Hypersensitivity Reactions

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Hypersensitivity Reactions
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Type III ( Immune complex mediated)
Hypersensitivity
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Type III ( Immune complex mediated)
Hypersensitivity

• Ag Ab complexes produces tissue damage by
  eliciting inflammation at the site of deposition
• Circulating immune complexes
• In- situ immune complexes

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Type III ( Immune complex mediated)
Hypersensitivity

• Two types of Ag
• Exogenous Ag
• Foreign protein serum sickness
• Bacteria post streptococcal GN
• Virus - PAN
• Endogenous Ag
• Immunoglobulins Rheumatoid arthrits
• Nuclear Ag - SLE

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Type III ( Immune complex mediated)
Hypersensitivity

• Systemic immune complex disease
• local immune complex disease (Arthus reaction)

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Systemic immune complex disease

• Acute serum sickness
• Foreign serum (horse antitetanus serum)
• Fever, urticaria, arthralgia, lymphnode
  enlargement and proteinuria

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Systemic immune complex disease

• Pathogenesis 3 phases
• Immune complex formation
• Immune complex deposition
• Immune complex mediated inflammation

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Systemic immune complex disease

• Factors affecting out come of immune complex
• Size of immune complex
• Functional status phagocytic system

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Systemic immune complex disease

• Factors affecting tissue deposition
• Charge of immune complex
• Affinity of Ag to various tissue component
• Hemodynamic factors
• Favoured sites glomeruli, joints, skin, small
  blood vessels

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Systemic immune complex disease

• immune complex elicit acute inflammatory reaction
• Activation of complement cascade
• Chemotactic factors, anphylotoxin,
• Activation of neutrophil macrophages through
  their Fc receptor
• Release of PG, vasodilator peptides, lysosomal
  enzymes oxygen free radicals
• Platelet aggregation activation of Hageman
  factor - moicrothrombi

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Systemic immune complex disease

• Morphology
• Acute necrotizing vasculitis - PAN
• Glomerulonephritis lupus nephritis

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Local immune complex disease (Arthus reaction)

• Localized area of tissue necrosis resulting from
  acute immune complex vasculitis
• Develop over few hours reaches peak 4-10 hours
  after injection
• M/s fibrinoid necrosis of vessel

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Type IV (Cell mediated) Hypersensitivity reaction
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Type IV (Cell mediated) Hypersensitivity reaction

• Intiated by specifically sensitized T lymphocytes
• Immunological reaction to M.Tuberculosis, virus,
  fungi,protozoa parasite
• Graft rejection
• Contact dermatitis

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Type IV (Cell mediated) Hypersensitivity reaction

• Classic delayed type
• Intiated by CD4 T cell
• T cell mediated cytotoxicity
• Intiated by CD8 T cell

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Delayed type Hypersensitivity

• Slowly developing inflammatory response
• Tuberculin reaction
• Protein lipopoysaccharide component of
  Tuberculous Bacilli
• Reddening induration in 8- 12 hours and reach
  peak in 24-72 hours

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Delayed type Hypersensitivity

• Lymphocytes are replaced by macrophages over 2-3
  weeks
• Epithelium like cells Epithelioid cells
• Granulomatous inflammation

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Delayed type Hypersensitivity

• Cytokines
• IL -12
• IFN - ?
• IL-2
• TNF-a
• IL -12
• Differentiate CD4 helper cell to TH1 cell
• Induces IFN ? secretion by T cells NK cell

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Delayed type Hypersensitivity

• IFN ?
• Important mediator of Delayed type
  Hypersensitivity
• Powerful activator of macrophages
• Stimulate secretion of IL12
• Express more class II molecule
• ? capacity to kill microbes / tumour cells
• Secretes PDGF TGF-ß ?stimulate fibroblast
  proliferation ? fibrosis

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Delayed type Hypersensitivity

• IL-2
• Autocrine paracrine proliferation of T cells
• TNF-a
• Act on endothelial cells
• ?Secretion of prostocyclin vasodilatation
• ? Expression of E- selectin
• Secretion of IL-8
• Extravasation accumulation of lymphocyte
  macrophages at the site of reaction

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T cell mediated cytotoxicity

• Sensitized CD8 T cells kill antigen bearing
  target cells
• CTL are directed against cell surface
  Histocompatibility antigens
• Graft rejection
• Resistance to virus infection
• Tumour immunity tumour associated antigens

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T cell mediated cytotoxicity

• Two mechanism
• Perforin granzyme dependent killing
• Fas Fas ligand dependent killing

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Transplant Rejection
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Transplant rejection

• Recipient immune system identify the graft/
  transplanted organ as foreign
• Antigens responsible for Transplant rejection is
  HLA molecule
• Any two individuals express 2 different HLA
  protein
• Transplant rejection involves different types of
  Hypersensitivity reaction

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Transplant rejection

• Autograft Donor recipient is same individual
• Isograft - Donor recipient is same genotype
• Allograft - Donor recipient is of same species
  but different genotype
• Xenograft Donar is different species from that
  of recipient
• Skin, kidney, BM, heart, lung, liver, cornea

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Transplant rejection

• Rejection is a complex process in which both cell
  mediated immunity circulating Ab play a role
• T cell mediated reaction
• Antibody mediated reaction

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Transplant rejection

• T cell mediated reaction
• CD4 helper cells mediate delayed
  hypersensitivity reaction
• CD8 CTLS mediate graft cell destruction

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Transplant rejection

• Antibody mediated reaction
• Exposure to class I class II HLA antigen evokes
  antibody production
• Tissue damage Initial target is graft
  vasculature
• Complement dependent cytotoxicity
• ADCC
• Immune complex mediated

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Transplant rejection

• Morphology underlying mechanism
• Hyper acute rejection
• Acute rejection
• Chronic rejection

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Hyper acute rejection

• Within minutes/ hours after transplantation
• Kidney cyanotic, flaccid excrete few drops of
  blood
• Occurs in sensitized recipient preformed Ab in
  circulation
• Ag-Ab complex deposited on vessel wall
  activation of complement (Arthus reaction)

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Hyper acute rejection

• Microscopy
• Neutrophils in arterioles, glomeruli
  peritubular capillaries
• Fibrin platelet thrombi
• Vascular endothelial damage
• Fibrinoid necrosis of arterial wall - Infarction

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Acute rejection

• Within few days in untreated patients
• Sudden onset months/ years later, after
  immunosuppresion is terminated
• cell mediated (acute cellular rejection)
• Ab mediated injury (Acute rejection vasculitis)

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Acute cellular rejection

• ? Creatinine level followed by renal failure
• Extensive interstitial mononuclear cell
  infiltration, edema haemorrhage
• Focal tubular necrosis
• Endothelitis
• In the absence of arteritis- patients responds to
  immunosuppressive therapy

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Acute rejection vasculitis

• Mediated by Antidonor antibody
• Necrotizing vasculitis
• Marked thickening of intima by proliferating
  fibroblasts, myocyte foamy macrophages
• infarction
• renal cortical atrophy

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Chronic rejection

• Progressive raise in creatinine over 4-6 months
• Vascular changes dense intimal fibrosis
• Interstitial fibrosis
• Tubular atrophy shrinkage of renal parenchyma
• Interstitial infiltrate plasma cells,
  Eosinophils

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Transplant rejection

• Increased graft survival
• Minimizing HLA disparity
• Class I class II matching
• Immunosuppresive therapy
• Azathioprine, steroids, cyclosporine
• Infections, EBV induced lymphoma, HPV induced
  squamous cell carcinoma, Kaposis sarcoma

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Bone marrow Transplantation

• Hematological malignancy
• Aplastic anemia
• Immunodeficiency
• Major problems
• Graft Versus Host (GVH) disease
• Transplant rejection

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Graft Versus Host (GVH) disease

• Immunologically competent cells or their
  precursor are transplanted into immunologically
  crippled recipient
• Bone marrow Transplantation
• Liver transplant
• Immunocompetent T cell derived from donor marrow
  recognizes recipient HLA as foreign react

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Acute Graft Versus Host (GVH) disease

• Occurs within days/ weeks of allogenic BMT
• Mainly affects immune system, epithelia of
  skin, liver intestine
• Infection CMV induced pneumonitis
• Skin rashes, desquamation
• Liver jaundice
• Intestine ulceration, bloody diarrhea
• Direct cytotoxicity by CD8 T cells cytokines
  released by donor T cells

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Chronic Graft Versus Host (GVH) disease

• Extensive cutaneous injury
• Destruction of appendages
• Dermal fibrosis
• Cholestatic jaundice
• Esophageal stricture
• Recurrent infection
• Depletion of donor T cells before transfusion
  eliminate GVHD

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Autoimmune diseases
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Autoimmune diseases

• Immunity reaction against self antigen
• Autoantibody directed against single organ/ cell
  type
• Autoantibody directed against many tissue/ cell
  type

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Autoimmune diseases

• Autoantibody directed against single organ/ cell
  type
• Hashimoto thyroiditis
• Autoimmune hemolytic anemia
• Autoimmune atrophic gastritis of pernicious
  anemia
• Autoimmune encephalomyelitis
• Autoimmune orchitis
• Goodpasture syndrome
• Autoimmune thrombocytopenia
• Insulin dependent diabetes mellitus
• Myasthenia gravis
• Graves disease

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Autoimmune diseases

• Systemic Autoimmune disease
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Sjogren syndrome
• Reiter syndrome
• Possible
• Inflammatory myopathies
• Systemic scerosis
• Polyarteritis nodosa

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Autoimmune diseases

• Three requirements
• Presence of Autoimmune reaction
• Autoimmune reaction should not be secondary to
  tissue damage but it is of primary pathogenetic
  significance
• Absence of another well defined cause of the
  disease

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Autoimmune diseases

• Loss of self tolerance
• Immunological tolerance
• Is a state in which individual is incapable of
  developing an immune response to a specific
  antigen
• Self tolerance
• Lack of responsiveness to self antigen
• Two mechanism
• Central tolerance
• Peripheral tolerance

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Autoimmune diseases

• Central tolerance
• Clonal deletion of self reactive T B lymphocyte
  during their maturation in the central lymphoid
  organs
• Developing T cells that expresses high affinity
  receptors for self antigens are deleted by
  apoptosis

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Autoimmune diseases

• Peripheral tolerance
• Clonal deletion by activation induced cell death
• Clonal anergy
• Peripheral suppresion by T cells

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Peripheral tolerance

• Clonal deletion by activation induced cell death
• Lymphocytes Fas(CD95)
• Activated lymphocytes ligand for Fas (fas L)
• Self Ag present in peripheral tissue causes
  persistent stimulation of self Ag specific T
  cells
• Engagement of Fas by Fas ligand induces apoptosis
  of activated T cells

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Peripheral tolerance

• Clonal anergy Prolonged or irreversible
  functional inactivation of lymphocyte
• Two signals are required for T cell activation
• MHC associated peptide
• CD28 must bind to their ligand (B7-1, B7-2)
• Costimulatory molecules are not expressed /weekly
  expressed on most normal tissue

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Peripheral tolerance

• Peripheral suppression by T cells
• CD4 T cells of TH2 type down regulate TH1
  response by secreting cytokines IL-4, IL-10
  TGF- ß

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Autoimmune diseases

• Defect / bypass in self tolerance result in
  Autoimmune diseases
• Mechanisms
• Immunologic
• Genetic factors
• Microbilogical agents

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Autoimmune diseases

• Failure of peripheral tolerance
• Breakdown of T cell anergy
• Failure of activation induced cell death
• Failure of T cell mediated suppression
• Molecular mimicry
• Polyclonal lymphocytic activation
• Release of sequestrated antigens
• Exposure of cryptic self epitopic spreading

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Autoimmune diseases

• Breakdown of T cell anergy
• Infection induced expression of costimulatory
  molecules (B7-1) secretion of IL-12 to generate
  TH1 T cells
• Upregulation of B7-1 molecule is seen in CNS of
  Multiple Sclerosis and synovium of Rheumatoid
  arthritis

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Autoimmune diseases

• Failure of activation induced cell death
• Defect in Fas Fas ligand mediated apoptosis
  result in proliferation of autoreactive T cells
• Molecular mimicry
• Some infectious agents share epitopes with self
  antigen
• RHD Ab to streptococcal M protein cross react
  with cardiac glycoprotein

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Autoimmune diseases

• Polyclonal lymphocytic activation
• Bacterial endotoxin can induce mouse lymphocytes
  to produce Anti DNA, Antithymocyte, Anti red
  cells antibodies in vitro
• Release of sequestrated antigens
• Spematozoa orchitis after vasectomy
• Occular antigen- post traumatic uveitis

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Autoimmune diseases

• Exposure of cryptic self epitopic spreading
• Each self antigen has many antigenic determinates
  (epitopes)
• Cryptic self epitopes (masked antigens) can
  produce autoimmunity by proliferation of T cells