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Disorders of Immunity A- Mechanisms of immune- mediated injury (Hypersensitivity Reactions) B- Autoimmune Diseases C- Immu...
<ul><li>Hypersensitivity (Allergy, immune mediated injury) </li></ul><ul><li>Hypersensitivity: A change in the tissue reac...
IMMUNE MECHANISMS OF TISSUE INJURY  Hypersensitivity reactions/diseases <ul><li>Classified into 4 types based on the immun...
Type I Hypersensitivity Anaphylaxis; Anaphylactic Reaction <ul><li>Mast cell proliferation and IgE production by plasma ce...
<ul><li>Phases of Type I Hypersensitivity </li></ul><ul><li>Initial  (rapid)  response :   within 5-30 min after re-exposu...
Type I Hypersensitivity A sequence of Events Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th  ed., Saunders, ...
<ul><li>Systemic anaphylaxis:  </li></ul><ul><li>-- Acute asthma </li></ul><ul><li>-- Laryngeal edema </li></ul><ul><li>--...
<ul><li>Local anaphylaxis   (Atopy):  </li></ul><ul><li>-  Food allergies </li></ul><ul><ul><li>-- Urticaria or Hives </li...
Type II Hypersensitivity <ul><li>1-   Complement Dependent Reaction: </li></ul><ul><ul><li>Antibody is directed against a ...
Type II Hypersensitivity 2- Antibody- Dependent Cell- Mediated Cytotoxicity (ADCC) <ul><ul><li>Targets are lysed by non- s...
Type II Hypersensitivity Reaction 3- Antibody- mediated cellular dysfunction   <ul><li>Myasthenia gravis :  Antibodies aga...
Type II Hypersensitivity Antibody-Mediated Injury <ul><li>Myasthenia gravis </li></ul><ul><li>(Acetylcholine receptor anti...
Type II Hypersensitivity Reaction Clinical Manifestations   <ul><li>Transfusion and transplant reactions </li></ul><ul><li...
Type II Hypersensitivity Reaction Clinical Manifestations   <ul><li>Autoimmune hemolytic anemia </li></ul><ul><li>Agranulo...
Type III Hypersensitivity Immune Complex Mediated <ul><li>Ag-Ab complexes is formed either in circulation or extravascular...
Type III Hypersensitivity Immune Complex Mediated <ul><li>Immune complexes can be deposited: </li></ul><ul><li>I-  Systemi...
I- Systemic Immune Complex Disease
Immune Complex Mediated (Type III) Damage Systemic <ul><li>Acute (single large dose of Ag exposure): </li></ul><ul><li>Acu...
Immune Complex Deposition in Glomerulus Type III Hypersensitivity
<ul><li>II- Local Immune Complex Disease (Arthus Reaction) </li></ul><ul><li>It is defined as a localized area of tissue n...
<ul><li>Type IV Hypersensitivity (Cell- Mediated) </li></ul><ul><li>Initiated by specifically sensitized T lymphocytes rat...
Type IV Hypersensitivity Delayed Hypersensitivity Reaction <ul><li>CD4+ T lymphocytes + class II HLA molecules </li></ul><...
Granuloma Formation Multinucleated  giant cell
<ul><li>2) T cell-Mediated Cytotoxicity </li></ul><ul><li>Sensitized  CD8+ cytotoxic T lymphocytes (CTLs)  is the principl...
 
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Immunopathology lecture 2+3 ,final Slide 1 Immunopathology lecture 2+3 ,final Slide 2 Immunopathology lecture 2+3 ,final Slide 3 Immunopathology lecture 2+3 ,final Slide 4 Immunopathology lecture 2+3 ,final Slide 5 Immunopathology lecture 2+3 ,final Slide 6 Immunopathology lecture 2+3 ,final Slide 7 Immunopathology lecture 2+3 ,final Slide 8 Immunopathology lecture 2+3 ,final Slide 9 Immunopathology lecture 2+3 ,final Slide 10 Immunopathology lecture 2+3 ,final Slide 11 Immunopathology lecture 2+3 ,final Slide 12 Immunopathology lecture 2+3 ,final Slide 13 Immunopathology lecture 2+3 ,final Slide 14 Immunopathology lecture 2+3 ,final Slide 15 Immunopathology lecture 2+3 ,final Slide 16 Immunopathology lecture 2+3 ,final Slide 17 Immunopathology lecture 2+3 ,final Slide 18 Immunopathology lecture 2+3 ,final Slide 19 Immunopathology lecture 2+3 ,final Slide 20 Immunopathology lecture 2+3 ,final Slide 21 Immunopathology lecture 2+3 ,final Slide 22 Immunopathology lecture 2+3 ,final Slide 23 Immunopathology lecture 2+3 ,final Slide 24 Immunopathology lecture 2+3 ,final Slide 25
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Immunopathology lecture 2+3 ,final

  1. 1. Disorders of Immunity A- Mechanisms of immune- mediated injury (Hypersensitivity Reactions) B- Autoimmune Diseases C- Immunodeficiency Diseases D- Amyloidosis
  2. 2. <ul><li>Hypersensitivity (Allergy, immune mediated injury) </li></ul><ul><li>Hypersensitivity: A change in the tissue reaction following re-exposure to antigen </li></ul><ul><li>Antigen (first time)  No harmful effect + stimulation of formation of specific antibodies </li></ul><ul><li>(Second time)  Ag will react with the specific antibody fixed on the cells </li></ul><ul><li>Cellular damage with severe inflammatory reaction = hypersensitivity </li></ul>OR Hypersensitivity is a state of altered immune responsiveness in which a severe and harmful immune reaction occurs on exposure to the antigen.
  3. 3. IMMUNE MECHANISMS OF TISSUE INJURY Hypersensitivity reactions/diseases <ul><li>Classified into 4 types based on the immune mechanisms of tissue injury: </li></ul><ul><li>Type I , Type II , Type III and Type IV. </li></ul>
  4. 4. Type I Hypersensitivity Anaphylaxis; Anaphylactic Reaction <ul><li>Mast cell proliferation and IgE production by plasma cells </li></ul><ul><li>IgE bound mast cells </li></ul><ul><li>Recurrent exposure: </li></ul><ul><li>-- Mast cell degranulation </li></ul><ul><li>-- Vasodilation </li></ul><ul><li>-- Bronchoconstriction, etc. </li></ul>ECF = eosinophil chemotactic factor NCF = neutrophil chemotactic factor PAF = platelet-activating factor
  5. 5. <ul><li>Phases of Type I Hypersensitivity </li></ul><ul><li>Initial (rapid) response : within 5-30 min after re-exposure with resolution within 30 min, mediated by primary mast cell mediators </li></ul><ul><li>Second (delayed) phase: 2-8 hours later, lasts for days and characterized by an intense infiltration by inflammatory cells and tissue damage. It is mediated by secondary mast cell mediators. </li></ul>
  6. 6. Type I Hypersensitivity A sequence of Events Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.
  7. 7. <ul><li>Systemic anaphylaxis: </li></ul><ul><li>-- Acute asthma </li></ul><ul><li>-- Laryngeal edema </li></ul><ul><li>-- Diarrhea </li></ul><ul><li>-- Urticaria </li></ul><ul><li>-- Shock (Anaphylactic shock) </li></ul><ul><li>Typically follows oral administration pf allergen as: </li></ul><ul><li>E.g.: penicillin allergy </li></ul><ul><li>E.g.: bee sting allergy </li></ul><ul><li>Antisera, Drugs, Hormones </li></ul>Type I Hypersensitivity Reaction Clinical Manifestations
  8. 8. <ul><li>Local anaphylaxis (Atopy): </li></ul><ul><li>- Food allergies </li></ul><ul><ul><li>-- Urticaria or Hives </li></ul></ul><ul><ul><li>-- Asthma </li></ul></ul><ul><ul><li>-- Hay fever/ allergic rhinitis </li></ul></ul><ul><ul><li>(Ragweed pollen) </li></ul></ul><ul><ul><li>-Wheal reaction: Local area </li></ul></ul><ul><ul><li>Of erythema and edema due to Intradermal injection of antigen in sensitized individual. </li></ul></ul>Type I Hypersensitivity Reaction Clinical Manifestations Eosinophil
  9. 9. Type II Hypersensitivity <ul><li>1- Complement Dependent Reaction: </li></ul><ul><ul><li>Antibody is directed against a tissue antigen </li></ul></ul><ul><ul><li>-- e.g. RBC or basement membrane </li></ul></ul><ul><ul><li>Ag-Ab complexes activate complement leading to cell lysis or extracellular tissue damage </li></ul></ul><ul><li>Two mechanisms: </li></ul><ul><li>A- Direct Lysis </li></ul><ul><li>B- Opsonization (Enhanced phagocytosis). </li></ul><ul><li>Ex: </li></ul><ul><li>Transfusion reactions </li></ul><ul><li>Hemolytic anemias </li></ul><ul><li>Goodpasture,s disease of the kidney </li></ul>
  10. 10. Type II Hypersensitivity 2- Antibody- Dependent Cell- Mediated Cytotoxicity (ADCC) <ul><ul><li>Targets are lysed by non- sensitized cells with Fc receptors. </li></ul></ul><ul><ul><li>NK (natural killer) cells, monocytes, and granulocytes then bind to the immunoglobulin Fc receptors and causes damage </li></ul></ul>
  11. 11. Type II Hypersensitivity Reaction 3- Antibody- mediated cellular dysfunction <ul><li>Myasthenia gravis : Antibodies against acetylcholine receptors in motor end plate of SM impair neuromuscular transmission & result in muscle weekness. </li></ul><ul><li>Grave's disease (thyrotoxicosis): </li></ul><ul><li>Anti-TSH receptor antibody stimulate thyroid and result in hyperthyroidism. </li></ul>Antibodies directed against cell surface receptors impirs or dysregulate function without causing cell injury. Ex:
  12. 12. Type II Hypersensitivity Antibody-Mediated Injury <ul><li>Myasthenia gravis </li></ul><ul><li>(Acetylcholine receptor antibody) </li></ul>Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.
  13. 13. Type II Hypersensitivity Reaction Clinical Manifestations <ul><li>Transfusion and transplant reactions </li></ul><ul><li>Rhesus incompatibility between Rh-negative mother and Rh-positive fetus ( erythroblastosis fetalis ) </li></ul><ul><li>Erythroblastosis fetalis </li></ul><ul><li>Elevated Rh antibody titers </li></ul><ul><li>Many immature RBCs in blood </li></ul><ul><li>Excess bilirubin from RBC breakdown </li></ul><ul><li>-- Hyperbilirubinemia (yellow tissues) </li></ul><ul><li>First baby = OK, because IgM cannot cross </li></ul><ul><li>placenta, after that, IgG takes over </li></ul><ul><li>Progressive anemia, ischemia, death </li></ul><ul><li>Brain damage from bilirubin: kernicterus </li></ul><ul><li>Prevention: Rh- mother gets anti-D </li></ul><ul><li>immunoglobulin after birth (covers antigenic </li></ul><ul><li>sites on baby’s RBCs in mother’s blood </li></ul><ul><li>Rx: phototherapy of baby (breaks bilirubin) </li></ul>Immune hydrops from Rh hemolysis
  14. 14. Type II Hypersensitivity Reaction Clinical Manifestations <ul><li>Autoimmune hemolytic anemia </li></ul><ul><li>Agranulocytosis </li></ul><ul><li>Thrombocytopenia </li></ul><ul><li>Pemphigus vulgaris </li></ul><ul><li>Pemphigoid </li></ul><ul><li>(Cicatricial pemphigoid) </li></ul>Pemphigoid Pemphigoid
  15. 15. Type III Hypersensitivity Immune Complex Mediated <ul><li>Ag-Ab complexes is formed either in circulation or extravascular. </li></ul><ul><li>Tissue damage primarily through complement activation </li></ul><ul><li>Exogenous antigen: i.e. bacterial, viral </li></ul><ul><li>Endogenous antigen: i.e. DNA antigens </li></ul><ul><li>C3b acts as an opsonin </li></ul><ul><li>C5a acts as a chemoattractant for neutrophils </li></ul><ul><li>-- Acute Necrotizing Vasculitis </li></ul>
  16. 16. Type III Hypersensitivity Immune Complex Mediated <ul><li>Immune complexes can be deposited: </li></ul><ul><li>I- Systemically (Serum sickness type) due to administration of large amount of foreign serum. </li></ul><ul><li>II- Locally (Arthus reaction type) </li></ul>Common clinical findings: Fever Urticaria Arthralgia Lymphadenopathy Proteinuria
  17. 17. I- Systemic Immune Complex Disease
  18. 18. Immune Complex Mediated (Type III) Damage Systemic <ul><li>Acute (single large dose of Ag exposure): </li></ul><ul><li>Acute serum sickness </li></ul><ul><li>Poststreptococcal glomerulonephritis </li></ul><ul><li>Chronic (persistent/repeated Ag exposure): </li></ul><ul><li>Systemic lupus erythematosus </li></ul><ul><li>Rheumatoid arthritis </li></ul><ul><li>Membranous glomerulonephritis </li></ul><ul><li>-- Inciting antigens = unknown </li></ul>
  19. 19. Immune Complex Deposition in Glomerulus Type III Hypersensitivity
  20. 20. <ul><li>II- Local Immune Complex Disease (Arthus Reaction) </li></ul><ul><li>It is defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis. </li></ul><ul><li>local formation and deposition of immune complexes </li></ul><ul><li>Planting of antigen within a particular tissue (e.g., renal glomeruli) with subsequent formation of immune complexes </li></ul><ul><li>Produced experimentally by intracutaneous antigen injection in a sensitized host carrying antibody= Ab in excess </li></ul><ul><li>Large immune complexes deposition  complement and coagulation cascades activation and platelets aggregation lead to fibrinoid necrosis </li></ul><ul><li>Superimposed thrombosis may cause tissue necrosis. </li></ul>
  21. 21. <ul><li>Type IV Hypersensitivity (Cell- Mediated) </li></ul><ul><li>Initiated by specifically sensitized T lymphocytes rather than antibodies. </li></ul><ul><li>Includes Delayed-type hypersensitivity and T-cell mediated cytotoxicity . </li></ul><ul><li>1) Delayed-Type Hypersensitivity (DTH): </li></ul><ul><li>Principle pattern of response in T.B., fungi, protozoa & parasites, & graft rejection and tumor immunity. </li></ul><ul><li>Mediated by CD4 cells of the Th1 that secrete specific cytokines after encounter the processed antigen in association with class II major histocompatibility complex. </li></ul><ul><li>The induction of CD4 response is facilitated by IL-12 that secreted by macrophages that have engulfed microbes or other antigen </li></ul><ul><li>cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages. </li></ul><ul><li>with persistence of non-degradable antigens, the initial non-specific infiltrate of T cells and macrophages is replaced by collections of macrophages that transform into epitheliod cells forming local granuloma. So a granuloma is a special form of DTH. </li></ul>
  22. 22. Type IV Hypersensitivity Delayed Hypersensitivity Reaction <ul><li>CD4+ T lymphocytes + class II HLA molecules </li></ul><ul><ul><li>Numerous cytokines </li></ul></ul><ul><ul><li>Macrophages </li></ul></ul>Anti-CD4 Antibodies
  23. 23. Granuloma Formation Multinucleated giant cell
  24. 24. <ul><li>2) T cell-Mediated Cytotoxicity </li></ul><ul><li>Sensitized CD8+ cytotoxic T lymphocytes (CTLs) is the principle pattern of response in this type of response. </li></ul><ul><li>e.g. a- Viral infection b- Tumor cells c- Transplant rejection </li></ul><ul><li>Class I MHC molecules bind to intracellular viral peptides and present them to CD8+ T lymphocytes. </li></ul><ul><li>Mechanism of of CTL Killing: </li></ul><ul><li>1- Perforin- granzyme- dependent killing: </li></ul><ul><li>Perforin and granzyme are soluble mediators of the CTLs that induce apoptosis of the target cells. </li></ul><ul><li>2- Fas- Fas ligand- dependent killing : </li></ul><ul><li>Activated CTLs express Fas ligand (a molecule with homology to TNF) which binds to Fas on target cells that leads to apoptosis. </li></ul>
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