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Diseases of the Immune System

NCS lecture of Diseases of the Immune System given August 3, 2011 at AUF SOM, Pathology

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Diseases of the Immune System

  1. 1. IMMUNE DISORDERS Noel C. Santos, M.D.
  2. 2. YOUR ACTIVE IMMUNE DEFENSES Innate Immunity - invariant (generalized) - early, limited specificity - the first line of defense Adaptive Immunity - variable (custom) - later, highly specific - ‘‘remembers’’ infection   1. Barriers - skin, tears 2. Phagocytes - neutrophils, macrophages 3. NK & M ast cells 4. Complement and other proteins <ul><li>APCs present Ag to T cells </li></ul>2. Activated T cells provide help to B cells & kill abN/ infected cells 3. B cells - produce Ab specific for Ag
  3. 3. Immunologic Deficiency Syndromes <ul><li>Primary - genetically determined </li></ul><ul><li>Secondary - infections, malnutrition, aging, iatrogenic, autoimmune </li></ul><ul><li>Humoral </li></ul><ul><li>Cellular </li></ul>
  4. 4. <ul><li>- genetically determined </li></ul><ul><li>- specific immunity (humoral and cellular, T and B cells) </li></ul><ul><li>- nonspecific (complements, phagocytes, NK cells) </li></ul><ul><li>- 6 months to 2 years of life </li></ul><ul><li>- susceptibility to recurrent infections </li></ul>Primary Immunodeficiencies
  5. 5. Primary Immunodeficiencies <ul><li>- X-linked Agammaglobulinemia of Bruton </li></ul><ul><li>- Isolated IgA Deficiency </li></ul><ul><li>- Common Variable Immunodeficiency </li></ul><ul><li>- Hyper IgM Syndrome </li></ul><ul><li>- Thymic Hypoplasia (DiGeorge Syndrome) </li></ul><ul><li>- Severe Combined Immunodeficiency Diseases </li></ul><ul><li>- Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome) </li></ul><ul><li>- Genetic Deficiencies of the Complement System </li></ul>
  6. 6. Secondary Immunodeficiencies <ul><li>- underlying cause: infections, malnutrition, aging, drugs, etc. </li></ul><ul><li>- Acquired Immunodeficiency Syndrome (AIDS) </li></ul>
  7. 7. X-linked Agammaglobulinemia (Bruton’s Disease) <ul><li>failure of B-cell precursors to differentiate </li></ul><ul><li>normally, heavy-chain rearranged first then the light-chain </li></ul><ul><li>maturation stops after heavy-chain rearrangement </li></ul><ul><li>no light chain produced no complete immunoglobulin </li></ul><ul><li>mutations in cytoplasmic tyrosine kinase (Bruton tyrosine kinase - btk) - signal transduction that drive maturation </li></ul><ul><li>long arm of the X chromosome </li></ul>
  8. 8. X-linked Agammaglobulinemia (Bruton’s Disease) <ul><li>males, 6 months of age </li></ul><ul><li>recurrent (bacterial) respiratory tract infections, viral infections, Giardiasis, arthritis </li></ul><ul><li>T-cell mediated immunity appears intact </li></ul><ul><li>absent to markedly decreased circulatory B-cells </li></ul><ul><li>underdeveloped or rudimentary germinal centers </li></ul><ul><li>absence of plasma cells </li></ul><ul><li>increased frequency in autoimmune diseases </li></ul>
  9. 9. Isolated IgA Deficiency <ul><li>low levels of both serum and secretory IgA </li></ul><ul><li>familial or acquired </li></ul><ul><li>most are asymptomatic </li></ul><ul><li>symptomatic: respiratory and gastrointestinal </li></ul><ul><li>respiratory allergy and autoimmune diseases </li></ul><ul><li>defective differentiation of IgA B lymphocytes to become plasma cells </li></ul><ul><li>antibodies to IgA (?) </li></ul>
  10. 10. Common Variable (Ig) Immunodeficiency <ul><li>heterogeneous group of disorders </li></ul><ul><li>hypogammaglobulinemia - all classes, sometimes only IgG </li></ul><ul><li>diagnosed by exclusion </li></ul><ul><li>sporadic or inherited </li></ul><ul><li>high incidence of selective IgA deficiency among relatives </li></ul><ul><li>normal or near normal B-cells, not able to differentiate into plasma cells </li></ul><ul><li>defects in T-cell to send maturational and activation signals to B-cells </li></ul><ul><li>defects in both cells </li></ul>
  11. 11. <ul><li>both sexes with respiratory tract infections, herpes, etc. </li></ul><ul><li>later onset (children or adolescence) </li></ul><ul><li>hyperplastic germinal centers - defective immunoregulation </li></ul><ul><li>able to respond, proliferate, no Ig production and thus no negative feedback </li></ul><ul><li>autoimmune, lymphoid malignancy, gastric CA </li></ul>Common Variable (Ig) Immunodeficiency
  12. 12. Hyper IgM Syndrome <ul><li>able to make IgM but not IgG, IgA, and IgE </li></ul><ul><li>defective T-cells that fail to induce B-cells to make isotypes of antibodies other than IgM </li></ul><ul><li>mutations that prevent T-cell and B-cell interaction for isotype switching </li></ul><ul><li>x-linked: males, pyogenic infections, P. carinii </li></ul><ul><li>normal or elevated IgM and IgD but no IgA and IgE and extremely low IgG </li></ul><ul><li>normal T and B cells </li></ul><ul><li>autoimmune: hemolytic anemia, thrombocytopenia and neutropenia </li></ul><ul><li>uncontrolled IgM-producing plasma cells </li></ul>
  13. 13. Thymic Hypoplasia (DiGeorge Syndrome) <ul><li>partial or total; deletion of genes </li></ul><ul><li>T-cell deficiency due to failure of development of the third and fourth pharyngeal pouches </li></ul><ul><li>variable loss of T cell-mediated immunity, tetany, congenital defects in heart/great vessels </li></ul><ul><li>abnormal physical appearance </li></ul><ul><li>low levels of T-cells </li></ul><ul><li>poor defense against viral and fungal infections </li></ul>
  14. 14. Severe Combined Immunodeficiency Diseases <ul><li>constellation of genetically distinct syndromes </li></ul><ul><li>variable defects in BOTH humoral and cell-mediated immnue responses </li></ul><ul><li>extremely susceptible </li></ul><ul><li>death within one year w/o BM transplantation </li></ul><ul><li>defect in common lymphoid stem cell (classic) </li></ul><ul><li>defective T cell with secondary humoral defects </li></ul><ul><li>x-linked: most commo, mutation in gamma chain subunit of cytokine receptors, failed stimulation with functional deficieincy </li></ul><ul><li>autosomal recessive: adenosine deaminase deficiency with accumulation of deoxyadempsome & derivatives which are toxic to immature lymphocytes </li></ul>
  15. 15. Severe Combined Immunodeficiency Diseases <ul><li>small thymus devoid of lymphoid cells </li></ul><ul><li>remnants of Hassall corpuscles </li></ul><ul><li>lobules of undifferentiated epithelial cells resembling fetal thymus </li></ul><ul><li>hypoplastic lymphoid tissues </li></ul><ul><li>BM transplant </li></ul>
  16. 16. Wiskott-Aldrich Syndrome <ul><li>x-linked; thrombocytopenia, eczema and recurrent infections </li></ul><ul><li>normal thymus with secondary depletion of T-lymphocytes </li></ul><ul><li>variable loss of cell-meidated immunity </li></ul><ul><li>no antibodies against polysaccharides </li></ul><ul><li>poor antibody response against proteins </li></ul><ul><li>prone to develop lymphomas </li></ul><ul><li>defective gene: protein involved in the integrity of cytoskeleton and signal transduction </li></ul><ul><li>BM transplantation </li></ul>
  17. 17. Complement Deficiencies <ul><li>most common - C2 (classic pathway) </li></ul><ul><li>increased susceptibility to infections </li></ul><ul><li>increased incidence of SLE-like disease </li></ul><ul><li>complexes are not cleared by MPS - deposited in tissues </li></ul><ul><li>deficient C3 (both pathways) - rare but serious </li></ul>
  18. 18. Acquired Immunodeficiency Syndrome (AIDS) <ul><li>retroviral disease </li></ul><ul><li>profound immunosuppression </li></ul><ul><li>opportunistic infectioons, secondary neoplasms, neurologic manifestations </li></ul><ul><li>Groups: </li></ul><ul><ul><li>homosexual or bisexual men </li></ul></ul><ul><ul><li>intravenous drug users </li></ul></ul><ul><ul><li>hemophiliacs and recipients of blood and its components </li></ul></ul><ul><ul><li>heterosexual contacts </li></ul></ul><ul><ul><li>newborns of infected mothers </li></ul></ul><ul><ul><li>no identifiable risk factors </li></ul></ul>
  19. 19. Acquired Immunodeficiency Syndrome (AIDS) <ul><li>sexual transmission </li></ul><ul><li>parenteral transmission </li></ul><ul><li>vertical transmission </li></ul><ul><li>Human Retrovirus (Lentivirus): Human Immunodeficiency Virus </li></ul><ul><li>HIV-1: U.S., Europe, and Central Africa </li></ul><ul><li>HIV-2: West Africa </li></ul>
  20. 20. <ul><li>Virus core: p24, nucleocapsid protein p7/p9, genomic RNA, viral enzymes (protease, reverese transcriptase and integrase) </li></ul><ul><li>Viral tropism - CD4+ cells </li></ul><ul><li>Neurologic - viral products and soluble factors produced by macrophages </li></ul>Acquried Immunodeficiency Syndrome (AIDS)
  21. 21. Acquired Immunodeficiency Syndrome (AIDS) <ul><li>Natural History </li></ul><ul><li>Phases: </li></ul><ul><ul><li>Early Acute (Group I: Acute Infection) </li></ul></ul><ul><ul><li>Middle, Chronic (Groups II: Asymptomatic Infection; Group III: Persistent Generalized Lymphadenopathy) </li></ul></ul><ul><ul><li>Final, Crisis (Groups IV: A - Constitutional disease; B Neurologic disease; C: Secondary infection; D: Secondary neoplasm; E: Other conditions </li></ul></ul>
  22. 22. Hypersensitivity Reactions <ul><li>- reactions that can be damaging to tissues </li></ul><ul><li>- exogenous antigens: dust, pollens, foods, drugs, microbiologic agents, chemicals, blood products </li></ul><ul><li>- endogenous antigens: homologous, autologous </li></ul><ul><li>- response: trivial to lethal </li></ul><ul><li>- classified based on immunologic mechanism that mediate the disease </li></ul>
  23. 23. <ul><li>Immune System Disorders </li></ul><ul><li>Hypersensitivity : An abnormal response to antigens. </li></ul><ul><li>Four Types of Hypersensitivity Reactions: </li></ul><ul><li>Type I (Anaphylactic) Reactions </li></ul><ul><li>Type II (Cytotoxic) Reactions </li></ul><ul><li>Type III (Immune Complex) Reactions </li></ul><ul><li>Type IV (Cell-Mediated) Reactions </li></ul>
  24. 24. <ul><li>Type I (Anaphylactic) Reactions </li></ul><ul><ul><li>Occur within minutes of exposure to antigen </li></ul></ul><ul><ul><li>Antigens combine with IgE antibodies </li></ul></ul><ul><ul><li>IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators: </li></ul></ul><ul><ul><ul><li>Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). </li></ul></ul></ul><ul><ul><ul><li>Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. </li></ul></ul></ul><ul><ul><ul><li>Leukotrienes: Bronchial spasms. </li></ul></ul></ul><ul><ul><li>Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes. </li></ul></ul>
  25. 25. Mast Cells and the Allergic Response
  26. 26. Mast Cells and the Allergic Response
  27. 27. <ul><li>Type II (Cytotoxic) Reactions </li></ul><ul><ul><li>Involve activation of complement by IgG or IgM binding to an antigenic cell. </li></ul></ul><ul><ul><li>Antigenic cell is lysed. </li></ul></ul><ul><ul><li>Transfusion reactions: </li></ul></ul><ul><ul><ul><li>ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. </li></ul></ul></ul><ul><ul><ul><li>Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells. </li></ul></ul></ul><ul><ul><ul><ul><li>Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta. </li></ul></ul></ul></ul>
  28. 28. <ul><li>Type III (Immune Complex) Reactions </li></ul><ul><ul><li>Involve reactions against soluble antigens circulating in serum. </li></ul></ul><ul><ul><li>Usually involve IgA antibodies. </li></ul></ul><ul><ul><li>Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. </li></ul></ul><ul><ul><ul><li>Glomerulonephritis: Inflammatory kidney damage. </li></ul></ul></ul><ul><ul><li>Occurs with slightly high antigen-antibody ratio is present. </li></ul></ul>
  29. 29. Immune Complex Mediated Hypersensitivity
  30. 30. <ul><li>Type IV (Cell-Mediated) Reactions </li></ul><ul><ul><li>Involve reactions by T D memory cells. </li></ul></ul><ul><ul><ul><li>First contact sensitizes person. </li></ul></ul></ul><ul><ul><ul><li>Subsequent contacts elicit a reaction. </li></ul></ul></ul><ul><ul><li>Reactions are delayed by one or more days (delayed type hypersensitivity). </li></ul></ul><ul><ul><ul><li>Delay is due to migration of macrophages and T cells to site of foreign antigens. </li></ul></ul></ul><ul><ul><li>Reactions are frequently displayed on the skin: itching, redness, swelling, pain. </li></ul></ul><ul><ul><ul><ul><li>Tuberculosis skin test </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Poison ivy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Metals </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Latex in gloves and condoms (3% of health care workers) </li></ul></ul></ul></ul><ul><ul><li>Anaphylactic shock may occur. </li></ul></ul>
  31. 31. Allergic Contact Dermatitis Response to Poison Ivy Hapten
  32. 32. Autoimmune Diseases <ul><li>Against self-antigens </li></ul><ul><li>Pathologic </li></ul><ul><ul><li>Presence of autoimmune reaction </li></ul></ul><ul><ul><li>The reaction is not secondary to tissue damage </li></ul></ul><ul><ul><li>Absence of another well-defined cause </li></ul></ul><ul><li>Tissue injury caused by T-cells &/or antibodies against self Ag’s </li></ul>
  33. 33. <ul><li>Spectrum: </li></ul><ul><ul><li>directed against a single organ: ORGAN-SPECIFIC DISEASE </li></ul></ul><ul><ul><li>widespread Ag’s: GENERALIZED or SYSTEMIC DISEASE </li></ul></ul><ul><ul><ul><li>Type I DM </li></ul></ul></ul><ul><ul><ul><li>Multiple Sclerosis </li></ul></ul></ul><ul><ul><ul><li>SLE </li></ul></ul></ul><ul><ul><ul><li>Goodpasture syndrome </li></ul></ul></ul>
  34. 34. Autoimmune Disease <ul><li>Loss of self-tolerance </li></ul><ul><ul><li>How? </li></ul></ul><ul><ul><li>Immunologic Tolerance </li></ul></ul><ul><ul><ul><li>State in which the individual is incapable of developing an immune response to a specific antigen </li></ul></ul></ul><ul><ul><li>Self Tolerance </li></ul></ul><ul><ul><ul><li>Lack of responsiveness to an individual’s own antigens </li></ul></ul></ul><ul><ul><ul><li>Two Groups </li></ul></ul></ul><ul><ul><ul><ul><li>Central Tolerance </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Peripheral Tolerance </li></ul></ul></ul></ul>
  35. 35. Normally <ul><ul><li>Central Tolerance – death/deletion of self-reactive T- and B- lymphocyte clones during maturation in the central lymphoid organs </li></ul></ul><ul><ul><li>CLONAL DELETION </li></ul></ul>
  36. 36. <ul><ul><li>Peripheral Tolerance – escaped deletion will be deleted/muzzled in the peripheral tissues (“back-ups”) </li></ul></ul><ul><ul><ul><ul><li>ANERGY: prolonged, irreversible functional inactivation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>SUPPRESSION OF REGULATORY T-cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CLONAL DELETION by ACTIVATION-INDUCED CELL DEATH: receive signals for apoptosis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>ANTIGEN SEQUESTRATION: immune-privileged sites </li></ul></ul></ul></ul>
  37. 38. Mechanisms of Autoimmune Diseases <ul><li>Role of Susceptibility Genes </li></ul><ul><ul><li>Strong genetic predisposition: HLA genes </li></ul></ul><ul><li>Role of Infections </li></ul><ul><ul><li>Associated with infections </li></ul></ul><ul><ul><li>Clinical flare-ups </li></ul></ul><ul><ul><ul><li>Up-regulate the expression of costimulators on antigen-presenting cells </li></ul></ul></ul><ul><ul><ul><li>Breakdown of clonal anergy </li></ul></ul></ul><ul><ul><ul><li>Activation of specific T-cells </li></ul></ul></ul>
  38. 39. <ul><li>Role of Infections ….. </li></ul><ul><ul><li>Molecular mimicry: microbial Ag causes activation of self-reactive lymphocytes </li></ul></ul><ul><ul><li>Induce other abnormalities that promote autoimmune reactions </li></ul></ul><ul><ul><ul><li>Release of self-antigens </li></ul></ul></ul><ul><ul><ul><li>Structural alteration of self-antigens </li></ul></ul></ul><ul><ul><ul><li>Production of cytokines and recruit self-reactive T-cells </li></ul></ul></ul>
  39. 40. Autoimmune Diseases Organ-Specific: Hashimoto thyroiditis Autoimmune hemolytic anemia Rheumatoid arthritis Autoimmune atrophic gastritis (pernicious anemia) Multiple sclerosis Reiter syndrome Autoimmune orchitis Inflammatory myopathies* Goodpasture syndrome Autoimmune thrombocytopenia Polyarteritis nodosa* Insulin-dependent diabetes mellitus Myasthenia gravis Graves disease Primary biliary cirrhosis* Systemic: Systemic lupus erythematosus Systemic sclerosis (scleroderma)* Sjögren syndrome Autoimmune (chronic active) hepatitis* Ulcerative colitis*
  40. 41. SYSTEMIC LUPUS ERYTHEMATOSUS <ul><li>Autoantibodies: antinuclear, against blood elements, anti-phospholipid </li></ul><ul><ul><li>Anti-double stranded DNA </li></ul></ul><ul><ul><li>Anti-Smith antigen </li></ul></ul><ul><li>Immunofluorescerence </li></ul><ul><ul><li>Homogeneous </li></ul></ul><ul><ul><li>Peripheral </li></ul></ul><ul><ul><li>Speckled </li></ul></ul><ul><ul><li>Nucleolar </li></ul></ul>
  41. 42. centromere homogenous speckled nucleolar rim
  42. 43. Etiology and Pathogenesis <ul><li>Genetic predisposition </li></ul><ul><li>Exogenous factors </li></ul><ul><ul><li>Drugs </li></ul></ul><ul><ul><li>UV irradiation </li></ul></ul><ul><ul><li>Virus infection </li></ul></ul><ul><ul><li>Estrogens </li></ul></ul><ul><li>Basic Defect in Maintence of Self-tolerance </li></ul><ul><li>Activation of B cells </li></ul><ul><ul><li>Heritable defects in the regulation of B-cell proliferation </li></ul></ul><ul><ul><li>Helper T-cell hyperactivity </li></ul></ul><ul><ul><li>Defects in suppressor T-cell function </li></ul></ul>
  43. 44. Clinical and Pathologic Manifestations of SLE Clin Mfnx Prevalence in Pts (%) Hematologic 100 Arthritis 90 Skin 85 Fever 83 Fatigue 81 Weight loss 63 Renal 50 CNS 50 Pleuritis 46 Myalgia 33 Pericarditis 25 Gastrointestinal 21 Raynaud phenomenon 20 Ocular 15 Peripheral neuropathy 14
  44. 45. Morphology <ul><li>Acute necrotizing vasculitis with fibrinoid deposits involving small arteries and arterioles </li></ul><ul><li>Deposits of Ig, DNA, and C3 </li></ul><ul><li>KIDNEYS – lupus nephritis </li></ul><ul><ul><li>Class I: Normal </li></ul></ul><ul><ul><li>Class II: Mesangial lupus GN </li></ul></ul><ul><ul><li>Class III: Focal Proliferative GN </li></ul></ul><ul><ul><li>Class IV: Diffuse Proliferative GN </li></ul></ul><ul><ul><li>Class V: Membranous GN </li></ul></ul><ul><li>Skin, Joints, CNS, Serous membranes, Heart, spleen, lungs </li></ul>
  45. 46. Pericarditis and valvular deposits (Libman-Sacks)
  46. 47. Organ Specific Autoimmune Diseases <ul><li>Hashimoto’s </li></ul><ul><li>Sjogren’s syndrome </li></ul><ul><li>Systemic Sclerosis (Scleroderma) </li></ul><ul><li>Inflammatory Myositis: dermatomyositis, polymyositis, inclusion body myositis </li></ul><ul><li>Polyarteritis nodosa </li></ul>
  47. 48. <ul><li>Goodpastures Syndrome: lungs and kidneys </li></ul><ul><li>Graves Disease </li></ul><ul><li>Myasthenia gravis </li></ul>
  48. 49. Thank you very much for listening……

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NCS lecture of Diseases of the Immune System given August 3, 2011 at AUF SOM, Pathology


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