechanisms of SCIDs: Purine nucleoside phosphorylase deficiency, TCR immunodeficiency, MHC class I or II deficiency (Bare Lymphocyte Syndrome), Defective IL-2 production

  15. Primary phagocyte deficiencies • (1) Neutropenia • (2) Chronic Granulomatous Disease • (3) Leukocyte Adhesion Deficiency

  16. Primary complement deficiencies Deficiency of Complement Components (a) Classic pathway: C1, C4, C2, C3 (b) Alternative pathway: Factor D, Properdin (c) MAC: C5, C6, C7, C8, C9 (d) Regulator proteins: Factors H, I, C1 inhibitor (e) Hereditary Angioedema (C1INH deficiency)

  17. What is XLA? • X linked agammaglobulinemia=‘prototypical antibody deficiency’. • First immunodeficiency described. • Defect on the X chromosome • affecting the Btk gene. • Results in an absence or severe • reduction in B lymphocytes and • hence immunoglobulin of all types.

  18. Clinical Findings • Symptoms appear at 6-9 months of age (after loss of maternal Ig) . • Sites of infection: mucous membranes, ear (otitis media), lungs (bronchitis/pneumonia), blood (sepsis), gut (Giardia, or enterovirus), skin, eyes, meningitis. Also seen: joint problems, kidney problems, neutropenia, malignancy in older patients.

  19. Patients with XLA repeatedly acquire infections with extracellular pyogenic organisms such as: Pneumococus Hemophiluss streptococus

  20. Susceptibility to encapsulated Bacteria • H Influenzae • S pneumoniae

  21. Sinusitis Pneumonia Otitis Media

  22. IgA Deficiency • Clinical feature: Recurrent sinopulmounary 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.

  23. 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.

  24. CVID ( commonvariableimmunodeficiency) abnormalities • CVID is a heterogenous group of disorders with intrinsic B-cell defect or a B-cell dysfunction related to abnormal T-cell B-cell interaction. • Lack of inducible costimulator (ICOS) expression by activated T cell which associated with lack of T cell help for B cell differentiation, class switching and memory B-cell generation. • In 10-20% of families another member may have selective IgA def.

  25. DiGeorge Syndrome • Defective development in thymus and parathyroid that develop from third and fourth Pharyngeal pouch • Thymic hypoplasia leading to variable immunodeficiency. Other features: • Characteristic faces • Deletion in 22q11 in > 80% • Abnormal calcium homeostasis

  26. Molecular mechanisms for constitutional chromosomal rearrangements in humans VCFS: CP, velopharyngeal insufficiency, small mouth, retrognathia, bulbous nasal tip, microcephaly, concotruncal heart defects, MR, learning disabilities, short stature, DGS: parathyroid hypoplasia, thymic hypoplasia and immune defect due to T cell deficit

  27. DiGeorge Syndrome ( T deficiency)

  28. Combined Immunodeficiencies: • Combined immunodeficiency (CID) • Severe combined immunodeficiency (SCID) • Omenn syndrome • ADA (Adenosine Deaminase Deficiency) • Ataxia-Telangiectasia syndrome (AT) • Wiskott -Aldrich syndrome (WAS)

  29. Common Features of Severe Combined Immunodeficiency (SCID) • Failure to thrive • Onset of infections in the neonatal period • Opportunistic infections • Chronic or recurrent thrush • Chronic rashes • Chronic or recurrent diarrhea • Paucity of lymphoid tissue

  30. WISKOTT-ALDRICH Syndrome • X-linked • Eczema ,thrombocytopenia ,bacterial infection (polysaccharide antigen) • Defective gene encode a cytoplasmic protein expressed in BM derived cells interact with adaptor molecule(Grb2)& G proteins regulate actin cytoskeleton. • Cell surface glycoproteins reduced ;CD43 • (or sialophorin) normally on Lymph .neut . Mac and Platelet • These alterations interfere with migration of Leuk. to inflammation sites.

  31. ATAXIA-TELANGIECTASIA • Autosomal recessive • Abnormal gait (ataxia) • Vascular malformations (telangiectasia), neurologic defects, tumors and ID • ID may affect T&B cells • IgA and IgG2 deficiency. • T cell function is variably depressed. • Gene responsible on chromosome 11 • Gene product may play a role in DNA repair

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

  33. Acquired Immunodeficiency can be caused by :

  34. Human Immunodeficiency Virus (HIV)

  35. Introduction • Etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). • Discovered independently by Luc Montagnier of France and Robert Gallo of the US in 1983-84. • Former names of the virus include: • Human T cell lymphotrophic virus (HTLV-III) • Lymphadenopathy associated virus (LAV) • AIDS associated retrovirus (ARV)

  36. Figure 9-13 Human Immunodeficiency Virus

  37. Figure 9-14

  38. Progression of AIDS • Infection • viremia (increase of the virus load in blood) • immune response to HIV: generation of Tc cells and antibody to HIV (seroconversion) • temporary reduction of virus-infected CD4 T cells (due to HIV-induced apoptosis and T cell attack) • partial recovery of CD4 T cell number • gradual decrease of CD4 T cell number over 2-15 years (clinical latency is a period of active infection and CD4 T cell renewal) • AIDS (CD4 T cell count < 200)

  39. Acquired Immune deficiency syndrome • HIV infection through the host CD4 molecule and chemokine receptors (CCR5 or CXCR4) • T cell activation is required for viral replication • Initial viremia and CD4 T cell number decrease (asymptomatic or mild flu-like) • Anti-HIV response and CD4 T cell number recovery • Long clinical latency (2- 15 yrs): a period of active viral infection and CD4 T cell renewal; gradual CD4 T cell number decrease • Immunodeficiency starts when the CD4 count is below 500  Opportunistic infection • Death due to secondary infection

  40. Gradual loss of CD4 T cells after infection • There are long-term non-progressors; some remain seronegative • Some people have mutant CCR5 thus can be resistant to HIV

  41. Primary HIV Syndrome • Mononucleosis-like, cold or flu-like symptoms may occur 6 to 12 weeks after infection. • lymphadenopathy • fever • rash • headache • Fatigue • diarrhea • sore throat • neurologic manifestations. • no symptoms may be present

  42. Primary HIV Syndrome • Symptoms are relatively nonspecific. • HIV antibody test often negative but becomes positive within 3 to 6 months, this process is known as seroconversion. • Large amount of HIV in the peripheral blood. • Primary HIV can be diagnosed using viral load titer assay or other tests. • Primary HIV syndrome resolves itself and HIV infected person remains asymptomatic for a prolonged period of time, often years.

  43. Clinical Latency Period • HIV continues to reproduce, CD4 count gradually declines from its normal value of 500-1200. • Once CD4 count drops below 500, HIV infected person at risk for opportunistic infections. • The following diseases are predictive of the progression to AIDS: • persistent herpes-zoster infection (shingles) • oral candidiasis (thrush) • oral hairy leukoplakia • Kaposi’s sarcoma (KS)

  44. AIDS • CD4 count drops below 200 person is considered to have advanced HIV disease • If preventative medications not started the HIV infected person is now at risk for: • Pneumocystis carinii pneumonia (PCP) • cryptococcal meningitis • toxoplasmosis • If CD4 count drops below 50: • Mycobacterium avium • Cytomegalovirus infections • lymphoma • dementia • Most deaths occur with CD4 counts below 50.

  45. Figure 9-22 Opportunistic infections and malignancies kill HIV patients

  46. Other Opportunistic Infections • Respiratory system • Pneumocystis Carinii Pneumonia (PCP) • Tuberculosis (TB) • Kaposi's Sarcoma (KS) • Gastro-intestinal system • Cryptosporidiosis • Candida • Cytomegolavirus (CMV) • Isosporiasis • Kaposi's Sarcoma • Central/peripheral Nervous system • Cytomegolavirus • Toxoplasmosis • Cryptococcosis • Non Hodgkin's lymphoma • Varicella Zoster • Herpes simplex • Skin • Herpes simple • Kaposi's sarcoma • Varicella Zoster

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