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HYPERSENSITIVITY (DOC)

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					                               HYPERSENSITIVITY
                                    OBJECTIVES

•     At the end of lecture you must be able to understand :
•     Hypersensitivity
•     Types of hypersensitivity
•     Pathogenesis of hypersensitivity

                               HYPERSENSITIVITY
      •   It is a process of reactions of antigen with antibody (or) sensitized lymphocytes that are
          harmful to the host
      •   When an adaptive immune response occur in an exaggerated or inappropriate form causing
          tissue damage, the term hypersensitivity is applied

               GELL & COOMBS CLASSIFICATION
Type      Description                                Effectors


I         Immediate or anaphylactic reaction         IgE antibodies


II        Cytotoxic reaction                         IgG & IgM antibodies


III       Immune complexes                           IgG & IgM antibodies


IV        Delayed type hypersensitivity (DTH)        T-cells




                            Type I: Hypersensitivity
It is characterized by an Allergic reaction immediately following contact with the antigen,
which is referred to as the allergens.
First exposure to allergen
     • T-helper-2 cell (TH2) releases IL4 to stimulate B-cell to produce IgE
   •   IgE antibody binds to the receptor on the surface of mast cell or basophil – no
       activation of mast cell




Anaphylactic (or) Immediate H.S.
Second exposure to allergen
  • Allergens cross-links with several IgE molecules on mast cell
  • These mast cells they, get activated and cell degranulates releasing powerful
     chemicals like histamine, heparin, prostaglandin and protease causing edema,
     increased mucus secretion smooth muscle contraction and increases vascular
     permeability leading to vasodilations hypotension and finally shock




                                MEDIATORS
Mediators stored and released    Effect
Histamine                        Smooth muscle contraction;
                                 increased vascular permeability
Heparin                          Anticoagulant
Prostaglandin E2                 Increased pain response and
                                 vascular permeability
Prostaglandin D2                 Increased smooth muscle
                                 contraction and vascular
                                 permeability
Leukotrences C4, D4, E4          Increased smooth muscle
                                 contraction and vascular
                                 permeability
Lekotriene B4                    Chemotactic for neutrophils




                       ALLERGIC DISEASES
Allergic Disease         Allergens                     Clinical Findings
Allergic rhinitis (hay   Trees, grasses, dust, cats,   Edema, irritation, mucus
fever)                   dogs, mites                   in nasal hmucosa
Food allergies           Milk, eggs, fish, cereals,    Hives and GI problems
                         grains
Wheal and flare          Insect bites, in vivo         Local skin edema,
                         allergy, skin testing         reddening, vasodilation
                                                       of vessels
Asthema                  Inhaled materials             Bronchial and tracheal
                                                       constriction, edema,
                                                       mucus production,
                                                       massive inflammation
Systemic anaphylaxis     Insect stings, snake,         Bronchial and tracheal
                         venoms, drug reactions        constriction and complete
                                                       vasodilation and death



                                   THERAPIES
   •   Avoidance of the allergen
   •   Antihistamine (Benadryl) to block histamine receptors
   •   Chromolyn sodium to stabilize mast cell membranes
   •   Epinephrine to increase intracellular cyclic AMP
   •   Epinephrine to increase bronchial dilation and increase heart rate to raise blood
       pressure
   •   Theophylline (xanthines_ to block phosphodiesterase enzyme that breaks down cyclic
       AMP
   •   Corticosteroids to reduce both inflammation and production of antibody
   •   Β-Adrenergic agonists – bronchial dilators that relax smooth muscle in airways e.g.
       albuterol or terbutaline

                       Type II: Hypersensitivity
   Cytotoxic Hypersensitivity or Antibody Mediated Hypersensitivity
            against our own cells or receptor or membrane
   •   It is mediated by antibodies (IgG, IgM), binds to antigen on the cell membrane,
       activates the complement forming “MAC” which finally damages the cell
       membrane (Lyses RBC)



          A) ERYTHROBLASTOSIS FETALIS (HDNB)
                      •  Rh-ve mother pregnant having Rh+ve child
                         • No problem or any harm to first child
    • During first delivery few erythrocytes leaks and enter in the mother circulation
                        • IgG antibodies produced against RhD
     • In subsequent pregnancy with another Rh+ve fetus IgG antibodies crosses
      placenta reacts with fetal Rh+ red cell activate compliment forming “MAC” which
                    lysis RBC causing haemolytic disease in new born




                 INDIRECT COOMB’S TEST
•    It is also called “Direct Antiglobulin Test”
•    It is used to detect antibody on pateints erythrocytes
•    If antibody present the erytrocytes can be agglutinated by anti-human immunoglobulin
•    If no antibody is present on red cells they are not agglutinated by anti-human
     immunoglobulin

              B) GOODPASTURE SYNDROME
•    A number of patients with nephritis may have (IgG) antibodies to a glycoprotein of the
     glomerular basement membrane
•    There is severe necrosis of the glomerulus with fibrin deposition


                    B) MYASTHENIA GRAVIS
C)    A disease with extreme muscular weakness
D)    An auto antibodies are produced against patients own acetylcholine receptors



     D) AUTO IMMUNE THROMBOCYTOPENIC PURPURA
     An auto antibody produced against the patient’s own platelets and causing
                  thrombocytopenia leading to bleeding tendency

ANTIBODY DEPENDENT CELL MEDIATED CYTOTOXICITY
                                       (ADCC)
•   It is a direct killing of virus infected cell by a combination of IgG and phagocytic cell
    (PMN-macrophage, neutrophil and NK cells)
•   Antibody is bound to the surface of infected cell is recognised by IgG receptor on
    PMN-macrophage
•   Virus infected cell is phagocyte by macrophage and finally killed by it

•   No activation of compliment system


TYPE III HYPERSENSITIVITY OR IMMUNE COMPLEX
                     H.S.
•   Immune complex hypersensitivity occur when antigen-antibody complexes induce an
    inflammatory response in tissues
•   Normally immune complexes are removed by the reticuloendothelial system, but
    occasionally they persist and deposited in tissues, resulting in several disorders
•   Deposition of immune complexes activate complement system
•   PMN cells are attracted to the site, hence inflammation and tissue injury take place.
•   Two typical type III Hypersensitivity reactions.



                      1. ARTHUS REACTION




•   There is inflammation caused by the deposition of immune complexes at a localized site in
    and found the walls of small blood vessels
•   However most frequently it is demonstrated in the skin
•   On injecting antigen S/C a reaction develops which reaches peak intensity in 4 to 10 hours
•   There is marked edema and haemorrhage at the site of injection
•   There reaction finally decreased after 48 hours
•   Infected antigen combines with specific antibody to form immune complexes
•   These complexes activate complement system followed by PMN infiltration and act on
    platelets, releasing vasoactive amines
   •    There is intravascular clumping of platelets leads to vascular occulusion and necrosis
   •    After 24 to 48 hours these PMN replaced by mononuclear cells and plasma cells appears.
   •




                            2. SERUM SICKNESS
   3.    It is a systemic inflammatory response to the presence of immune complexes deposited in
         many area of the body
   4.    After the injection of foreign serum the production of antibody starts, leads to the
         formation of immune complexes
   5.    These immune complexes they may circulate or deposited at various sites
   6.    In typical S sickness there is fever, utricaria, arthralgia, lymphadenopathy, splenomegally
         and eosionphilia a few days to 2 weeks after injection


               IMMUNE COMPLEX DISEASES

                           1. Mysthenia gravis:
(antibodies to receptors) Antibodies to
Acetylcholine receptors of Neuromuscular
 junction cause Severe muscular weakness




       2. SYSTEMIC LUPUS ERYTHEMATOSUS
                      (SLE)
Auto-antibodies against DNA, histones, nucleolar proteins and other components of cell nucleus

Inducing agent Not known (most cases)


                      3. RHEUMATOID ARTHRITIS (RA)
   •    Auto-antibodies are formed
   •   against IgG
   •   These auto-antibodies are called as rheumatoid factors and are of IgM class
   •   People with HLA-DR4 genes are predisposing to RA
   •   Trigger agent – not known
   •   Immune complexes – activate complement tissue damage




                  4. GOODPASTURE’S SYNDROME:
Auto-antibodies are formed against the collagen in basement membranes of the kidney and lungs

 The agent that induces these auto-antibodies are known but disease occur after a viral infection


                               PATHOGENESIS
Auto-antibodies
Activate compliment system
Damage the tissues of
Kidney and lung
Clinical findings appear

   TYPE IV: HYPERSENSITIVITY OR CELL MEDIATED
                    HYPERSENSITIVITY
   •   Delayed hypersensitivity is a function of T-lymphocytes, not antibody, causing harm to
       body
   •   The response is delayed i.e. it starts hours or days after contact with the antigen often last
       for days
   •   Clinically important delayed hypersensitivity reactions



                        MECHANISM OF ACTION
                                      T-H CELLS INDUCED
STEP 1
ANTIGEN ENTERS THE BODY

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS

       T-H CELLS BECOMES ACTIVATED AND INCREASED IN NUMBER

                        MECHANISM OF ACTION
                           T-H CELLS INDUCED
STEP 2
SECOND EXPOSURE

ENGULFED BY MACROPHAGES

PRESENTED TO T-H CELLS


T-H CELLS RELEASE CYTOKINES

                 MECHANISM OF ACTION
                           T-H CELLS INDUCED




                 MECHANISM OF ACTION
                       CTOTOXIC T CELLS INDUCED

STEP 1
ANTIGEN BINDS TO NORMAL CELL

EPITOPE PRESENTED WITH MHC-1

CTL ATTACHED BY TCR/CD8+

ACTIVATION OF T-CELL
STEP 2

ACTIVATION OF CYTOTOXIC T-CELL
RELEASE OF
   1.      PORE-FORMING PROTEINS CALLED PERFORINS
   2. PROTEOLYTIC ENZYMES CALLED GRANZYMES
   3. CHEMOKINES
STEP 3

PERFORINS FORM PORES

GRANZYMES PASS THROUGH PORES

ACTIVATE ENZYMES OF CELLS

APOPTOSIS



             A) CONTACT HYPERSENSITIVITY
              CONTACT HYPERSENSITIVITY
  •   It occurs after sensitization with simple chemicals like nicke and formaldehyde, plant
      materials, topically applied drugs like sulphonamide, nedmycin, some cosmetics, soaps,
      etc.
  •   In all these cases their small molecules enters the skin, attach to body protein and become
      complete antigen
  •   The immune system recognized it as foreign, cell mediated hypersensitivity is induced,
      particularly in skin

  •   Upon a later skin contact with the offending agent, the sensitized person
      developes erythema, itching, vesicles, eczema or necrosis of skin with in 12 – 48
      hours
  •   Patch skin test on small area of skin can sometimes identify the offending antigen
  •   Subsequent avoiding of material will prevent recurrence




      B) TUBERCULIN TYPE HYPERSENSITIVITY
  •   A small amount of tuberculin (PPD) given intradermally to a previously exposed persons
      to M.Tuberculosis
  •   In duration and redness develops and reached at peak in 48 to 72 hours
  •   A positive skin test indicates that a person has been infected with the agent

  •   A positive skin test response assist in diagnosis and provides support for treatment. For
      example in leprosy, a positive lepromin test indicates the presence of tuberculoid leprosy
      with competent cell mediated immunity on the other hand if lepromin test is negative
      suggest the presence of lepromatous leprosy with impaired cell mediate immunity
                      REFERENCE
• Text book of pathology by robbins and cotrans


                          Thanks

				
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posted:3/20/2012
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