IMMUNOPATHOLOGY

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IMMUNOPATHOLOGY

  1. 1. IMMUNOPATHOLOGY Dr Russell Watkins
  2. 2. HYPERSENSITIVITY  Overview: – Types I - IV, each varying in severity from mild to life-threatening – Inappropriate or excessive activation of immune system, often to usually harmless antigens
  3. 3. TYPE I HYPERSENSITIVITY  Appears within minutes of exposure to antigen  Interaction of antigen, specific IgE & tissue mast cells  IgE is normally found at low serum concentrations but is raised in people susceptible to Type I hypersensitivity  IgE raised in parasitic infections
  4. 4. TYPE I HYPERSENSITIVITY  Previous exposure to antigen is necessary  Mast cells have specific IgE receptors  IgE bind to receptors & crosslink
  5. 5. TYPE I HYPERSENSITIVITY  Mast cell degranulation results - release of intracellular contents  Histamine, heparin, proteases & other substances
  6. 6. TYPE I HYPERSENSITIVITY  These mediators affect local smooth muscle, blood vessels, cause neutrophil & eosinophil chemotaxis  This is the immediate response
  7. 7. TYPE I HYPERSENSITIVITY  Arachidonic acid metabolism is also invoked resulting in formation of leukotrienes, prostaglandins, thromboxanes etc  These products are released 4-6 hrs later & exacerbate the disease & contribute to the clinical picture
  8. 8. TYPE I HYPERSENSITIVITY  Effects include – Vasodilatation – Increased vascular permeability – Bronchoconstriction et al
  9. 9. TYPE I HYPERSENSITIVITY  Examples include – Allergic rhinitis – Asthma – Eczema – Urticaria – Systemic anaphylaxis  Such people are called “atopic” & suffer from “atopy”
  10. 10. TYPE I HYPERSENSITIVITY  Systemic anaphylaxis – Precipitous drop in BP due to vasodilatation Bronchoconstriction Laryngeal oedema Rash
  11. 11. TYPE II HYPERSENSITIVITY  Also antibody mediated but IgG & IgM  Ig is expressed against antigenic components of cell surfaces  Thus tend to be tissue specific  Binding of Ig to cell antigen causes: – Complement activation – Antibody-dependent cell-mediated cytotoxicity (ADCC)
  12. 12. TYPE II HYPERSENSITIVITY  These responses are normally mounted against infection  ?Molecular mimicry  Examples include: – Graves’ disease – Myasthenia gravis – Hyperacute graft rejection
  13. 13. TYPE II HYPERSENSITIVITY  Graves’ disease – Thyroid cells are not destroyed – IgG binds to TSH receptor – Mimics effect of TSH & causes cell to secrete excess thyroxine
  14. 14. TYPE III HYPERSENSITIVITY  Also antibody mediated  Antigenic target is soluble & not cell surface bound  The combination of IgG/IgM & antigen is termed an immune complex  These circulate & lodge in tissues at remote sites throughout the body
  15. 15. TYPE III HYPERSENSITIVITY  The formation of immune complexes is a normal antibody response  Usually cleared by macrophages  If immune complexes persist, they may promote an inflammatory response & then become defined as a hypersensitivity reaction
  16. 16. TYPE III HYPERSENSITIVITY  Antigens may be exogenous (infection, environmental agents)  Endogenous antigens may cause an autoimmune response  Factors influencing IC persistence: – Complex size – Antigen exposure duration – Host response – Local tissue factors
  17. 17. TYPE III HYPERSENSITIVITY  Complex size – Large & small ICs are efficiently cleared - intermediate sized ICs cause hypersensitivity  Duration of exposure – Chronic exposure allows continuous IC formation & accumulation
  18. 18. TYPE III HYPERSENSITIVITY  Host response – Deficiency of some complement components impairs clearing of ICs  Local tissue factors – Blood pressure, turbulence & filtration affect IC deposition
  19. 19. TYPE III HYPERSENSITIVITY  Examples: – Systemic lupus erythematosus – Post-streptococcal glomerulonephritis
  20. 20. TYPE IV HYPERSENSITIVITY  Cell mediated rather than antibody mediated (especially Tdth-cell)  Also called “delayed-type hypersensitivity” as reactions occur >12hrs after exposure  Tdth-cell activation causes chemotaxis of other lymphocytes, macrophages, neutrophils
  21. 21. TYPE IV HYPERSENSITIVITY  Classified as – Contact (peaks at 48-72hrs) – Tuberculin (peaks at 48-72hrs) – Granulomatous (peaks at 21-28 days)
  22. 22. TYPE IV HYPERSENSITIVITY  Contact hypersensitivity – LMW “haptens” bind to normal body proteins eliciting response – Occurs in epidermis of skin – E.g nickel hypersensitivity, drug sensitivity
  23. 23. TYPE IV HYPERSENSITIVITY  Tuberculin hypersensitivity – Occurs in dermis of skin – Basis of Mantoux test for TB
  24. 24. TYPE IV HYPERSENSITIVITY  Granulomatous hypersensitivity – Granulomata form when antigen persists – Occurs in many organs, not just skin – E.g. leprosy, tuberculosis, sarcoidosis
  25. 25. AUTOIMMUNE DISEASE  A failure of discrimination between self & non-self antigens  Self-reactivity normally prevented by a number of processes which occur in early lymphocyte development
  26. 26. AUTOIMMUNE DISEASE  These mechanisms may break down & the immune system attacks normal body structures  Almost every organ may be affected
  27. 27. AUTOIMMUNE DISEASE  Autoimmune disease may be – Organ-specific  e.g. Grave’s disease, type I DM, myasthenia gravis, pemphigus & pemphigoid – Systemic e.g. SLE, rheumatoid arthritis, scleroderma
  28. 28. AUTOIMMUNE DISEASE  Explanatory theories – Microbial antigens cross-reacting with host tissues induce a response against self – Alteration of self-antigens exposing new antigenic determinants unavailable at the time of induction of fetal tolerance
  29. 29. AUTOIMMUNE DISEASE  Explanatory theories – Attachment of hapten to self-molecule forming a hapten-carrier complex – Deficiency of suppressor T-cells – Spontaneous emergence of clones of cells capable of mounting an autoimmune response
  30. 30. AUTOIMMUNE DISEASE  There is often overlap of features in the systemic group e.g. patients with SLE may have features of RA  Patients may be predisposed to suffer more than one organ-specific autoimmune disease e.g. pernicious anaemia is more common in sufferers of type 1 DM  Both organ-specific & systemic autoimmune disease are associated with specific HLA types
  31. 31. AUTOIMMUNE DISEASE  Cytokines & Th -cells are implicated - certain cytokines influence expression of HLA types  Antibodies (autoantibodies) & the B-cells producing these are a normal finding. Under normal conditions, they are not auto- aggressive  Th-cells induce the B-cells to produce more auto antibodies in response to triggering by self-antigen
  32. 32. AUTOIMMUNE DISEASE  Contributory factors – Genetics  Familial tendencies, twin concordance (less than 100% for IDDM)  HLA associations (e.g. DR1 & DR4 in RA) – Hormone effects  Autoimmune diseases tend to be more common in females – Environment  Infectious agents  Drugs & chemicals
  33. 33. IMMUNODEFICIENCY  Immunodeficiency causes increased susceptibility to infections & other diseases  The immune system essentially consists of: – Humoral immunity – Cell-mediated immunity – Phagocytosis – Complement
  34. 34. IMMUNODEFICIENCY  Deficiencies in each of the functional systems may occur. They may be – Genetically determined – Due to disease states – Due to environmental factors Drugs Viral infections

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