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Diseases Of Immunity

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Diseases Of Immunity

  2. 2. <ul><li>The immune system protects the host from invasion by foreign and potentially harmful agents. </li></ul><ul><li>Characteristics: </li></ul><ul><li>1. distinguish self from non-self </li></ul><ul><li>2. discriminate among potential invaders (specificity) </li></ul><ul><li>3. maintain the presence of immune memory (anamnesis) </li></ul><ul><li>4. recall previous exposures and mount an amplified response to them </li></ul>
  3. 3. <ul><li>☻ Immune responses can be elicited by a wide range of agents (termed antigens ) including microorganisms, chemicals, toxins, drugs, and transplanted tissues </li></ul><ul><li>☻ Adaptive immunity – immune responses that show antigen specificity and immune memory </li></ul><ul><li>☻ Innate immunity – does not demonstrate immune memory and lacks the exacting specificity of adaptive immunity </li></ul>
  4. 4. Mechanisms involved in Innate and Adaptive immunity
  5. 5. Innate and Adaptive Immunity <ul><li>Innate Immunity </li></ul><ul><ul><ul><li>Natural or native immunity </li></ul></ul></ul><ul><ul><ul><li>Defense mechanisms present even before infection </li></ul></ul></ul><ul><ul><ul><li>First line of defense </li></ul></ul></ul><ul><ul><ul><li>Components </li></ul></ul></ul><ul><ul><ul><ul><li>Epithelial barriers </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Phagocytic cells (PMN’s and Macrophages) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Dendritic cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>NK cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Several plasma proteins, including the Complement system </li></ul></ul></ul></ul>
  6. 6. Innate and Adaptive Immunity <ul><li>Innate Immunity </li></ul><ul><li>Two most important cellular reactions </li></ul><ul><li>1. Inflammation </li></ul><ul><li> phagocytic leukocytes are </li></ul><ul><li>recruited and activated to kill microbes </li></ul><ul><li>2. Anti-viral defense </li></ul><ul><li> mediated by dendritic cells and NK cells </li></ul>
  7. 7. Innate and Adaptive Immunity <ul><li>Innate Immunity </li></ul><ul><li> Pathogen-associated molecular patterns </li></ul><ul><li>* Microbial structures recognized by </li></ul><ul><li>leukocytes and epithelial cells </li></ul><ul><li> Danger-associated molecular patterns </li></ul><ul><li>* Molecules released by injured and necrotic cells that </li></ul><ul><li>are recognized by leukocytes </li></ul><ul><li>*Pattern recognition receptors </li></ul><ul><li> Toll-like receptors (TLR’s) </li></ul>
  8. 8. Innate and Adaptive Immunity <ul><li>Toll-like Receptors (TLR’s) </li></ul><ul><li> homologous to the Drosophila protein </li></ul><ul><li> specific for components of different bacteria and viruses </li></ul><ul><li> located on the cell surface and in endosomes </li></ul><ul><li>*Recognize and initiate cellular responses </li></ul>
  9. 9. Different TLRs involved in response to different microbial products
  10. 11. Innate Immunity <ul><li>Epithelia (skin, respiratory, GIT) </li></ul><ul><li> provide mechanical barriers to the entry of </li></ul><ul><li>microbes </li></ul><ul><li> produce anti-microbial molecules = defensins </li></ul>
  11. 12. Innate Immunity <ul><li>Monocytes and Neutrophils </li></ul><ul><li> phagocytes in the blood recruited at the site of infection </li></ul><ul><li> monocytes that enter the tissues and mature are called macrophages </li></ul>
  12. 13. Innate Immunity <ul><li>Dendritic cells </li></ul><ul><li> produce type I interferons, anti-viral </li></ul><ul><li>cytokines that inhibit viral infection and </li></ul><ul><li>replication </li></ul><ul><li>Natural killer cells </li></ul><ul><li> provide early protection against many viruses </li></ul><ul><li>and intracellular bacteria </li></ul>
  13. 14. Innate Immunity <ul><li>Complement proteins </li></ul><ul><li>* activated by binding to microbes using the </li></ul><ul><li>alternative and lectin pathways </li></ul>
  14. 15. Innate Immunity <ul><li>Mannose-binding lectin and C-reactive protein </li></ul><ul><li>* coat microbes for phagocytosis and complement activation </li></ul><ul><li>Lung surfactant </li></ul><ul><li>* protection against inhaled microbes </li></ul>
  15. 16. Adaptive Immunity <ul><li> consists of lymphocytes and their products, including antibodies </li></ul>
  16. 17. Adaptive Immunity <ul><li>Cell-mediated (cellular) immunity </li></ul><ul><li> responsible for defense against intracellular microbes </li></ul><ul><li> mediated by T (Thymus-derived) lymphocytes </li></ul><ul><li>Humoral immunity </li></ul><ul><li> protects against extracellular microbes and their toxins </li></ul><ul><li> mediated by B (Bone-marrow derived) lymphocytes </li></ul><ul><li>and their secreted products  antibodies </li></ul>
  17. 21. CELLS OF THE IMMUNE SYSTEM Present Ag to CD4 T cells Precursors to macrophage lineage; cytokine release Class II MHC expressing cells Horse-shoe shaped nucleus Found in LN, blood, lungs and other organs Antigen Presenting Cells Monocytes Phagocytose and kill bacteria Parasitic defense and allergic response ___ None Staining with eosin ___ Granulocyte; short lifespan; multilobed nucleus Bilobed nucleus; heavily granulated cytoplasm See below Phagocytic cells: PMN’s Eosinophils Macrophages Kill antibody-decorated cells and virus-infected or tumor cells (no MHC restriction) Fc receptors for antibody: CD16, CD56, CD57 Large granular lymphocytes Natural Cytolytic cells: NK cells FUNCTION MARKERS CHARACTERISTICS CELLS
  18. 22. CELLS OF THE IMMUNE SYSTEM Initiate inflammatory and acute phase response; have antibacterial, antiviral and anti-tumor activities Transport Ag to LN Efficient Ag presenters Produce cytokines Filter particles from blood Large, granular cells; Fc and C3 receptors __ __ __ __ __ Possible residence in tissue, spleen, LN, and other organs; activated by IFN- γ and TNF Presence in skin LN, tissues CNS and brain Presence in liver See below Antigen Presenting Cells Macrophages Langerhan’s cells Dendritic cells Microglial cells Kupffer cells B cells FUNCTION MARKERS CHARACTERISTICS CELLS
  19. 23. CELLS OF THE IMMUNE SYSTEM Produce IL-2, other cytokines; stimulate T-cell and B-cell growth; promote B-cell differentiation, antibody production Promotes initial defenses (local) DTH, T killer cells Promote later humoral responses CD2, CD3, T-cell receptor CD2, CD3, T-cell receptor, CD4 IL-2, IFN- γ , lympho-toxin production IL-4, IL-5, IL-6, IL-10 production Mature in Thymus; large nucleus, small cytoplasm Helper/DTH cells; Activation by APCs via Class II MHC antigen presentation TH 1 subtype TH 2 subtype Antigen-Responsive Cells T cells (all) CD4 T cells FUNCTION MARKERS CHARACTERISTICS CELLS
  20. 24. CELLS OF THE IMMUNE SYSTEM Release Histamine, provide allergic response, anti-parasitic Fc receptor for IgE Granulocytic Other cells Basophils/Mast cells Produce antibody and present antigen Terminally differentiated, antibody factories Surface antibody, Class II MHC antigens __ Mature in Peyer’s patches, BM, bursal equivalent; large nucleus, small cytoplasm; activation by Ag and T-cell factors Small nucleus, large cytoplasm Antibody-, Producing Cells B cells Plasma cells Kill viral, tumor, non-self cells; secrete TH 1 lymphokines Suppress T- cell and B-cell response CD2, CD3, T-cell receptor, CD8 CD2, CD3, T-cell receptor, CD8 Recognition of Ag presented by Class I MHC antigens Recognition of Ag presented by Class I MHC antigens Antigen-Responsive Cells CD8 T killer cells CD8 T cells (suppressor cells ) FUNCTION MARKERS CHARACTERISTICS CELLS
  21. 25. T Lymphocytes <ul><li>Generated from immature precursors in the thymus </li></ul><ul><li>Mature, naïve T cells enters the circulation, constituting 60-70% of lymphocytes </li></ul><ul><li>Found in the paracortical areas of LN and periarteriolar sheaths of spleen </li></ul><ul><li>Each T cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen-specific T cell receptor (TCR) </li></ul>
  22. 26. B lymphocytes <ul><li>Develop from immature precursors in the bone marrow </li></ul><ul><li>Mature B cells constitute 10-20% of the circulating peripheral lymphocytes </li></ul><ul><li>Also seen in the LN (superficial cortex), spleen (white pulp), tonsils, and extralymphatic organs (e.g. GIT) </li></ul><ul><li>Recognizes antigen via the B-cell antigen receptor complex </li></ul><ul><li>Has unique antigen specificity derived partly from somatic rearrangements of immunoglobulin gene </li></ul>
  23. 28. Cytokines <ul><li>☻ Short-acting soluble mediators </li></ul><ul><li>☻ Includes lymphokines, monokines and other polypeptides that regulate immunologic, inflammatory, and reparative host responses </li></ul><ul><li>☻ Molecularly defined cytokines - Interleukins </li></ul>
  24. 29. Cytokines <ul><li>Mediate innate (natural) immunity </li></ul><ul><ul><ul><li>♣ IL-1, TNF, type 1 IFN, IL-6 </li></ul></ul></ul><ul><ul><ul><li>♣ IL-12 and IFN- γ (innate and adaptive immunity) </li></ul></ul></ul><ul><li>Regulate lymphocyte growth, activation and differentiation </li></ul><ul><li>♣ IL-2, IL-4, IL-12, IL-15 and TGF-B </li></ul>
  25. 30. Cytokines <ul><li>3. Activate inflammatory cells </li></ul><ul><li>♣ IFN- γ – macrophages </li></ul><ul><li>♣ IL-5 – eosinophils </li></ul><ul><li>♣ TNF and TNF- Β – PMN’s and endothelial cells </li></ul><ul><li>4. Affect leukocyte movement (Chemokines) </li></ul><ul><li>♣ C-C and C-X-C chemokines </li></ul><ul><li>5. Stimulate hematopoiesis </li></ul><ul><li>♣ derived from lymphocytes or stromal cells </li></ul><ul><li>♣ colony-stimulating factors </li></ul>
  26. 31. Cytokines <ul><li>General Properties </li></ul><ul><li>☺ produced by different cell types </li></ul><ul><li>☺ pleiotropic actions </li></ul><ul><li>☺ induce effects in 3 ways </li></ul><ul><li>1. act on the same cell that produces them (autocrine effect) </li></ul><ul><li>2. affect other cells in the vicinity (paracrine effect) </li></ul><ul><li>3. affect many cells systematically (endocrine effect) </li></ul><ul><li>☺ mediate their effects by binding to specific high- affinity receptors on their target cells </li></ul>
  28. 33. Histocompatibility Molecules <ul><li>☼ Important for the induction and regulation of the immune response </li></ul><ul><li>☼ Principal physiologic function is to bind peptide fragments of foreign proteins for presentation to antigen-specific T cells </li></ul><ul><li>☼ Encoding genes are found in chromosome 6 </li></ul><ul><li>MHC or HLA complex </li></ul><ul><li>☼ Class I and Class II genes encode cell surface glycoproteins involved in antigen presentation </li></ul><ul><li>☼ Class III genes encode components of the complement system </li></ul>
  29. 34. Histocompatibility Molecules <ul><li>Categories: </li></ul><ul><li>1. Class I MHC molecules </li></ul><ul><li>► expressed on all nucleated cells and platelets </li></ul><ul><li>► encoded by 3 closely linked loci – HLA-A, Hla-B, and HLA-C </li></ul><ul><li>► heterodimer molecules – polymorphic α linked noncovalently to nonpolymorphic peptide β -2 microglobulin </li></ul><ul><li>► CD8 T cells </li></ul>
  30. 35. Histocompatibility Molecules <ul><li>Categories: </li></ul><ul><li>2. Class II MHC molecules </li></ul><ul><li>► coded in the HLA-D region (HLA-DP, HLA-DQ, and HLA-DR) </li></ul><ul><li>► heterodimer, noncovalently binded α and β chains </li></ul><ul><li>► CD4 T cells </li></ul>
  31. 36. Histocompatibility Molecules <ul><li>HLA and Disease Association </li></ul><ul><li>► mechanisms not fully understood </li></ul><ul><li>► grouped into the following categories </li></ul><ul><li>◘ Inflammatory diseases </li></ul><ul><li>◘ Inherited errors of metabolism </li></ul><ul><li>◘ Autoimmune disorders </li></ul>
  32. 37. HLA and Disease Association 15.0 BW47 21-Hydroxylase deficiency 5 6 20 DR3 DR4 DR3/DR4 Type I diabetes 9 DR3 Primary Sjogren syndrome 13 DR3 Chronic active hepatitis 4 DR4 Rheumatoid arthritis 14 B27 Acute anterior uveitis 14 B27 Post-gonococcal arthritis 90 B27 Ankylosing spondylitis Relative Risk HLA Allele Disease
  33. 38. Disorders of the Immune System <ul><li>╬ Hypersensitivity reactions </li></ul><ul><li>╬ Autoimmune diseases </li></ul><ul><li>╬ Immunologic deficiency syndromes </li></ul><ul><li>╬ Amyloidosis </li></ul>
  34. 39. Hypersensitivity Reactions and Tissue injury <ul><li>۩ Hypersensitivity is a misnomer </li></ul><ul><li>۩ These diseases result from normal immune responses </li></ul><ul><li>۩ Not Excessive or ‘Hyper’ responses </li></ul><ul><li>۩ Classification based on Immunologic Mechanisms </li></ul>
  35. 40. General features of hypersensitivity disorders <ul><li>Both exogenous and endogenous antigens may elicit hypersensitivity reactions </li></ul><ul><li>The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes </li></ul><ul><li>Hypersensitivity reflects an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to normally limit such responses </li></ul>
  36. 41. ۩ Results in tissue injury or other pathophysiological changes ۩ Occurs when an already sensitized individual is re- exposed to the same foreign substance ۩ May be immediate or delayed Hypersensitivity Reactions and Tissue Injury
  37. 42. Ensuing tissue injury may be caused by: ۩ Release of vasoactive substances ۩ Phagocytosis or lysis of cells ۩ Activation of inflammatory & cytolytic components of complement system ۩ Release of cytokines, proteolytic enzymes and other mediators of tissue injury or inflammation Hypersensitivity Reactions and Tissue Injury
  38. 45. Immediate (Type I) Hypersensitivity <ul><li>A rapidly developing immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen </li></ul><ul><li>The reaction is called an allergy, and the antigen that cause them are termed allergen </li></ul><ul><li>Most are mediated by IgE antibody-dependent activation of mast cells and other leukocytes </li></ul>
  39. 46. Immediate (Type I) Hypersensitivity <ul><li>Anaphylactic type </li></ul><ul><ul><li>Occurs within minutes </li></ul></ul><ul><ul><li>IgE mediated </li></ul></ul><ul><ul><li>Provoked by re-exposure to the same antigen (by contact, inhalation, ingestion, or injection) </li></ul></ul><ul><ul><li>Mediated by antigen binding with antibody previously bound to mast cells or basophils </li></ul></ul><ul><ul><li>Local or systemic </li></ul></ul>
  40. 47. Immediate (Type I) Hypersensitivity <ul><li>LOCAL ANAPHYLAXIS </li></ul><ul><li>♠ Atopy  genetically determined predisposition to develop localized anaphylactic reactions to inhaled or ingested allergens </li></ul><ul><li>♠ positive family history  chromosome 5q31 </li></ul><ul><li>♠ With higher serum IgE levels compared to general population </li></ul>
  41. 48. Immediate (Type I) Hypersensitivity <ul><li>Two Phase Reaction </li></ul><ul><ul><li>♠ Initial response is rapid - 5-30 min after exposure to antigen (subsides in 60 minutes) </li></ul></ul><ul><ul><ul><li>◘ Vasodilatation, edema, smooth muscle spasm </li></ul></ul></ul><ul><ul><li>♠ Late phase response - 2-8 hrs later </li></ul></ul><ul><ul><ul><li>◘ Occurs in 50% of patients </li></ul></ul></ul><ul><ul><ul><li>◘ Infiltration by monocytes, eosinophils, basophils, PMN’s </li></ul></ul></ul><ul><ul><ul><li>and CD4 T cells </li></ul></ul></ul><ul><ul><ul><li>◘ With mucosal epithelial damage </li></ul></ul></ul>
  42. 49. Kinetics of the immediate and late-phase reactions
  43. 50. Type I Hypersensitivity <ul><li>♠ Mast cells in tissues; Basophils circulate </li></ul><ul><li>♠ Both contain granules with Inflammatory Mediators </li></ul><ul><li>♠ Activated by cross-linking to IgE Fc receptors </li></ul>
  44. 57. Vasodilatation, increased vascular permeability Smooth muscle spasm Cellular infiltration
  45. 58. Immediate (Type I) Hypersensitivity <ul><li>Primary Mediators </li></ul><ul><li>♠ Preformed and stored in granules </li></ul><ul><li>♠ Histamine </li></ul><ul><li>♠ Chemotactic factors for eosinophils and PMN’s </li></ul><ul><li>♠ Proteases </li></ul>
  46. 59. Immediate (Type I) Hypersensitivity <ul><li>Secondary Mediators </li></ul><ul><li>♠ Lipid Mediators </li></ul><ul><ul><li>◘ Platelet Activating Factor </li></ul></ul><ul><ul><li>◘ Arachidonic Acid </li></ul></ul><ul><ul><ul><li>☻ Leukotrienes and Prostaglandin </li></ul></ul></ul><ul><li>♠ Cytokines </li></ul><ul><ul><li>◘ TNF-alpha </li></ul></ul><ul><ul><li>◘ Interleukins 1, 4, 5, 6 </li></ul></ul>
  47. 60. Immediate (Type I) Hypersensitivity <ul><li>۞ Is the result of release of ‘a variety of chemotactic, vasoactive and spasmogenic compounds’ </li></ul>
  48. 61. Immediate (Type I) Hypersensitivity <ul><li>CLINICAL MANIFESTATIONS </li></ul><ul><li>♠ Systemic Disorder </li></ul><ul><li>♠ Local Reaction </li></ul>
  49. 62. Immediate (Type I) Hypersensitivity <ul><li>SYSTEMIC ANAPHYLAXIS </li></ul><ul><li>♠ characterized by vascular shock, widespread edema, and difficulty in breathing </li></ul><ul><li> ♠ Hospital setting = Antisera, hormones, enzymes, polysaccharides, and drugs (penicillin) </li></ul><ul><li>♠ Community setting = food allergies, insect toxins </li></ul><ul><li> ♠ Itching, hives, skin erythema within minutes  respiratory difficulty or GIT symptoms </li></ul><ul><li>♠ Shock and Death can occur within minutes </li></ul>
  50. 63. Immediate (Type I) Hypersensitivity <ul><li>LOCAL REACTIONS </li></ul><ul><li>♠ A ffects 10-20% of the population </li></ul><ul><li>♠ Skin or Mucosal Surfaces </li></ul><ul><ul><li>◘ Urticaria (Hives) </li></ul></ul><ul><li>♠ Skin and food allergies </li></ul><ul><li>♠ Hay fever </li></ul><ul><li>♠ Atopy - familial predisposition to allergy </li></ul>
  51. 65. Immediate (Type I) Hypersensitivity What good is it? <ul><li>☻ Fights Worm infection </li></ul><ul><li>☻ EEEEWWWWWW!!!! </li></ul>
  52. 66. What is Asthma? <ul><li>♠ Hypersensitivity – Allergy , Type I </li></ul><ul><li>♠ Affects airways of lungs - Bronchi </li></ul><ul><li>♠ Allergens – in the air, mast cell - IgE ab. </li></ul><ul><li>♠ Inflammation of airways – Bronchitis. </li></ul><ul><li>♠ Genetic, Environmental, Race, Age. </li></ul><ul><li>♠ High in industrial cities 4-19%, Fiji < 1% </li></ul><ul><li>♠ Increasing incidence …! </li></ul>
  53. 67. Pathogenesis of Atopic Asthma
  54. 68. Asthma Mechanism: ► Allergy ► Inflammation of bronchi ► Obstruction ► Mucous Plugs
  55. 69. INFLAMMATION Airflow Limitation TRIGGERS Exercise Cold Air, diseases, Airway Hyperresponsiveness Genetic* INDUCERS Allergens,pollutants
  56. 70. Lung in Asthma with Mucous plugs
  57. 71. Mucous plug in asthma:
  58. 72. Asthma Microscopic Pathology Obstructed and inflamed bronchi
  59. 73. Asthma - Bronchial morphology <ul><li>◘ Inflammation </li></ul><ul><li>◘ Eosinophils </li></ul><ul><li>◘ Gland hyperplasia </li></ul><ul><li>◘ Mucous plug in lumen </li></ul><ul><li>◘ Hypertrophy of muscle layer </li></ul>
  60. 74. IgE and parasites: IgE binds to parasite, then Eosinophil binds Degranulation!
  61. 75. schistosoma ova eosinophils
  62. 76. Type I Hypersensitivity <ul><li>DIAGNOSIS: </li></ul><ul><li>♠ History </li></ul><ul><li>♠ Skin prick test – (+) wheal & flare </li></ul><ul><li>♠ CBC showing eosinophilia </li></ul><ul><li>♠ RAST (Radioallergosorbent assay) </li></ul>
  63. 77. Type I Hypersensitivity <ul><li>TREATMENT: </li></ul><ul><li>♠ Anti-histamine – acts on first phase only </li></ul><ul><li>♠ Corticosteroids – late phase reaction </li></ul><ul><li>♠ Desensitization – to induce tolerance; no IgE production  deplete already bound IgE </li></ul>
  64. 78. Antibody-Mediated (Type II) Hypersensitivity <ul><li>♥ Mediated by antibodies directed toward antigens present on the cell surfaces or extracellular matrix </li></ul><ul><li>♥ IgG and IgM </li></ul><ul><li>♥ Antigenic determinants – intrinsic or exogenous </li></ul>
  65. 79. Antibody-Mediated (Type II) Hypersensitivity <ul><li>MECHANISMS: </li></ul><ul><li>♥ Opsonization and Complement-and Fc Receptor-Mediated Phagocytosis </li></ul><ul><li> Cells targeted by antibodies are coated (opsonized) with molecules that make them attractive for phagocytes </li></ul><ul><li> Activates the complement system producing C3b and C4b  deposited on the surface of the cells and recognized by phagocytes (Fc receptors) </li></ul><ul><li> Results to the phagocytosis of the opsonized cells and their destruction </li></ul><ul><li> Complement activation  formation of MAC  disrupts membrane integrity  osmotic lysis of cells </li></ul>
  66. 80. Type II Hypersensitivity Reaction – Opsonization and Complement-and Fc-Receptor Mediated Phagocytosis
  67. 82. Antibody-Mediated (Type II) Hypersensitivity <ul><li>*Antibody-dependent cellular cytotoxicity (ADCC) </li></ul><ul><li> does not involve fixation of complement, requires cooperation of leukocytes </li></ul><ul><li> Coated cells with low concentrations of IgG antibody are killed by a variety of effector cells (monocytes, PMNs, eosinophils, and NK cells)  bind to the target by their receptors to the Fc fragment of IgG  cell lysis without phagocytosis </li></ul>
  68. 83. MECHANISMS: Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Source: Robbins PATHOLOGIC BASIS OF DISEASE 6 th ed.
  69. 84. Antibody-Mediated (Type II) Hypersensitivity <ul><li>Clinical Conditions </li></ul><ul><li>1. Transfusion reaction </li></ul><ul><li>- cells from an incompatible donor react with and are opsonized by preformed antibody in the host </li></ul><ul><li>2. Erythroblastosis fetalis </li></ul><ul><li>- there is an antigenic difference b/w the mother and the fetus, and antibodies (IgG) from the mother cross the placenta and cause destruction of RBCs </li></ul><ul><li>3. Autoimmune hemolytic anemia, agranulocytosis, thrombocytopenia </li></ul><ul><li>- individuals produce antibodies to their own blood cells which are then destroyed </li></ul><ul><li>4. Certain drug reactions </li></ul><ul><li>- antibodies are produced that reacts with the drug, which may be attached to the surface of RBCs or other cells </li></ul>
  70. 85. An example of type II hypersensitivity
  71. 86. Pathogenic functions of auto-antibodies ------------------------------------------------------------ type II hypersensitivity response - ex: RBC autoantibodies ==> hemolysis ------------------------------------------------------------ C’
  72. 87. Antibody-Mediated (Type II) Hypersensitivity <ul><li>♥ Complement-and Fc Receptor-Mediated Inflammation </li></ul><ul><li> antibodies deposited in extracellular tissues (basement membrane and matrix  activate complement (C5a, C4a, and C3a)  recruits PMNs and monocytes  release injurious substances (enzymes and reactive O2 intermediates  inflammation </li></ul>
  73. 88. Antibody-Mediated (Type II) Hypersensitivity – Complement-and Fc Receptor-Mediated Inflammation
  74. 89. Antibody-Mediated (Type II) Hypersensitivity <ul><li>***Responsible for tissue injury in some form of glomerulonephritis, vascular rejection in organ grafts, and other diseases </li></ul>
  75. 90. Antibody-Mediated (Type II) Hypersensitivity <ul><li>♥ Antibody-Mediated Cellular Dysfunction </li></ul><ul><li> Antibodies directed against cell-surface receptors impair or dysregulate function without causing cell injury or inflammation </li></ul>
  76. 91. Antibody-Mediated (Type II) Hypersensitivity – Antibody-Mediated Cellular Dysfunction
  77. 92. An example of type II hypersensitivity
  78. 93. Pathogenic functions of auto-antibodies ------------------------------------------------------------ type II hypersensitivity response - ex: GBM autoantibodies ==> glomerulonephritis Goodpasture’s syndrome GBM Podocytes
  79. 95. Immune Complex-Mediated (Type III) Hypersensitivity <ul><li>☻ Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition </li></ul>
  80. 96. Immune Complex-Mediated (Type III) Hypersensitivity <ul><li>♦ Antigen - Antibody Complexes initiate acute inflammation </li></ul><ul><ul><li>◘ Complement activation and accumulation of PMN’s </li></ul></ul><ul><li>♦ Endogenous Antigens – DNA </li></ul><ul><li>◘ circulating Ag’s present in the blood, or, more commonly, antigenic components of one’s own cells and tissues </li></ul><ul><li>♦ Exogenous Antigens - Bacteria, Viruses, Foreign protein, etc. </li></ul><ul><li>♦ Immune Complexes form in circulation or </li></ul><ul><li>♦ Antigens are ‘planted’ and IC’s form in situ </li></ul><ul><li>♦ Can be generalized or localized </li></ul>
  81. 98. Pathogenesis of immune-complex disease
  82. 100. Systemic Immune Complex Disease <ul><li>Prototype disorder – Acute serum sickness </li></ul><ul><li>Frequent sequela to the administration of large amounts of foreign serum (e.g. horse immune serum for passive immunization) </li></ul><ul><li>Pathogenesis (3 phases) </li></ul><ul><li>1. formation of Ag-Ab complexes </li></ul><ul><li>2. deposition of immune complexes </li></ul><ul><li>3. inflammatory reaction at the site of deposition </li></ul>
  83. 103. Systemic Immune Complex Disease <ul><li>Two mechanisms causing inflammation at the site of deposition </li></ul><ul><li>1. activation of the complement cascade </li></ul><ul><li>2. activation of neutrophils and macrophages through their Fc receptors  release of pro-inflammatory substances (prostaglandins, vasodilator peptides, chemotactic substances, lysosomal enzymes, oxygen free radicals) </li></ul>
  84. 104. Systemic Immune Complex Disease <ul><li>*** The important role of complement in the pathogenesis of the tissue injury is supported by the observations that during the active phase of the disease, consumption of complement decreases the serum levels, and experimental depletion of the complement greatly reduces the severity of the lesion. </li></ul>
  85. 105. Systemic Immune Complex Disease <ul><li>***Chronic form of serum sickness results from repeated or prolonged exposure to an antigen </li></ul><ul><li>***Continous antigenemia is necessary for the development of chronic immune complex disease because complexes in antigen excess are the ones deposited in vascular beds – e.g. SLE </li></ul>
  86. 106. Systemic Immune Complex Disease <ul><li>Morphology </li></ul><ul><li> acute necrotizing vasculitis, with necrosis of vessel wall and intense neutrophilic infiltration </li></ul><ul><li> fibrinoid necrosis – smudgy, eosinophilic deposit that obscures the underlying cellular detail </li></ul><ul><li> affected glomeruli are hypercellular because of swelling and proliferation of endothelial and mesangial cells, accompanied by neutrophilic and monocytic infiltration </li></ul><ul><li> IF microscopy – granular lumpy deposits of Ig and Complement </li></ul><ul><li> Electron microscopy – electron-dense deposits along GBM </li></ul>
  87. 107. Systemic Immune Complex Disease <ul><li>◘ Tissues affected </li></ul><ul><ul><li>☼ Kidneys, joints, skin, heart, serosal surfaces and small vessels </li></ul></ul><ul><li>◘ The reason(s) for this specific organ/tissue predeliction is unknown </li></ul>
  88. 108. Vasculitis Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink “fibrinoid” material.
  89. 109. Fig 5-13 IF
  90. 110. Fig 5-12 EM
  91. 111. Local Immune Complex Disease <ul><li>♦ LOCAL (ARTHUS REACTION) </li></ul><ul><li>◘ Localized tissue necrosis from acute immune vasculitis </li></ul><ul><li>◘ Can induce experimentally by injecting antigen into the skin of a pre-sensitized recipient </li></ul><ul><li>◘ Local PMN recruitment and fibrinoid necrosis  thrombi formation  local ischemic injury </li></ul>
  92. 113. T Cell-Mediated (Type IV) Hypersensitivity <ul><li>♣ T-Cells are the active agents not Antibodies </li></ul><ul><ul><li>☼ Otherwise Type II is very similar to Type IV </li></ul></ul><ul><li>♣ Delayed-Type </li></ul><ul><li> mediated by CD4+ T cells </li></ul><ul><li>♣ Direct Cell Cytotoxicity </li></ul><ul><li> mediated by CD8+ T cells </li></ul>
  93. 114. Mechanisms of Delayed Type Hypersensitivity Reactions
  94. 115. Mechanism of Direct T Cell Cytotoxicity
  95. 116. Type IV Hypersensitivity Delayed Type <ul><li>♣ Tuberculin Skin Test (Mantoux Reaction) </li></ul><ul><li>♣ Granuloma Formation </li></ul><ul><ul><li>Nodular aggregate of Epithelioid Macrophages surrounded by a rim of lymphocytes </li></ul></ul><ul><ul><li>Multinucleated Giant Cells may be present </li></ul></ul><ul><li>♣ Persistent organisms that are poorly degraded (tuberculosis) </li></ul>
  96. 117. Type IV Hypersensitivity Delayed Type <ul><li>♣ “ The Type of inflammation characteristic of this Reaction is called Granulomatous Inflammation” </li></ul><ul><li>♣ The key cell is the epithelioid macrophage NOT the Giant Cell!! </li></ul>
  97. 118. Formation of granuloma in Type IV Hypersensitivity
  98. 119. Granulomas Low Power High Power
  99. 120. Langhan’s Giant Cell Picture Robbins Textbook of Pathology 1971
  100. 121. Type IV - Cell Mediated Delayed Hypersensitivity <ul><li>♣ TB antigen processing by macrophages  </li></ul><ul><ul><li>presentation to CD4 T cells  sensitized CD4 cells that remain in the circulation </li></ul></ul><ul><ul><li>Re-exposure  activation, amplification and recruitment of Macrophages which cause the majority of tissue damage </li></ul></ul><ul><ul><li>IL-2 and IFN-gamma are the most important cytokines </li></ul></ul>
  101. 122. Type IV - Cell Mediated Delayed Type <ul><li>♣ Major defense against Tuberculosis & Fungi </li></ul>
  102. 123. Type IV - Cell Mediated Delayed Type <ul><li>♣ Major defense against Tuberculosis & Fungi </li></ul><ul><li>♣ Patients with AIDS have little defense against these organisms due to the extreme decline in CD4 cells </li></ul>
  103. 124. Type IV - T-cell Mediated Cytotoxicity <ul><li>♣ Sensitized T cell directly kill cells </li></ul><ul><li>♣ Major role in Transplant Rejection </li></ul><ul><li>♣ Protects against Viral Infections </li></ul>
  104. 125. Type IV - T-cell Mediated Cytotoxicity <ul><li>♣ CD8 or Cytotoxic T Lymphocytes are the effector cells </li></ul><ul><ul><li>◘ Lyse target cells </li></ul></ul><ul><ul><ul><li>Perforin release leads to osmotic lysis </li></ul></ul></ul><ul><ul><ul><li>Fas binding leads to apoptosis </li></ul></ul></ul><ul><ul><li>◘ Release cytokines e.g. interferon gamma </li></ul></ul>
  105. 126. Key Facts on Hypersensitivity Reactions <ul><li>Type I : IgE/mast cell-mediated liberation of histamine. Local and systemic anaphylaxis. </li></ul><ul><li>Type II: antibodies bind to cell surface. Damage by complement activation or cellular cytotoxicity, or may stimulate/block a receptor </li></ul><ul><li>Type III: antigen-antibody complexes, either local or circulating. Cause damage by activating complement in tissues at site of trapping of complexes. </li></ul><ul><li>Type IV: T-cell mediated: CD4 cells recruit macrophages; CD8 cells cause cytotoxicity </li></ul>
  107. 128. Transplant Rejection <ul><li>Factors enhancing graft survival </li></ul><ul><ul><li>ABO blood group compatibility between recipients and donors </li></ul></ul><ul><ul><li>Absence of pre-formed anti-HLA cytotoxic antibodies in recipients </li></ul></ul><ul><ul><ul><li>People must have previous exposure to blood products to develop HLA cytotoxic antibodies </li></ul></ul></ul><ul><ul><li>Close matches of HLA-A, -B, and –D loci between recipients and donors </li></ul></ul>
  108. 129. Transplant Rejection <ul><li>Type of grafts </li></ul><ul><ul><li>Autograft (i.e., self to self) </li></ul></ul><ul><ul><ul><li>Associated with the best survival rate </li></ul></ul></ul><ul><ul><li>Syngenetic graft (isograft) </li></ul></ul><ul><ul><ul><li>Between identical twins </li></ul></ul></ul><ul><ul><li>Allograft </li></ul></ul><ul><ul><ul><li>Between genetically different individuals of the same species </li></ul></ul></ul><ul><ul><li>Xenograft </li></ul></ul><ul><ul><ul><li>Between two species </li></ul></ul></ul><ul><ul><ul><li>Example = transplant of heart valve from pig to human </li></ul></ul></ul>
  109. 130. Transplant Rejection <ul><li>◙ Involves recognition of major histocompatibility antigens (HLA) </li></ul><ul><ul><li>The most important HLA presenting cells are the donor lymphocytes, especially dendritic cells, contained within the graft </li></ul></ul><ul><ul><li>Mediated by: CD8+ & CD4+ T cells </li></ul></ul>
  110. 131. Transplant Rejection <ul><li>◙ T cells </li></ul><ul><ul><li>Lyse graft cells </li></ul></ul><ul><ul><li>Attract and activate macrophages </li></ul></ul><ul><ul><li>Increase vascular permeability with local accumulation of lymphocytes and macrophages </li></ul></ul>
  111. 132. Hyperacute Transplant Rejection <ul><li>◙ Preformed anti-donor antibodies are present </li></ul><ul><ul><li>Hx of previous Transplant </li></ul></ul><ul><ul><li>Multiparous women </li></ul></ul><ul><ul><li>Previous blood transfusions </li></ul></ul><ul><li>◙ Circulating antibodies react with the graft </li></ul>
  112. 133. Hyperacute Rejection <ul><li>Pathogenesis </li></ul><ul><ul><li>ABO incompatibility or action of preformed anti-HLA antibodies in the recipient directed against donor antigens in vascular endothelium </li></ul></ul><ul><ul><li>Type II hypersensitivity reaction </li></ul></ul>
  113. 134. Hyperacute Transplant Rejection <ul><li>◙ Complement fixes, PMN’s arrive </li></ul><ul><li>◙ Graft destroyed in MINUTES to hours </li></ul><ul><li>◙ This no longer occurs </li></ul><ul><ul><li>Much better graft screening </li></ul></ul>
  114. 135. Morphology of Rejection Hyper-acute Rejection <ul><ul><li>۩۩۩ Widespread arteritis, thrombosis of vessels, and ischemic necrosis </li></ul></ul>
  115. 136. Normal Kidney
  116. 137. <ul><li>Microthrombi </li></ul><ul><li>PMN’s </li></ul>Hyperacute Rejection
  117. 138. Antibody- mediated damage to the blood vessel in a renal allograft. The blood vessel is markedly thickened and the lumen is obstructed by proliferating fibroblast and foamy macrophages.
  118. 139. Acute Rejection <ul><li>Most common transplant rejection </li></ul><ul><li>Reversible reaction that occurs within days to weeks </li></ul><ul><ul><li>1) Type IV cell-mediated hypersensitivity </li></ul></ul><ul><ul><ul><li>CD4 T cells release cytokines, resulting in activation of host macrophages, proliferation of CD8 T cells  destruction of donor graft cell </li></ul></ul></ul><ul><ul><ul><li>Extensive interstitial round cell lymphocytic infiltrate in the graft, edema, and endothelial cell injury </li></ul></ul></ul>
  119. 140. Acute Rejection <ul><li>2) Antibody-mediated Type II hypersensitivity reaction </li></ul><ul><li>- Cytokines from CD4 T cells promote B-cell </li></ul><ul><li>differentiation into plasma cells  anti-HLA antibodies  attack vessels in the donor graft </li></ul><ul><li>- Vasculitis with intravascular thrombosis in recent grafts </li></ul><ul><li>- Intimal thickening with obliteration of vessel lumens in older grafts </li></ul>
  120. 141. Acute Rejection <ul><li>***Acute rejection is potentially reversible with immunosuppressive agents such as cyclosporine (blocks CD4 T-cell release of IL-2), OKT3 (monoclonal antibody against T-cell antigen recognition site and corticosteroids (lymphotoxic) </li></ul><ul><li>***Immunosuppressive therapy is associated with an increased risk of cervical squamous cancer, malignant lymphoma, and skin squamous cell carcinoma (most common) </li></ul>
  121. 142. Morphology of Acute Rejection <ul><li>۞ Onset usually 7-10 days </li></ul><ul><li>۞ Detected by slight rise in serum creatinine </li></ul><ul><li>۞ Mononuclear cell tubulo-interstitial infiltrate with tubular injury and interstitial edema </li></ul><ul><li>۞ Vasculitis is very uncommon </li></ul>
  122. 143. Acute cellular rejection of a renal allograft R – Intense mononuclear cell infiltrate between the glomerulus and the tubules L – Tubules undergoing destruction by invading lymphocytes
  123. 144. Acute Tubulointerstitial Rejection
  124. 145. Acute Tubulointerstitial Rejection <ul><li>Tubulitis </li></ul>
  125. 146. Acute Vascular Rejection <ul><li>Vasculitis </li></ul>
  126. 147. Chronic Rejection <ul><li>۞ Irreversible reactions that occurs over months to years </li></ul><ul><li>۞ Involves continued vascular injury with ischemia to tissues </li></ul><ul><li>۞ Dominant histological features </li></ul><ul><ul><li>arterial and arteriolar intimal thickening </li></ul></ul><ul><ul><li>thick glomerular capillary walls </li></ul></ul><ul><ul><li>tubular atrophy </li></ul></ul><ul><ul><li>interstitial fibrosis </li></ul></ul><ul><li>۞ Cause is unclear </li></ul><ul><li>۞ Therapy is ineffective </li></ul>
  127. 148. Schematic representation that lead to the destruction of histo-incompatible grafts
  128. 149. Transplantation of Other Solid Organs <ul><ul><li>In heart and liver transplants, unlike kidney transplantation, no effort is made to match HLA antigens in donor and hosts </li></ul></ul><ul><ul><li>This is due to size compatibility requirements & </li></ul></ul><ul><ul><li>The time a liver/heart remains viable is low </li></ul></ul>
  129. 150. Allogeneic Hematopoietic Cell Transplant Bone Marrow Transplants <ul><li>Graft - versus - host disease and transplant rejection can occur </li></ul><ul><li>Rejection is mediated by T cells and NK cells </li></ul>
  130. 151. Bone Marrow Transplants Graft - Versus - Host Disease <ul><li>Causes </li></ul><ul><ul><li>Potential complication in bone marrow transplant </li></ul></ul><ul><ul><li>Potential complication in blood transfusions given to patients with a T-cell immunodeficiency and newborns </li></ul></ul>
  131. 152. Bone Marrow Transplants Graft - Versus - Host Disease <ul><li>Pathogenesis </li></ul><ul><ul><li>Donor T-cells recognize host tissue as foreign and activate host CD4 and CD8 T cells </li></ul></ul><ul><li>Clinical Findings </li></ul><ul><ul><li>Bile duct necrosis (jaundice) </li></ul></ul><ul><ul><li>Gastrointestinal mucosa ulceration (bloody diarrhea) </li></ul></ul><ul><ul><li>Dermatitis </li></ul></ul>
  132. 153. Bone Marrow Transplants Graft - Versus - Host Disease <ul><li>Donor marrow cells recognize host as “Foreign” </li></ul><ul><li>The host is “rejected” </li></ul><ul><li>Three principal targets: </li></ul><ul><ul><li>Liver </li></ul></ul><ul><ul><li>Skin </li></ul></ul><ul><ul><li>GI tract </li></ul></ul>
  133. 154. SOME TYPES OF TRANSPLANTS Graft contains pluripotential cells that repopulate host stem cells Host assumes donor ABO group Danger of graft-versus-host reaction and CMV infection Bone marrow Better survival with kidney from living donor than from cadaver Kidney Best allograft survival rate Danger of transmission of C-J disease Cornea COMMENTS TYPE OF TRANSPLANT
  135. 156. Introduction <ul><li>Autoimmunity- immune reaction against “self-antigens”  Tissue damage </li></ul><ul><li>Single organ or multi-system diseases </li></ul><ul><li>More than 1 auto-antibody in a given disease may occur </li></ul><ul><li>Common in females </li></ul>
  136. 157. Autoimmunity <ul><li>Three Requirements </li></ul><ul><ul><li>1. The presence of an immune reaction specific for some self-antigen or self-tissue </li></ul></ul><ul><ul><li>2. Evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance </li></ul></ul><ul><ul><li>3. The absence of another well-defined cause of the disease </li></ul></ul>
  137. 158. Autoimmunity <ul><li>Clinical manifestations </li></ul><ul><ul><li>Variable </li></ul></ul><ul><ul><ul><li>Organ-specific disease </li></ul></ul></ul><ul><ul><ul><ul><li>immune responses are directed against a single organ or tissue </li></ul></ul></ul></ul><ul><ul><ul><li>Systemic or generalized disease </li></ul></ul></ul><ul><ul><ul><ul><li>Autoimmune reactions are against widespread antigens </li></ul></ul></ul></ul><ul><ul><ul><ul><li>*** Results from loss of self-tolerance </li></ul></ul></ul></ul>
  138. 159. Immune-mediated Inflammatory Disease <ul><li>Diseases mediated by antibodies and immune complexes </li></ul><ul><ul><li>Organ-specific autoimmune diseases </li></ul></ul><ul><ul><ul><ul><li>Autoimmune Hemolytic anemia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Autoimmune thrombocytopenia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Myastenia gravis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Graves disease </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Goodpasture syndrome </li></ul></ul></ul></ul><ul><ul><li>Systemic autoimmune diseases </li></ul></ul><ul><ul><ul><ul><li>Systemic Lupus Erythematosus (SLE) </li></ul></ul></ul></ul><ul><ul><li>Diseases caused by autoimmunity or by reactions to microbial antigens </li></ul></ul><ul><ul><ul><ul><li>Polyarteritis nodosa </li></ul></ul></ul></ul>
  139. 160. Immune-mediated Inflammatory Disease <ul><li>Diseases mediated by T cells </li></ul><ul><ul><li>Organ-specific autoimmune diseases </li></ul></ul><ul><ul><ul><ul><li>Type I Diabetes mellitus </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Multiple sclerosis </li></ul></ul></ul></ul><ul><ul><li>Systemic autoimmune diseases </li></ul></ul><ul><ul><ul><ul><li>Rheumatoid arthritis* </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Systemic sclerosis* </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Sjogren syndrome* </li></ul></ul></ul></ul><ul><ul><li>Diseases caused by autoimmunity or by reactions to microbial antigens </li></ul></ul><ul><ul><ul><ul><li>Inflammatory bowel disease (Crohn disease, Ulcerative colitis) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inflammatory myopathies </li></ul></ul></ul></ul><ul><ul><ul><ul><li>*Antibodies may also play a role in these diseases </li></ul></ul></ul></ul>
  140. 161. Immunological Tolerance <ul><li>It is the phenomenon of unresponsiveness to an antigen as a result of exposure to lymphocytes to that antigen </li></ul><ul><li>Self-tolerance  lack of responsiveness to an individual’s own antigen </li></ul><ul><ul><ul><ul><ul><li>Underlies our ability to live in harmony with our cells and tissues </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Lymphocytes with receptors capable of recognizing self-antigens are being generated constantly  eliminated or inactivated as soon as they recognize the antigens </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Mechanisms : Central tolerance and Peripheral tolerance </li></ul></ul></ul></ul></ul>
  141. 162. CENTRAL TOLERANCE <ul><li>Negative selection or deletion of self-reactive T and B lymphocytes during their maturation in the central lymphoid organs </li></ul><ul><li>T cells </li></ul><ul><li>T lymphocytes that bear high-affinity receptors for self-antigens are negatively selected or deleted  undergo apoptosis </li></ul><ul><li>AIRE (autoimmune regulator) – a protein that stimulates expression of some “peripheral tissue-restricted” self-antigens in thymus  critical for deletion of immature T cells specific for these antigens </li></ul><ul><li>occur during fetal development </li></ul>
  142. 163. CENTRAL TOLERANCE <ul><li>B cells </li></ul><ul><li>Also undergo negative selection or deletion </li></ul><ul><li>Receptor Editing – when developing B cells strongly recognize self antigens in the BM  reactivate the machinery of antigen receptor gene rearrangement  express new antigen receptors not specific for self-antigens </li></ul><ul><ul><ul><li>Failure  self-reactive cells undergo apoptosis  purging dangerous lymphocytes from the mature pool </li></ul></ul></ul><ul><li>Occurs throughout life </li></ul>
  143. 164. PERIPHERAL TOLERANCE <ul><li>Self-reactive T cells that escape </li></ul><ul><li>intra-thymic negative selection are </li></ul><ul><li>deleted or muzzled in the peripheral </li></ul><ul><li>tissues </li></ul>
  144. 165. PERIPHERAL TOLERANCE  Silence potentially autoreactive T and B cells in peripheral tissues  Best defined for T cells  Mechanisms: 1. Anergy 2. Suppression by regulatory T cells 3. Deletion by activation-induced cell death
  145. 166. PERIPHERAL TOLERANCE <ul><li>Anergy </li></ul><ul><ul><li> Prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens </li></ul></ul><ul><ul><li> T cells – due to absence of co-stimulatory molecules on APCs, such as B7-1 & B7-2 </li></ul></ul><ul><ul><li> B cells – due to lack of T cell help for antibody synthesis (T cell anergy or down-regulation of surface IgM) </li></ul></ul>
  146. 167. PERIPHERAL TOLERANCE Suppression by regulatory T cells  Regulatory T cells plays a major role in preventing immune reactions against self-antigens  CD4 T cells is the best defined regulatory T cells that expresses CD25, the alpha chain of the IL-2 receptor, and a transcription factor of the forkhead family (Foxp3) ***both are required for the development and maintenance of functional CD4+ regulatory T cells  Mutations in Fox3p result in severe autoimmunity ***cause of autoimmune disease called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
  147. 168. PERIPHERAL TOLERANCE Deletion by activation-induced cell death  CD4+ T cells that recognize self-antigens may receive signals that promote their death by apoptosis  two mechanisms 1. Expression of a pro-apoptotic member of the Bcl family (Bim), without anti-apoptotic members of the family, Bcl-2 and Bcl-x  unopposed Bim triggers apoptosis by the mitochondrial pathway 2. Involves the Fas-Fas ligand system  engagement of Fas by FasL induces apoptosis of activated T cells by the death receptor pathway
  150. 171. Mechanism of Autoimmunity <ul><li>Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes </li></ul><ul><li>These genetic and environmental influences conspire to create an imbalance between control mechanisms that normally function to prevent self-reactivity and pathways that lead to activation of pathogenic effector lymphocytes </li></ul>
  151. 172. Pathogenesis of Autoimmunity
  152. 173. Mechanism of Autoimmunity <ul><li>ROLE OF SUSCEPTIBILITY GENES </li></ul><ul><ul><li>Most autoimmune diseases are complex multigenic disorders </li></ul></ul><ul><ul><li>HLA genes – affects the negative selection of T cells in the thymus or the development of regulatory T cells </li></ul></ul><ul><ul><li>Non-MHC genes </li></ul></ul><ul><ul><ul><ul><li>PTPN-22 = most frequently implicated in autoimmunity; encodes for the protein tyrosine phosphatase </li></ul></ul></ul></ul><ul><ul><ul><ul><li>NOD-2 = cytoplasmic sensor of microbes; associated with Crohn disease </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Genes encoding the IL-2 receptor (CD25) and IL-7 receptor alpha chain </li></ul></ul></ul></ul><ul><ul><ul><ul><li> = control the maintenance of regulatory T cells </li></ul></ul></ul></ul>
  153. 174. Mechanisms of Autoimmunity <ul><li>ROLE OF INFECTIONS </li></ul><ul><ul><li>Infections may up-regulate the expression of costimulators on APCs </li></ul></ul><ul><ul><ul><ul><li>Results in breakdown of anergy and activation of T cells specific for the self-antigens </li></ul></ul></ul></ul><ul><ul><li>Molecular mimicry </li></ul></ul><ul><ul><ul><ul><li>Microbes may express antigens that have the same amino acid sequences as self-antigens </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Immune responses against the microbial antigens may result in activation of self-reactive lymphocytes </li></ul></ul></ul></ul><ul><ul><ul><ul><li>RHD – antibodies against streptococcal proteins cross-react with myocardial proteins </li></ul></ul></ul></ul><ul><ul><li>Polyclonal B-cell activation </li></ul></ul><ul><ul><ul><ul><li>Some viral infections may result in production of autoantibodies </li></ul></ul></ul></ul><ul><ul><ul><ul><li>EBV and HIV </li></ul></ul></ul></ul>
  155. 176. Mechanisms of Autoimmunity <ul><li>RELEASE OF SEQUESTERD ANTIGENS </li></ul><ul><li> Some antigens are hidden (sequestered) from the immune system, because the tissues in which antigens are located do not communicate with the blood and lymph. </li></ul><ul><li>self-antigens in these tissues do not induce tolerance but fail to elicit immune responses and are essentially ignored by the immune system </li></ul><ul><li>Immune-privileged sites – testis, eye, and brain </li></ul><ul><ul><ul><li>Trauma to these sites  release antigens  tissue inflammation and injury </li></ul></ul></ul>
  156. 177. General Features of Autoimmune Diseases <ul><li>Once induced it tends to be progressive, sometimes with sporadic relapses and remissions, and the damage becomes inexorable </li></ul><ul><ul><li>Epitope Spreading </li></ul></ul><ul><ul><ul><ul><li>Infections and initial autoimmune response  damage tissues, release self antigens and exposed epitopes of the antigens that are normally concealed from the immune system  continuing activation of lymphocytes </li></ul></ul></ul></ul><ul><li>The clinical and pathologic manifestations of an autoimmune disease are determined by the nature of the underlying immune response </li></ul><ul><li>Different autoimmune diseases show substancial clinical, pathologic, and serologic overlaps </li></ul>
  157. 178. Microbial infections associated with autoimmune diseases Multiple sclerosis Mixed cryoglobulinemia Allergic encephalitis Scleroderma VIRUSES Hepatitis B virus Hepatitis C virus Measles virus Cytomegalovirus Rheumatic fever Guillain-Barre syndrome Primary biliary cirrhosis Reiter’s syndrome Reiter’s syndrome Grave’s disease Lyme arthritis BACTERIA Streptococcus pyogenes Campylobacter jejuni Escherichia coli Chlamydia trachomatis Shigella sp. Yersinia enterocolitica Borrelia burgdorferi Autoimmune disease Microbe
  158. 179. ORGAN-SPECIFIC AUTOIMMUNE DISEASES Intrinsic factor and parietal cells BM of kidney & lung Islet cell Adrenal cortex Sperm Desmoglein in tight junctions of skin Thyroglobulin Thyroid peroxidase Pernicious anemia Goodpasture’s synd. IDDM Addison’s disease Male infertility Pemphigus Hashimoto’s Primary myxedema Antibody to cell components other than receptors Acetylcholine receptor TSH receptor Myasthenia gravis Grave’s disease Antibody to receptors Target of Immune Response Autoimmune Disease Type of Immune Response
  159. 180. NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES IgG in joints dsDNA, histones RNP antigens (SS-A/Ro and SS-B/La) Myelin protein Rheumatoid arthritis SLE Sjogren’s syndrome (Sicca syndrome) Guillain-Barre synd. Antibody to cell components other than receptors Target of Immune Response Autoimmune Disease Type of Immune Response
  160. 181. Systemic Lupus Erythematosus (SLE) <ul><li>Etiology: Unknown </li></ul><ul><li>Pathogenesis: Failure to maintain self-tolerance due to polyclonal autoantibodies </li></ul><ul><li>Multisystem: Skin, kidneys, serosal surfaces, joints, CNS & heart </li></ul><ul><li>Incidence: 1:2500 more common in black Americans; 10X F > M; 2nd- 3rd decades </li></ul>
  161. 182. SLE: Predisposing Factors <ul><li>Genetic factors </li></ul><ul><ul><li>30% concordance in monozygotic twins </li></ul></ul><ul><ul><li>Associated w/ HLA-DR 2 & 3 loci </li></ul></ul><ul><li>Non-genetic factors </li></ul><ul><ul><li>Drugs (procainamide, isoniazid, d- penicillamine & hydralazine)  LE like s/s </li></ul></ul><ul><ul><li>Androgens protect, estrogens enhance </li></ul></ul><ul><ul><li>UV light may trigger </li></ul></ul>
  162. 183. SLE <ul><li>Immunologic factors </li></ul><ul><ul><li>B-cell hyper-reactivity caused by excess T-helper activity </li></ul></ul><ul><ul><li>How self-tolerance is lost is not known </li></ul></ul>
  163. 184. Model for the pathogenesis of SLE
  165. 186. Revised Criteria for Classification of SLE <ul><li>Malar rash </li></ul><ul><li>Discoid rash </li></ul><ul><li>Photosensitivity (Photodermatitis) </li></ul><ul><li>Oral ulcers </li></ul><ul><li>Arthritis </li></ul><ul><li>Serositis- Pleuritis; Pericarditis </li></ul><ul><li>Renal disorder </li></ul><ul><ul><li>Persistent proteinuria > 0.5 gms/ day or > 3+ if quantitation not performed, or; </li></ul></ul><ul><ul><li>Cellular casts- red cell, hemoglobin, granular, tubular, or mixed </li></ul></ul>
  166. 187. Revised Criteria for Classification of SLE <ul><li>Neurologic disorder- Seizures; Psychosis </li></ul><ul><li>Hematologic disorder </li></ul><ul><ul><li>Hemolytic A with reticulocytosis </li></ul></ul><ul><ul><li>PANCYTOPENIA </li></ul></ul><ul><li>Immunologic disorder: </li></ul><ul><ul><li>(+) LE cell prep; </li></ul></ul><ul><ul><li>(+) Anti- dsDNA </li></ul></ul><ul><ul><li>(+) Anti-Sm </li></ul></ul><ul><ul><li>(+) Antiphospholipid antibodies </li></ul></ul><ul><ul><ul><li>Anticardiolipin antibodies </li></ul></ul></ul><ul><ul><ul><li>(+) lupus anticoagulant </li></ul></ul></ul><ul><ul><ul><li>False-positive serologic test for syphilis </li></ul></ul></ul><ul><li>ANA </li></ul>
  167. 188. CLINICAL MANIFESTATIONS OF SLE 100 80-90 85 55-85 80-100 60 50-70 25-35 45 35 25 20 15-40 15 15 8 th Edition
  168. 189. Multisystem manifestations of Systemic Lupus Erythematosus. SLE affects a wide range of tissues and organ systems
  169. 191. DISCOID RASH
  170. 192. Revised Criteria for Classification of SLE <ul><li>Any 4 or more of the 11 criteria present, serially or simultaneously, during any interval of observation = SLE </li></ul><ul><li>In 1997, anti-phospholipid antibody was added to the list of criteria for the classification of SLE </li></ul>
  171. 193. SLE <ul><li>Antinuclear antibodies </li></ul><ul><ul><li>Antibodies to DNA (Classic SLE) </li></ul></ul><ul><ul><li>Antibodies to histones (Drug induced SLE) </li></ul></ul><ul><ul><li>Antibodies to non- histone proteins bound to RNA </li></ul></ul><ul><ul><li>Antibodies to nucleolar antigens </li></ul></ul><ul><li>ANA test is sensitive, but non specific </li></ul>
  172. 194. SLE <ul><li>Mechanisms of tissue injury </li></ul><ul><ul><li>Type III hypersensitivity reactions with DNA-anti-DNA complexes depositing in vessels </li></ul></ul><ul><li>LE cell - any phagocytic leukocyte (neutrophil or macrophage) that engulfs denatured nuclei of injured cells (evidence of cell injury and exposed nuclei) </li></ul>
  173. 196. SLE: Morphology <ul><li>BV: Acute necrotizing vasculitis of small arteries or arterioles in any organs </li></ul><ul><li>Skin: Erythematous maculopapular eruption over malar regions exacerbated by sun-exposure; some patients have discoid LE with no systemic involvement </li></ul><ul><ul><ul><ul><ul><li>Liquefactive degeneration of basal layer </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Interface dermatitis w/ superficial & deep perivascular lymphocytic infiltrates w/ deposits of immunoglobulins along DEJ </li></ul></ul></ul></ul></ul>
  174. 197. <ul><li>SLE involving the skin. </li></ul><ul><li>An H & E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema of the dermo-epidermal junction </li></ul><ul><li>B. An IF micrograph stained for IgG reveals deposits of Ig along the dermo-epidermal junction </li></ul>
  175. 198. SLE <ul><li>Serosa: Pericardial & pleural serosanguinous exudate </li></ul><ul><li>Heart: Nonbacterial verrucous endocarditis (Libman- Sacks) multiple warty deposits on any valve on either surface of leaflets </li></ul>
  176. 199. Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are indicated by arrows.
  177. 200. SLE <ul><li>Joint: No striking anatomic changes nor deformities, non- specific lymphocytic infiltrates </li></ul><ul><li>Spleen: Splenomegaly, capsular thickening, and follicular hyperplasia </li></ul><ul><li>Lungs: Pleuritis and pleural effusions </li></ul><ul><li>CNS: Multifocal cerebral infarcts from microvascular injury </li></ul><ul><li>Other Organs and Tissues: LE or hematoxylin bodiesnin the bone marrow or other organs. Lymph nodes may be enlarged with hyperplastic follicles or even demonstrate necrotizing lymphadenitis </li></ul>
  178. 201. SLE: Morphology- Renal <ul><li>Mesangial GN Mild s/s </li></ul><ul><ul><li>(10-25%) </li></ul></ul><ul><li>Focal Proliferative GN Mild s/s </li></ul><ul><ul><li>(20-35%) </li></ul></ul><ul><li>Diffuse Proliferative GN Hematuria, </li></ul><ul><ul><li>(35%- 60%) proteinuria & hypertension  renal failure </li></ul></ul><ul><li>Membranous GN Severe proteinuria </li></ul><ul><ul><li>(10-15%) & NS </li></ul></ul>
  179. 202. Lupus nephritis, focal proliferative type. There are two focal necrotizing lesions in the glomerulus (arrows)
  180. 203. Lupus nephritis, diffuse proliferative type. There is marked increase in cellularity throughout the glomrulus
  181. 204. Immune complex deposition in SLE. IF micrograph of a glomrulus stained with anti-IgG from a patient with diffuse proliferative lupus nephritis.
  182. 205. Immune complex deposition in SLE. Electron micrograph of a renal glomerular capillary loop showing subendothelial dense deposits corresponding to “wire loops” seen by light microscopy. Deposits are also seen in the mesangium.
  183. 206. Lupus nephritis. A glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes.
  184. 207. Rheumatic Fever <ul><li>Etiology: Group A, streptococcal pharyngitis </li></ul><ul><li>Pathogenesis: antibody cross-react with connective tissue in susceptible individuals  Autoimmune reaction (2- 3 wks)  Inflammation (T cells, macrophages)  Heart, skin, brain & joints </li></ul>
  185. 208. Morphology: <ul><li>Acute RF </li></ul><ul><ul><li>Acute Inflammatory Phase </li></ul></ul><ul><ul><li>Heart– Pancarditis </li></ul></ul><ul><ul><li>Skin– Erythema Marginatum </li></ul></ul><ul><ul><li>CNS– Sydenham Chorea </li></ul></ul><ul><ul><li>Migratory polyarthritis </li></ul></ul><ul><li>Chronic RF </li></ul><ul><ul><li>Deforming fibrotic valvular disease </li></ul></ul>
  186. 209. Acute Rheumatic vegetations:
  187. 210. Fish-mouth Mitral stenosis
  188. 211. Rheumatoid Arthritis: Etiology <ul><li>HLA- DR4/ DR1 associated (increased incidence) </li></ul><ul><li>Incidence: 1% of population; 4 th & 5 th decades; 3 - 5X F > M </li></ul><ul><li>80% of patients with Rheumatoid Factors (Abs against Fc portion of IgG) </li></ul>
  189. 212. Rheumatoid Arthritis: Pathogenesis <ul><li>Precise trigger is unknown </li></ul><ul><li>Activation of T-helper cells  cytokines  activate B cells  Abs  Non-suppurative proliferative synovitis (destruction of articular cartilage & progressive disabling arthritis) </li></ul><ul><li>Extra-articular manifestations resemble SLE or scleroderma </li></ul>
  190. 213. Multisystem manifestations of Rheumatoid arthritis. Although the initial manifestation is usually arthritis, Rheumatoid disease is a systemic illness.
  191. 214. Rheumatoid Arthritis: Clinical course <ul><li>Symmetrical, polyarticular arthritis </li></ul><ul><li>Weakness, fever, malaise may accompany joint symptoms </li></ul><ul><li>Stiffness of joints in AM early  claw-like deformities </li></ul><ul><li>Anemia of chronic disease present in late cases </li></ul><ul><li>Severely crippling in 15-20 years, life expectancy reduced 4-10 years </li></ul><ul><li>Amyloidosis develops in 5%-10% of patients </li></ul>
  192. 215. Rheumatoid Arthritis: Morphology <ul><li>Symmetric arthritis of small joints (proximal interphalangeal & metacarpophalangeal </li></ul><ul><li>Chronic synovitis, proliferation of synovial lining cells (villous projections) </li></ul><ul><li>Subsynovial inflammatory cells  lymphoid nodules </li></ul><ul><li>Pannus- highly vascularized, inflamed, reduplicated synovium </li></ul><ul><li>Fibrosis & calcification  ankylosis </li></ul><ul><li>Synovial fluid contains neutrophils </li></ul>
  193. 216. Rheumatoid synovitis. The synovium is swollen and shows villous pattern. There is great increase in chronic inflammatory cells in the synovial stroma, often with exudate in the joint space and fibrin deposited on the synovial surface.
  194. 217. Articular cartilage destruction. Vascular granulation tissue grows across the surface of the carilage (pannus) from the edges of the joint, and the articular surface shows loss of cartilage beneath the extending pannus.
  195. 218. The inflammatory pannus causes FOCAL DESTRUCTION OF BONE. At the edges of the joint there is osteolytic destruction of bone. This phase is associated with joint deformity.
  196. 220. The characteristic deformity and soft tissue swelling associated with long-standing rheumatoid disease of the hands.
  197. 223. Rheumatoid Arthritis: Morphology <ul><li>Rheumatoid nodules (25% of patients) </li></ul><ul><ul><li>Subcutaneous nodules along extensor surfaces of forearms or other sites of trauma </li></ul></ul><ul><ul><li>Firm, non-tender, up to 2 cm. diameter </li></ul></ul><ul><li>Dermal nodules with fibrinoid necrosis surrounded by macrophages & granulation tissue </li></ul><ul><li>Progressive interstitial fibrosis of lungs some cases </li></ul>
  198. 224. Rheumatoid nodule. At the elbow there is a large raised subcutaneous nodule. The nodule is composed of degenerate collagen (arrow) surrounded by a chronic reaction with macrophages and giant cells, and walled off by fibrosis.
  199. 225. Juvenile Rheumatoid Arthritis <ul><li>Chronic idiopathic arthritis in children </li></ul><ul><li>Some variants involve few large joints (pauciarticular) </li></ul><ul><li>Do not have rheumatoid factor </li></ul><ul><li>Others assoc. w/ HLA-B27 </li></ul><ul><li>Uveitis may be present </li></ul><ul><li>Still’s disease </li></ul><ul><ul><li>Acute febrile onset </li></ul></ul><ul><ul><li>Leukocytosis </li></ul></ul><ul><ul><li>Hepatosplenomegaly </li></ul></ul><ul><ul><li>Lymphoadenopathy & skin rash </li></ul></ul>
  200. 226. Sjogren’s Syndrome: Features <ul><li>Dry eyes (keratoconjunctivitis sicca) & dry mouth (xerostomia) due to immune destruction of the lacrimal and salivary glands </li></ul><ul><li>Sicca syndrome- this phenomenon occurring as an isolated syndrome </li></ul><ul><li>Frequently associated with RA, some with SLE or other autoimmune processes </li></ul><ul><li>Associated with HLA- DR3 </li></ul>
  201. 227. Sjogren’s syndrome: Pathogenesis <ul><li>Primary target is ductal epithelial cells of exocrine glands </li></ul><ul><li>B-cell hyperactivity  hypergammaglobulinemia, ANAs </li></ul><ul><li>Primary defect is in T-helper cells (too many) </li></ul><ul><li>Most have anti -SS-A & anti-SS-B Abs </li></ul>
  202. 228. Sjogren’s syndrome: Clinical course <ul><li>Primarily in women > 40 </li></ul><ul><li>Dry mouth, lack of tears </li></ul><ul><li>Salivary glands enlarged </li></ul><ul><li>Lacrimal & salivary gland inflammation of any cause (including Sjogren's) is called Mikulicz's syndrome </li></ul><ul><li>60% w/ other CTD </li></ul><ul><li>1% develop lymphoma, 10% w/ pseudolymphomas </li></ul>
  203. 232. Sjogren’s syndrome: Morphology <ul><li>All secretory glands can be involved </li></ul><ul><li>Intense lymphoplasmacellular infiltrates </li></ul><ul><li>2ndary inflammation of corneal epithelium (due to drying)  ulceration & xerostomia </li></ul><ul><li>Can develop respiratory symptoms </li></ul><ul><li>25% develop extraglandular disease (most with anti-SS-A) CNS, kidneys, skin & muscles </li></ul>
  204. 235. Systemic Sclerosis (Scleroderma) <ul><li>A chronic disease characterized by </li></ul><ul><ul><li>Chronic inflammation thought to be a result of autoimmunity </li></ul></ul><ul><ul><li>Widespread damage to small blood vessels </li></ul></ul><ul><ul><li>Progressive interstitial and perivascular fibrosis in the skin and multiple organs </li></ul></ul>
  205. 236. Systemic Sclerosis (Scleroderma) <ul><li>Etiology: Unknown </li></ul><ul><li>Most common in 3 rd - 5 th decades </li></ul><ul><li>3X as frequent in women as in men </li></ul><ul><li>95% w/ skin involvement </li></ul><ul><li>Can be Diffuse or Limited </li></ul>
  206. 237. Systemic Sclerosis (Scleroderma) <ul><li>Pathogenesis: </li></ul><ul><ul><li>Abnormal immune responses </li></ul></ul><ul><ul><ul><li>CD4+ T cells responding to an unidentified antigen accumulates in the skin and release cytokines that activate inflammatory cell and fibroblasts </li></ul></ul></ul><ul><ul><li>Vascular damage </li></ul></ul><ul><ul><ul><li>Microvascular disease is consistently present early in the course of systemic sclerosis and may be the initial lesion </li></ul></ul></ul><ul><ul><li>Collagen deposition </li></ul></ul>
  207. 238. Possible mechanisms leading to systemic sclerosis
  208. 239. Schematic illustration of the possible mechanisms leading to systemic sclerosis
  209. 240. Systemic Sclerosis (Scleroderma) <ul><li>Diffuse Scleroderma: </li></ul><ul><ul><li>Anti-DNA topoisomerase I (Scl-70) is highly specific in 75% of patients (nucleolar pattern of staining) </li></ul></ul><ul><li>Limited Scleroderma (CREST): </li></ul><ul><ul><li>Anti-centromere pattern in 60%-80% of patients </li></ul></ul><ul><li>Suggested that microvascular disease may play some role in development of fibrosis </li></ul>
  210. 241. Systemic Sclerosis: Clinical course <ul><li>Raynaud’s phenomenon reversible vasospasm of digital arteries  color changes; sensitivity to cold </li></ul><ul><li>Fibrosis  joint immobilization </li></ul><ul><li>Eosphageal fibrosis  dysphagia & GI hypomotility </li></ul><ul><li>Pulmonary fibrosis  dyspnea & chronic cough  RSHF </li></ul><ul><li>Malignant HPN (hyperplastic arteriolosclerosis)  renal failure </li></ul><ul><li>35%-70% 10 year survival with Diffuse SS </li></ul>
  211. 242. Systemic Sclerosis: Clinical course <ul><li>CREST (Limited Scleroderma) </li></ul><ul><li>C alcinosis </li></ul><ul><li>R aynaud’s phenomenon </li></ul><ul><li>E sophageal dysmotility </li></ul><ul><li>S clerodactyly (Dermal fibrosis) </li></ul><ul><li>T elangiectasia </li></ul><ul><li>Better long-term survival than Diffuse PSS </li></ul>
  212. 243. Multisystem manifestations of Systemic Sclerosis. Systemic Sclerosis affects a wide range of tissues and organ systems, often as a result of vascular obliteration.
  213. 244. The fingers in some patients with Systemic Sclerosis are narrowed, with tight shiny skin. Subcutaneous calcification (calcinosis cutis) can also be seen as white spots on the edges of the fingers.
  214. 248. Systemic Sclerosis: Morphology <ul><li>Skin: fingers & distal extremities then spreads, shows edema & inflammation  thickened collagen & epidermal atrophy; subcutaneous calcification (esp in CREST); Morphea- skin fibrosis only </li></ul><ul><li>GI tract (80% of patients): atrophy & fibrosis of esophageal wall w/ mucosal atrophy, BV thickening </li></ul>
  215. 249. Systemic Sclerosis: Morphology <ul><li>MS: inflammatory synovitis  fibrosis  joint destruction; muscle atrophy </li></ul><ul><li>Lungs: interstitial fibrosis (honeycomb) & BV thickening </li></ul><ul><li>Kidneys: </li></ul><ul><ul><li>66% concentric thickening of vessels </li></ul></ul><ul><ul><li>30% malignant hypertension (fibrinoid necrosis of arterioles) </li></ul></ul><ul><li>Heart: focal interstitial fibrosis & slight inflammation </li></ul>
  216. 251. Mixed Connective Tissue Disease <ul><li>Used to describe a disease with clinical features that are a mixture of the features of SLE, systemic sclerosis, and polymyositis </li></ul><ul><li>Characterized serologically by high titers of antibodies to ribonucleoprotein particle-containing U1ribonucleoprotein </li></ul>
  217. 252. Polyarteritis Nodosa and Other Vasculitides <ul><li>Belongs to a group of diseases characterized by necrotizing inflammation of the walls of blood vessels and showing strong evidence of an immunological pathogenetic mechanism </li></ul>
  218. 253. Polymyositis- Dermatomyositis- inclusion body myositis <ul><li>Inflammation of skeletal muscle with weakness </li></ul><ul><li>Sometimes associated w/ skin rash (dermatomyositis) </li></ul><ul><li>Incidence: 40-60 also in 5-15 y/o, mostly in women </li></ul><ul><li>Mainly mediated by cytotoxic CD8 cells </li></ul><ul><li>In dermatomyositis, mainly ICs produce a vasculitis in muscle & skin </li></ul><ul><li>Adults (10-20%) develop cancer </li></ul>
  219. 254. Polymyositis- Dermatomyositis- inclusion body myositis <ul><li>I. Adult polymyositis (w/o skin involvement nor visceral CA; CD8 mediated) </li></ul><ul><li>II. Adult dermatomyositis (Ab mediated) </li></ul><ul><li>III. Polymyositis or dermatomyositis w/ malignancy </li></ul><ul><li>IV. Childhood dermatomyositis </li></ul><ul><li>V. Polymyositis or dermatomyositis w/ immunologic disease </li></ul>
  220. 255. Polymyositis- Dermatomyositis- inclusion body myositis <ul><li>Immunologic abnormality: </li></ul><ul><ul><li>Anti PM 1 & anti Jo </li></ul></ul><ul><li>Pathology: </li></ul><ul><ul><li>Striated muscles: necrosis, regeneration, mononuclear infiltrates & atrophy of symmetric proximal muscle groups </li></ul></ul><ul><ul><li>Skin: Heliotrope rash; Grottons lesions </li></ul></ul>
  221. 256. DERMATOMYOSITIS Take note of the rash affecting the eyelids.
  222. 257. DERMATOMYOSITIS The histologic appearance of muscle shows fascicular inflammation and atrophy.
  223. 258. INCLUSION BODY MYOSITIS Shows a vacuole within a myocyte.
  224. 259. Polymyositis- Dermatomyositis- inclusion body myositis: Diagnosis <ul><li>Location of muscles involved </li></ul><ul><li>Elevation of CPK MM </li></ul><ul><li>EMG </li></ul><ul><li>Biopsy </li></ul><ul><li>Cutaneous lesions </li></ul>
  227. 263. IMMUNODEFICIENCY SYNDROMES <ul><li>Primary immunodeficiency disorders </li></ul><ul><ul><li>Almost always genetically determined </li></ul></ul><ul><ul><li>Affect the humoral and/or cellular arms of adaptive immunity or the defense mechanisms of innate immunity </li></ul></ul><ul><li>Secondary immunodeficiency states </li></ul><ul><ul><li>May arise as complications of cancers, infections, malnutrition, or side-effects of immunosuppression, irradiation, or chemotherapy for cancer and other diseases </li></ul></ul>
  228. 264. IMMUNODEFICIENCY SYNDROMES <ul><li>Risk factors for immune disorders </li></ul><ul><ul><li>Prematurity </li></ul></ul><ul><ul><li>Autoimmune diseases (e.g., SLE) </li></ul></ul><ul><ul><li>Lymphoproliferative disorders </li></ul></ul><ul><ul><li>Infections (e.g., HIV) </li></ul></ul><ul><ul><li>Immunosuppressive drugs (e.g., corticosteroids) </li></ul></ul>
  229. 265. Simplified scheme of lymphocyte development and sites of block in primary immunodeficiency diseases
  230. 268. PRIMARY IMMUNODEFICIENCIES <ul><li>X-linked Agammaglobulinemia of Bruton </li></ul><ul><li>◘ Failure of B-cell precursors ( pro-B cells and pre-B cells) to differentiate into B cells </li></ul><ul><li>◘ maturation stops after the rearrangement of heavy- chain genes; light chains are not produced </li></ul><ul><li>◘ the block in differentiation is due to mutations in a cytoplasmic tyrosine kinase – Bruton tyrosinase kinase ( btk ) </li></ul>
  231. 269. PRIMARY IMMUNODEFICIENCIES <ul><li>X-linked Agammaglobulinemia of Bruton </li></ul><ul><li>◘ seen almost entirely in males but sporadic cases seen in females </li></ul><ul><li>◘ does not become apparent until about 6 months of life </li></ul><ul><li>◘ recurrent bacterial infections of the respiratory tract call attention to the underlying immune defect – H. influenzae, S. pneumoniae, or S. aureus </li></ul><ul><li>◘ 35% of children develop arthritis that respond to Ig therapy </li></ul><ul><li>◘ SLE and Dermatomyositis occur with increased frequency </li></ul><ul><li>◘ Treatment is replacement therapy with Ig </li></ul>
  232. 270. PRIMARY IMMUNODEFICIENCIES <ul><li>X-linked Agammaglobulinemia of Bruton </li></ul><ul><li>Characteristics: </li></ul><ul><li>◘ B cells are absent or remarkably decreased and serum classes of all Ig are depressed </li></ul><ul><li>◘ Germinal centers of LN, Peyer’s patches, the appendix, and tonsils are underdeveloped or rudimentary </li></ul><ul><li>◘ there is remarkable absence of plasma cells throughout the body </li></ul><ul><li>◘ T cell-mediated reactions are entirely normal </li></ul>
  233. 271. PRIMARY IMMUNODEFICIENCIES <ul><li>2. Common Variable Immunodeficiency </li></ul><ul><li>◘ Feature common to all patients is hypogammaglobulinemia, generally affecting all classes of antibody but sometimes only IgG </li></ul><ul><li>◘ Diagnosis is based on exclusion of other well-defined causes of decreased antibody synthesis </li></ul><ul><li>◘ No evidence of any intrinsic B cell defect </li></ul>
  234. 272. PRIMARY IMMUNODEFICIENCIES <ul><li>Common Variable Immunodeficiency </li></ul><ul><li>◘ Clinical manifestations resemble X-linked agammaglobulinemia </li></ul><ul><li>◘ 20% of patients have recurrent herpesvirus infections </li></ul><ul><li>◘ Affects both sexes equally </li></ul><ul><li>◘ Onset of symptoms is later – in childhood or adolescence </li></ul><ul><li>◘ Histologically, B cell areas of lymphoid tissues are hyperplasplastic </li></ul><ul><li>◘ Increased incidence of RA, PA, HA, lymphoid malignancy, and gastric cancer (50-fold) </li></ul>
  235. 273. PRIMARY IMMUNODEFICIENCIES <ul><li>3. Isolated IgA deficiency </li></ul><ul><li>◘ Affected individuals have extremely low levels of both serum and secretory IgA </li></ul><ul><li>◘ Most individuals with this disease are completely asymptomatic </li></ul><ul><li>◘ Mucosal defenses are weakend and infections occur in the respiratory, gastrointestinal and urogenital tracts </li></ul><ul><li>◘ Symptomatic patients commonly present with recurrent sino-pulmonary infections and diarrhea </li></ul>
  236. 274. PRIMARY IMMUNODEFICIENCIES <ul><li>Isolated IgA deficiency </li></ul><ul><li>◘ Basic defect is in the differentiation of IgA B lymphocytes </li></ul><ul><li>◘ In most patients, the number of IgA positive B cells is normal, but only few of these cells can be induced to transform into IgA plasma cells in vitro </li></ul><ul><li>◘ Serum antibodies to IgA are found in approximately 40% of the patients </li></ul><ul><li>◘ Fatal anaphylactic reactions occur if transfused with blood containing normal IgA </li></ul>
  237. 275. PRIMARY IMMUNODEFICIENCIES <ul><li>4. Hyper IgM Syndrome </li></ul><ul><li>◘ Affected patients make IgM antibodies but are deficient in their ability to produce IgG, IgA, and IgE antibodies </li></ul><ul><li>◘ A T cell disorder in which functionally abnormal T cells fail to induce B cells to make antibodies of isotypes other than IgM </li></ul><ul><li>◘ Clinically, male patients with the X-linked form present with recurrent pyogenic infections, susceptible to Pneumocystis carinii pneumonia </li></ul><ul><li>◘ Serum of patients contains normal or elevated levels of IgM and IgD but no IgA or IgE and extremely low levels of IgG </li></ul>
  238. 276. PRIMARY IMMUNODEFICIENCIES <ul><li>5. DiGeorge Syndrome (Thymic Hypoplasia) </li></ul><ul><li>◘ T cell deficiency that derives from failure of development of the 3 rd and 4 th pharyngeal pouches – thymus, parathyroids, some clear cells of the thyroid, and ultimobranchial body </li></ul><ul><li>◘ Variable loss of T cell-mediated immunity, tetany, congenital defects of the heart and great vessels </li></ul><ul><li>◘ Appearance of the mouth, ears, and facies maybe abnormal </li></ul>
  239. 277. PRIMARY IMMUNODEFICIENCIES <ul><li>DiGeorge Syndrome (Thymic Hypoplasia) </li></ul><ul><li>◘ Low levels of circulating T lymphocytes and a poor defense against certain fungal and viral infections </li></ul><ul><li>◘ Plasma cells are present in normal numbers in lymphoid tissues; depleted in paracortical areas of the LN and periateriolar sheaths of spleen </li></ul><ul><li>◘ Ig levels maybe normal or reduced, depending on the severity of the T cell deficiency </li></ul>
  240. 278. PRIMARY IMMUNODEFICIENCIES <ul><li>DiGeorge Syndrome (Thymic Hypoplasia) </li></ul><ul><li>◘ Partial DiGeorge syndrome – small but histologically normal thymus, T cell function improves with age </li></ul><ul><li>◘ Complete absence of thymus – transplantation of fetal thymus may be of benefit </li></ul><ul><li>◘ A component of 22q11 deletion syndrome </li></ul>
  241. 279. PRIMARY IMMUNODEFICIENCIES <ul><li>6. Severe Combined Immunodeficiency Diseases </li></ul><ul><li>◘ Involves both humoral and cell-mediated immune responses </li></ul><ul><li>◘ Affected infants present with oral candidiasis, extensive diaper rash, and failure to thrive </li></ul><ul><li>◘ Definitive treatment – bone marrow transplantation </li></ul>
  242. 280. PRIMARY IMMUNODEFICIENCIES <ul><li>Severe Combined Immunodeficiency Diseases </li></ul><ul><li>◘ Classic Form – defect in the common lymphoid stem cell </li></ul><ul><li>◘ X-linked – genetic defect is mutation in the common γ chain subunit ( γ c) of several cytokine receptors </li></ul><ul><li>◘ Autosomal recesive – deficiency of the adenosine deaminase (ADA) enzyme </li></ul><ul><li>= leads to accumulation of deoxyadenosine and its derivatives which are toxic to immature lymphocytes esp. of T cell lineage </li></ul><ul><li>***histologic findings = small thymus devoid of lymphoid cells </li></ul>
  243. 281. PRIMARY IMMUNODEFICIENCIES <ul><li>7. Immunodeficiency with Thrombocytopenia and Eczema (Wiskott-Aldrich Syndrome) </li></ul><ul><li>◘ X-linked recessive disease char. by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection ending in early death </li></ul><ul><li>◘ Thymus is morphologically normal, but there is progressive secondary depletion of T lymphocytes in the peripheral blood and in the paracortical areas of LN </li></ul><ul><li>◘ IgM is low; IgG normal; IgA & IgE elevated </li></ul><ul><li>◘ The syndrome maps to Xp11.23 – inc. lymphoma </li></ul><ul><li>◘ Treatment is bone marrow transplantation </li></ul>
  244. 282. PRIMARY IMMUNODEFICIENCIES <ul><li>8. Genetic Deficiencies of the Complement System </li></ul><ul><li>◘ Deficiency of C2 is the most common </li></ul><ul><li>= inc. incidence of SLE-like disease </li></ul><ul><li>◘ Deficiency of C3 </li></ul><ul><li>= serious and recurrent pyogenic infections </li></ul><ul><li>= immune complex-mediated GN </li></ul><ul><li>◘ C5, 6, 7, 8, and 9 </li></ul><ul><li>= increased susceptibility to recurrent neisserial infections </li></ul><ul><li>◘ C1 inhibitor deficiency = hereditary angioedema </li></ul>
  245. 286. ACQUIRED IMMUNODEFICIENCY SYNDROME <ul><li>◘ A retroviral disease characterized by by profound immunosuppression that leads to opportunistic infections, secondary neoplasms, and neurologic manifestations </li></ul><ul><li>◘ Second leading cause of death in men 25-44 years old </li></ul><ul><li>◘ 3 rd leading cause of death in women </li></ul>
  246. 287. HUMAN IMMUNODEFICIENCY VIRUS (HIV) <ul><li>Etiologic agent of AIDS </li></ul><ul><li>Discovered independently by Luc Montagnier of France and Robert Gallo of the US in 1983-1984 </li></ul><ul><li>Former names of the virus include : </li></ul><ul><ul><li>Human T cell Lymphotrophic virus (HTLV-III) </li></ul></ul><ul><ul><li>Lymphadenopathy associated virus (LAV) </li></ul></ul><ul><ul><li>AIDS associated retrovirus (ARV) </li></ul></ul><ul><ul><li>***HIV-2 discovered in 1986, antigenically distinct virus endemic in West Africa </li></ul></ul>
  247. 288. ACQUIRED IMMUNODEFICIENCY SYNDROME <ul><li>◘ Groups at risk of developing AIDS </li></ul><ul><li>1. Homosexual or bisexual men – over 50% </li></ul><ul><li>2. Intravenous drug abusers – 20% </li></ul><ul><li>3. Hemophiliacs – 0.5% </li></ul><ul><li>4. Recipients of blood and blood components – 1.0% </li></ul><ul><li>5. Heterosexual contacts of members of other high-risk groups – 10% </li></ul>
  248. 289. ACQUIRED IMMUNODEFICIENCY SYNDROME <ul><li>◘ 2% of all cases occurs under 13 years old, 90% of these resulted from transmission of the virus from mother to child, remaining 10% are hemophiliacs or received blood/blood products </li></ul><ul><li>◘ 3 major routes of transmission </li></ul><ul><li>1. sexual transmission – 75% </li></ul><ul><li>2. parenteral transmission </li></ul><ul><li>  IV drug users, hemophiliacs, BT </li></ul><ul><li>3. mother-to-infant transmission </li></ul><ul><li> </li></ul>
  249. 290. ACQUIRED IMMUNODEFICIENCY SYNDROME <ul><li>◘ mother-to-infant transmission – pediatric AIDS </li></ul><ul><li>1. in utero by transplacental spread </li></ul><ul><li>2. during delivery through an infected birth canal </li></ul><ul><li>3. after birth by ingestion of breast milk </li></ul><ul><li>☻☻ Extensive studies indicate that HIV infection cannot be transmitted by casual personal contact in the household, workplace, or school </li></ul><ul><li>☻☻ Seroconversion after needle-stick injury – 0.3% </li></ul>
  250. 291. ACQUIRED IMMUNODEFICIENCY SYNDROME <ul><li>◘ Etiology: </li></ul><ul><li>1. HIV-1 – most common type associated with AIDS in the US, Europe, and Central Africa </li></ul><ul><li>2. HIV-2 – West Africa and India </li></ul>
  251. 292. ACQUIRED IMMUNODEFICIENCY SYNDROME <ul><li>◘ Contents of the viral core </li></ul><ul><li>1. major capsid protein p24 </li></ul><ul><li>2. nucleocapsid protein p7/p9 </li></ul><ul><li>3. two copies of genomic RNA </li></ul><ul><li>4. three viral enzymes – protease, reverse transcriptase, and integrase </li></ul><ul><li>۞ p24 most readily detected viral antigen hence the target for the antibodies used for diagnosis </li></ul>
  252. 293. Schematic illustration of an HIV-1 virion
  253. 294. HIV proviral genome. Several viral genes and their corresponding functions
  254. 295. Life cycle of HIV, showing the steps from viral entry to production of infectious virions
  255. 296. Molecular basis of HIV entry into host cells.
  256. 297. Pathogenesis of HIV-1 infection.
  257. 298. Pathogenesis of HIV infection
  258. 299. Mechanisms of CD4+ T-cell loss in HIV infection
  259. 300. Multiple effects of loss of CD4 + T cells as a result of HIV infection
  260. 302. CDC Classification Categories of HIV infection AIDS, indicator conditions: constitutional disease, neurologic disease, or neoplasm B3 B2 B1 Symptomatic, not A nor C conditions A3 A2 A1 Asymptomatic, acute (primary) HIV, or persistent generalized lymphadenopathy 3 <200 cells/uL 2 200-499 cells/uL 1 > 500 cells/uL Clinical Categories
  261. 305. Typical course of HIV infection
  262. 309. Algorithm for Serologic Testing for AIDS
  263. 310. AMYLOIDOSIS
  264. 311. AMYLOIDOSIS <ul><li>◘ Amyloid is a pathologic proteinaceous substance, deposited in between cells in various tissues and organs of the body in a wide variety of clinical settings </li></ul><ul><li>◘ Appears as an amorphous, eosinophilic, hyaline, extracellular substances that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells </li></ul>
  265. 312. Structure of an amyloid fibril
  266. 313. Amyloid structure
  267. 314. A section of the liver stained with Congo Red Yellow-green birefringence of the deposits observed under polarizing microscope
  268. 315. AMYLOIDOSIS <ul><li>◘ Chemical nature </li></ul><ul><li>- 95% consist of fibril proteins, 5% P component and other glycoproteins </li></ul><ul><li>- 3 most common amyloid proteins </li></ul><ul><li>1. AL (amyloid light chain) – derived from plasma cells and contains Ig light chains </li></ul><ul><li>2. AA (amyloid-associated) – non-Ig protein synthesized by the liver </li></ul><ul><li>3. A β amyloid – found in Alzheimer disease </li></ul><ul><li>◘ Other biochemical distinct proteins found in amyloid deposits </li></ul><ul><li>- Transthyretin (TTR), β 2-microglobulin, prion proteins </li></ul>
  269. 316. Types of Amyloidosis <ul><li>1. Systemic </li></ul><ul><ul><li>Similar tissue involvement in both primary and secondary types </li></ul></ul><ul><ul><li>Primary amyloidosis </li></ul></ul><ul><ul><ul><li>AL amyloid deposition </li></ul></ul></ul><ul><ul><ul><li>Associated with multiple myeloma (30% of cases) </li></ul></ul></ul><ul><ul><li>Secondary (reactive) </li></ul></ul><ul><ul><ul><li>AA amyloid </li></ul></ul></ul><ul><ul><ul><li>Associated with chronic inflammation (e.g., RA, Tb) </li></ul></ul></ul>
  270. 317. Types of Amyloidosis <ul><li>2. Localized </li></ul><ul><ul><li>Confined to a single organ (e.g. brain) </li></ul></ul><ul><ul><li>Alzheimer’s disease </li></ul></ul><ul><ul><ul><li>A ß </li></ul></ul></ul><ul><ul><ul><li>Most common cause of dementia </li></ul></ul></ul><ul><li>3. Hereditary </li></ul><ul><ul><li>Autosomal recessive disorder involving AA amyloid (e.g., Familial Mediterranean fever) </li></ul></ul>
  271. 319. AMYLOIDOSIS <ul><li>Pathogenesis </li></ul><ul><ul><li>Abnormal folding of proteins, which are deposited as fibrils in extracellular tissues and disrupt normal function </li></ul></ul>
  272. 320. Proposed mechanisms in the pathogenesis of amyloidosis
  273. 321. Amyloidosis - Morphology <ul><li>◘ Gross – Affected organs are often enlarged and firm and have a waxy appearance. </li></ul><ul><li> - Painting the cut surface with iodine imparts a yellow color that is transformed to blue violet after application of sulfuric acid </li></ul><ul><li>◘ Microscopic – Based almost entirely on its staining characteristics (Congo Red) </li></ul>
  274. 322. Amyloidosis - Morphology <ul><li>◘ Kidney </li></ul><ul><li>- most common and potentially the most serious form of organ involvement </li></ul><ul><li>- may appear normal in size and color or it may be enlarged in advanced cases </li></ul><ul><li>- it may be shrunken and contracted due to vascular narrowing induced by amyloid deposits </li></ul><ul><li>- deposited primarily in glomeruli, but also affected are the interstitial peritubular tissue, arteries, and arterioles </li></ul>
  275. 323. Amyloidosis - Morphology <ul><li>◘ Kidney </li></ul><ul><li> thickening of the mesangial matrix + uneven widening of the basement membrane of glomerular capillaries  capillary narrowing and distortion of glomerular vascular tuft  obliteration of capillary lumens  masses or interlacing broad ribbons of amyloid </li></ul>
  276. 324. Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid
  277. 325. Amyloidosis - Morphology <ul><li>◘ Spleen </li></ul><ul><li>- inapparent grossly or may cause moderate to marked splenomegaly (up tp 800 grams) </li></ul><ul><li>- Sago spleen  deposit limited largely the the splenic follicles, producing tapioca-like granules on gross inspection </li></ul><ul><li>- Lardaceous spleen  involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the early deposits gives rise to large, maplike areas of amyloidosis </li></ul>
  278. 326. Amyloidosis - Morphology <ul><li>◘ Liver </li></ul><ul><li>- grossly inapparent or cause moderate to marked hepatomegaly </li></ul><ul><li>- appears first in the space of Disse  encroach on adjacent hepatic parenchymal cells and sinusoids  deformity, pressure atrophy, disappearance of hepatocytes </li></ul><ul><li>- Vascular involvement and Kupffer cell depositions are frequent </li></ul><ul><li>- Normal liver function is usually preserved </li></ul>
  279. 327. Amyloidosis - Morphology <ul><li>◘ Heart </li></ul><ul><li>- may be enlarged and firm, shows no significant changes on cross-section of the myocardium </li></ul><ul><li>- deposits begin in subendocardial accumulations and within the myocardium between the muscle fibers  expansion  pressure atrophy </li></ul><ul><li>- conduction system damaged leads to electrocardiographic abnormalities </li></ul>
  280. 328. Amyloidosis - Morphology <ul><li>◘ Other organs </li></ul><ul><li>- encountered in systemic disease </li></ul><ul><li>- adrenals, thyroid, and pituitary </li></ul><ul><li>- GIT </li></ul><ul><li>- tongue – tumor-forming amyloid of the tongue </li></ul><ul><li>- Respiratory tract </li></ul><ul><li>- Brain – Alzheimer’s disease </li></ul><ul><li>- Peripheral and Autonomic nerves </li></ul><ul><li>- median nerve – carpal tunnel syndrome </li></ul>
  281. 329. THANK YOU!