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FAILURE OF HUMAN DEFENSE MECHANISMS

FAILURE OF HUMAN DEFENSE MECHANISMS. FAILURE OF HUMAN DEFENSE MECHANISMS. Mechanisms of Failure Evasion and subversion of the immune system by pathogens Immunodeficiencies Inherited (Primary) Acquired (Secondary) Malnutrition Drugs Radiation Pathogens.

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FAILURE OF HUMAN DEFENSE MECHANISMS

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  1. FAILURE OF HUMAN DEFENSE MECHANISMS

  2. FAILURE OF HUMAN DEFENSE MECHANISMS • Mechanisms of Failure • Evasion and subversion of the immune system by pathogens • Immunodeficiencies • Inherited (Primary) • Acquired (Secondary) • Malnutrition • Drugs • Radiation • Pathogens

  3. MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS • Genetic variation (antigenic differences) • Numerous different surface antigens (serotypes / serovars) without modification • Streptococcus pneumoniae • 90 serotypes (capsular polysaccharides) • Salmonella species • 2,500 serotypes (cell wall polysaccharides) • Rhinoviruses • 100 serotypes (capsid proteins) • Poliovirus • 3 serotypes (capsid proteins)

  4. MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS • Genetic variation (antigenic differences) • Few different surface antigens with frequent modification • Influenza viruses • Classification into “types” on nucleoprotein • A, B and C • Classification of Influenza A virus into “subtypes • Hemagglutinin (HA or H) • Avian (16) and Human (3) • Neuramindase (NA or N) • Avian (9) and Human (2) • Influenza A subtypes (H3N2, H1N1, H5N1)

  5. MECHANISMS OF GENETIC CHANGE IN INFLUENZA A VIRUS • Antigenic Drift • Point mutations in HA and NA genes • No proofreading of replication • Minor antigenic change resulting in new “strains” • Antigenic Shift • Re-assortment of gene segments from avian and human viruses in same host (swine or humans) • Major antigenic change resulting in new “subtype” of Influenza A virus

  6. MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS • Establishment of a dormant state (latency) with reactivation • Blocking of antigen processing and presentation • MHC I degradation • Interference with proteasome • Interference with TAP • Interference with Tapasin • Retention of MHC 1 in ER • Interference with NKG2A receptor • Inhibition of humoral immunity

  7. MECHANISMS OF EVASION AND SUBVERSION BY PATHOGENS • Characteristic of the Herpesviruses • Herpes simplex virus, type 1 (HSV-1) • Herpes simplex virus, type 2 (HSV-2) • Varicella-Zoster virus (VZV) • Epstein-Barr virus (EBV) • Cytomegalovirus (CMV) • Human herpesvirus 6 (HHV-6) • Human herpesvirus 7 (HHV-7) • Human herpesvirus 8 (HHV-8)

  8. HUMAN HERPES VIRUS 8 (HHV-8) • One of seven oncogenic viruses • History of stealing human genes • IL-6, BCL-2, cyclin D • Etiologic agent • Kaposi’s sarcoma • Multicentric Castleman’s Disease • Non-malignant tumor in lymph nodes • Hyperproliferation of B cells

  9. HUMAN HERPES VIRUS 8 (HHV-8) • Target cell for latency • B lymphocyte • Mechanism of latency (genes and proteins) • Cyclin D • LANA (latency associated nuclear antigen) • K 13 • Blocks Fas apotosis pathway • Target cell for Kaposi’s sarcoma • Spindle cell

  10. MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM • Production of exotoxins (superantigens) • Staphylococcus aureus • Streptococcus pyogenes • Staphylococcus aureus superantigens • Toxic shock syndrome toxin-1 (TSST-1) • 75% of cases (99% M and 40% NM) • Staphylococcal enterotoxin B (SEB) • 20% of cases • Staphylococcal enterotoxin C (SEC)

  11. MECHANISMS OF SUBVERSION OF THE IMMUNE SYSTEM Streptococcus pyogenes superantigens Streptococcus pyrogenic exotoxins A, B and C Exotoxins produced primarily from M types 1 and 3 Mechanism of action Activation of 5 to 30% of T cells Cytokine storm

  12. TOXIC SHOCK SYNDROME (TSS) • Staphylococcal TSS • First reported in 1978 followed by outbreak in 1980 • Clinical manifestations (acute onset) • Fever (>102 F), chills, headache • Hypotension (<90 mmHg) • Diffuse macular erythroderma rash • Myalgias • Nausea, vomiting and diarrhea • Cutaneous desquamation (palms and soles)

  13. IMMUNODEFICIENCY DISEASES • A group of diseases where one or more components of the immune system are either absent or defective • Classification • Primary (Inherited) • Gene defects may be autosomal or X-linked • Secondary (Acquired) • Malnutrition, diseases, drugs, radiation, microorganisms

  14. COMPONENTS OF THE IMMUNE SYSTEM AND CLINICAL PRESENTATION IN IMMUNODEFICIENCY DISEASES Humoral Persons with history of recurrent infections with encapsulated bacteria Streptococcus pneumoniae Haemophilus influenzae Cellular (Cell mediated) Persons with history of recurrent infections with opportunistic pathogens Pneumocystis jiroveci (carinii)

  15. EVALUATION OF PATIENTS WITH IMMUNODEFICIENCY DISEASES • Humoral • Measure antibody levels by nephelometry • IgM • IgG + subclasses • IgA + subclasses • Measure absolute number and percent of B cells by flow cytometry • Cellular • Measure absolute numbers and percentages of T lymphocytes by flow cytometry

  16. PRIMARY IMMUNODEFICIENCY DISEASES • WHO currently recognizes 100 primary immunodeficiency diseases • < 20 account for >90% of all cases • General Classification • Primarily humoral deficiency • Primarily cellular deficiency • Combined humoral and cellular deficiency • Phagocyte dysfunction or deficiency • Complement deficiency • MHC deficiency

  17. PRIMARY IMMUNODEFICIENCY DISEASES Prevalence of primary immunodeficiency diseases B cell (50 to 60%) T cell (5 to 10%) B and T cells (20%) Phagocytes (10 to 15%) Complement (2%) NK (< 0.1%)

  18. PRIMARY IMMUNODEFICIENCY DISEASES Most common primary immunodeficiency diseases B cell Selective IgA deficiency T cell DiGeorge syndrome ZAP-70 deficiency B and T cells SCID Phagocytes Chronic granulomatous disease Complement Immune complex disease NK Viral infections and tumors

  19. PRIMARY IMMUNODEFICIENCY DISEASES • Gene defects • Autosomal recessive or dominant • X-linked • Examples • CVID (autosomal dominant) • Selective IgA (autosomal dominant) • Hyper-IgM (autosomal recessive or X-linked) • Classic complement (autosomal recessive) • First PID described in 1952 • Bruton’s X-linked agammaglobulinemia

  20. CASE STUDY – 13 YEAR OLD MALE • Bone marrow transplantation (BMT) for SCID • BM from sister was unmatched • 3 months later developed • Fever • Nausea, vomiting and diarrhea • Abdominal pain • Intestinal bleeding • Autopsy revealed • Hundreds of intraabdominal malignant tumors

  21. CASE STUDY – DAVID P. VETTER • Parents – David J and Carol Ann • Children • Katherine (1968) • David J III (1970) • Died of SCID at 7 months • Advised of risk of another male child • David P born on September 21, 1971 • Unmatched BMT on 12/21/83 • Died of SCID on 2/22/84

  22. SELECTIVE IgA DEFICIENCY • Most common and mildest of PI • Prevalence • 1 in 700 caucasians • 1 in 18,000 Japanese • Majority of patients are asymptomatic • Clinical presentation • Recurrent sinopulmonary and GI disease, allergy, autoimmunity

  23. SELECTIVE IgA DEFICIENCY • Incidence of allergy and asthma is increased • Food allergy • Asthma may be more severe • Allergic rhinitis • Incidence of autoimmune disease is increased • Rheumatoid arthritis (RA) • Systemic lupus erythematosus (SLE) • Mechanism is unclear • 30% of patients have Anti-IgA (IgG > IgM > IgE)

  24. SELECTIVE IgA DEFICIENCY • IgA deficiency significant risk factor for • Anaphylactic transfusion reactions • Mechanism is unclear • Classic anaphylaxis involves IgE • Anti-IgA, IgG most prevalent • Definition • Deficiency (< 7 mg/dL) • Severe deficiency (<0.05 mg/dL)

  25. SELECTIVE IgG DEFICIENCY • Selective IgG subclass deficiency • IgG2 in children • IgG3 in adults • Combined deficiency relatively common • IgG2 with IgA • IgG1 and IgG3 • IgG2 and IgG4 • Clinical presentation • Recurrent upper and lower respiratory tract infections

  26. SELECTIVE IgG DEFICIENCY – CASE STUDY • 9 year old male presented to family physician by his mother for evaluation of short stature and recurrent infections • Past medical history • Recurrent URI and LRI with • Streptococcus pneumoniae, Haemophilus influenzae, Influenza virus, Respiratory Syncytial Virus, Parainfluenza virus • 2 to 3 each year since age 1 • Recurrent diarrhea since age 4

  27. SELECTIVE IgG DEFICIENCY – CASE STUDY • Laboratory results for total serum antibodies • IgG of 6.0 gm/L (5.4 to 16.1 gm/L) • IgA of 0.9 gm/L (0.7 to 2.5 gm/L) • IgM of 0.6 gm/L (0.5 to 1.8 gm/L) • Laboratory results for IgG subclasses • IgG1 of 4.6 gm/L (3.6 to 7.3 gm/L) • IgG2 of 0.1 gm/L (1.4 to 4.5 gm/L) • IgG3 of 0.5 gm/L (0.3 to 1.1 gm/L) • IgG4 of 0.2 gm/L (0.1 to 1.0 gm/L)

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