Lecture Slide eczema

							  Hypersensitivity
     reactions
Department of Microbiology and Immunology
       Presented by Ahmed Elkaaky
Hypersensitivity reactions

Learning Objectives
1. Understand the classification of hypersensitivity reactions
2.   Know the diseases associated with hypersensitivity
     reactions
3.   Understand the mechanisms of damage in hypersensitivity
     reactions
4.   Know the methods for diagnosing conditions due to
     hypersensitivity
5.   Know the modes of treating disease due to hypersensitivity
     and their rationale
Exaggerated
                   Disorders of the immune   Deficient
Hypersensitivity           response          Immuno-
                                             deficiency




                         Misdirected
                         Autoimmune
Hypersensitivity reactions


 Hypersensitivity Definition
 Excessive undesirable (damaging, discomfort
    producing and sometimes fatal) reactions
    produced by the exaggerated normal
    immune system.
 Hypersensitivity reactions require a pre-
    sensitized (immune) state of the host.
• Type I hypersensitivity(immediate)
                 IgE mediated
• TypeII hypersensitivity:
              Antibody mediated
• Type III hypersensitivity:
               Immune complex
• Type IV hypersensitivity:
               Cell mediated
   The first 3 are mediated by antibody
          Hypersensitivity
             reactions


                                Cell
Humoral                      mediated
                              Type IV
             Type I

            Type II
            Type III
  Table 4: Comparison of Different Types of hypersensitivity


characteristics    type-I             type-II              type-III          type-IV
                   (anaphylactic)     (cytotoxic)           (immune          (delayed type)
                                                           complex)
antibody           IgE                IgG, IgM             IgG, IgM          None
antigen            Exogenous          cell surface         Soluble           tissues & organs

response time      15-30 minutes      minutes-hours        3-8 hours         48-72 hours

Appearance         wheal & flare      lysis and necrosis   erythema and      erythema and
                                                           edema, necrosis   induration

Histology          basophils and      antibody and         complement and    macrophages and
                   eosinophil         complement           neutrophils       T cells

transferred with   Antibody           Antibody             Antibody          T-cells

examples           allergic asthma,   erythroblastosis     SLE, farmer’s     tuberculin test,
                   hay fever          fetalis,             lung disease      poison ivy,
                                      Goodpasture’s                          granuloma
                                      nephritis
Type I Hypersensitivity

     The reaction may involve skin (urticaria and eczema), eyes
      (conjunctivitis),    nasopharynx    (rhinorrhea,  rhinitis),
      bronchopulmonary tissues (asthma) and gastrointestinal
      tract (gastroenteritis).
     The reaction takes 15-30 minutes from the time of exposure
      to the antigen.


     Ag combines with IgE Ab. IgE binds to mast
       cells &basophils,causing them to undergo
           degranulation and release several
                       mediators
Mast cell and allergic response
Pathogenic mechanism

   First exposure to allergen
It stimulate the formation of IgE Ab
IgE fixes by its FC portion to mast
  cells&basophils.
   Second exposure to the same
    allergen
It bridges between IgE molecules fixed to mast
  cells leading to their activation&degranulation
  and release of contents.
MECHANISM OF ACTION

BASIC ELEMENTS ARE:

1- MEDIATOR = IgE
2-PRIMARY CELLULAR COMPONENT =
   MAST CELL AND BASOPHILS
3-AMPLIFIER = PLATELETS, NEUTROPHILS
   AND EIOSINOPHILS
MECHANISM OF ACTION

STEP 1:
    EXPOSURE OF ANTIGEN TO ANTIGEN PRESENTING CELL

STEP 2:
RECOGNITION BY T- HELPER CELLS

ACTIVATION OF B-CELLS INTO PLASMA AND MEMORY CELLS

SECRETION OF ANTIBODIES (IgE)
STEP 3:
IgE BINDS TO HIGH AFFINITY RECEPTORS ON THE
   SURFACE OF MAST CELLS




STEP 4:
           SUBSEQUENT EXPOSURE OF ANTIGEN

  ANTIGEN BINDS WITH IgE ON THE SURFACE OF MAST
                        CELLS
STEP 5:
  RELEASE OF PRIMARY INFLAMMATORY METABOLTES

          ACTIVATION OF SECONDARY METABOLITES
CLINICAL DISEASES


 1.   Anaphylaxis
 2.   Asthma
 3.   Allergic Rhinitis
 4.   Food Allergy
 5.   Eczema and Urticaria
Atopy

    Inherited propensity to respond immunologically to
    many common naturally occuring inhaled and
    ingested allergens with the continual production of
    IgE antibodies.
    Allergic rhinitis and allergic asthma are the most
    common manifestations of clinical disease following
    exposure to these allergens.
    Allergens responsible for atopic diseases are
    derived from natural airborne organic particles: plant
    pollens,fungal spores,animal and insect
    debris,ingested food.
Type II Hypersensitivity


 known as cytotoxic hypersensitivity and may affect a
  variety of organs and tissues. The antigens are
  normally   endogenous, although exogenous
  chemicals (haptens) that can attach to cell
  membranes can also lead to type II.
 Mechanism of action
 I-   Complement mediated

 II-Antibody dependent cellular cytotoxicity
   ( ADCC)

 III-   Antibody mediated cellular dusfunction
Type II hypersensitivity mechanisms
Schematic illustration of three different mechanisms of antibody-
mediated injury in type Ⅱ hypersensitivity. A, Complement-dependent
reactions that lead to lysis of cells or render them susceptible to
phagocytosis.
      Clinical Conditions

1) Transfusion reaction due to ABO incompatibility

2) Rh-incompatability (Hemolytic disease of the newborn)

3) Autoimmune diseases
    The mechanism of tissue damage is cytotoxic reactions
    e.g. SLE, autoimmune hemolytic anaemia, idiopathic thrombocytopenic
     purpura, myasthenia gravis, nephrotoxic nephritis, Hashimoto’s
     thyroiditis

4) A non-cytotoxic Type II hypersensitivity is Graves’s disea
    It is a form of thyroditits in which antibodies are produced against TSH
      surface receptor
    This lead to mimic the effect of TSH and stimulate cells to over- produce
      thyroid hormones
  Clinical Conditions

5- Graft rejection cytotoxic reactions:
 In hyperacute rejection the recipient already has performed antibody
  against the graft


6- Drug reaction:
  Penicillin may attach as haptens to RBCs and induce antibodies which
  are cytotoxic for the cell-drug complex leading to haemolysis

  Quinine may attach to platelets and the antibodies cause platelets
  destruction and thrombocytopenic purpura.
Type III Hypersensitivity

   Definition :
    A hypersensitivity resulting from large
    quantities of soluble antigen-antibody
    complexes passing between endothelial cells
    of the blood vessels and becoming trapped
    on the surrounding basement membrane.
Type III Hypersensitivity

 Take   3-10 hours after exposure to the
  antigen (as in Arthus reaction).
 Soluble immune complexes.
 IgG class, although IgM may also be
  involved.
  The antigen may be exogenous (chronic
  bacterial, viral or parasitic infections), or
  endogenous          (non-organ        specific
  autoimmunity:      e.g.,   systemic     lupus
  eythematosus-SLE).
CAUSE OF TYPE III
HYPERSENSITIVITY

 NORMALLY
   SOLUBLE ANTIGEN-ANTIBODY COMPLEX FORMATION

   REMOVED BY MACROPHAGES IN SPLEEN AND LIVER

 ABNORMALLY
    INCREASED SOLUBLE ANTIGEN-ANTIBODY COMPLEX
                   FORMATION

  NOT ALL REMOVED BY MACROPHAGES IN SPLEEN AND
                     LIVER

    DEPOSITION OF COMPLEXES VIA BLOOD VESSELS
MECHANISM OF ACTION

STEP 1
Large quantities of soluble antigen-antibody complexes form in
 the blood and are not completely removed by macrophages.
MECHANISM OF ACTION

STEP 2
 These antigen-antibody complexes lodge in the blood vessels
 between the endothelial cells and the basement membrane.
MECHANISM OF ACTION

STEP 3
These antigen-antibody
 complexes activate the
classical complement
pathway leading to
vasodilataion
MECHANISM OF ACTION

STEP 4
The complement
proteins and
antigen-antibody
 complexes
attract leukocytes
to the area.
     MECHANISM OF ACTION


STEP 5
The leukocytes discharge
their Killing agents
 and promote massive
 inflammation.
This can lead to tissue
death and hemorrhage.
Immune Complex Mediated Hypersensitivity
EXAMPLES OF TYPE III
HYPERSENSITIVITY


1.   SERUM SICKNESS, A COMBINATION TYPE I
     AND TYPE III HYPERSENSITIVITY
2.   AUTOIMMUNE ACUTE GLOMERULONEPHRITIS
3.   RHEUMATOID ARTHRITIS
4.   SOME CASES OF CHRONIC VIRAL HEPATITIS
Type IV hypersensitivity
cell mediated immunity (DTH)

 Definition:
                Refers to inflammation generated by
   reaction of Ag with its corresponding Ag specific T-
   lymphocytes. In previously immunized individual, the
   effector T-cell that produce CMI are called TDH
   cells.
    It is a hypersensitivity reaction resulting from cell-
    mediated immunity (cytotoxic T-lymphocytes and
    cytokines) and causing harm to the body.
Type IV Hypersensitivity


 It is also known as cell mediated or delayed type
   hypersensitivity. The classical example of this
   hypersensitivity is tuberculin (Montoux) reaction that
   peaks 48 hours after the injection of antigen (PPD or old
   tuberculin). The lesion is characterized by induration and
   erythema.
Type IV Hypersensitivity




 Mechanisms of damage in delayed hypersensitivity
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
Histopathology

The hallmark of CMI is granuloma, a focal
   accumulation
Of mononuclear cells,granulocytes,fibrin, destroyed
Tissue, in advanced cases liquefaction of tissues
   occure ( caseation necrosis).
Granuloma is the end result of CMI when the Ag persist
at the site causing persistent Ag stimulation.
  CMI is acquired
 during many infections eg :
   virueses,fungi,bacteria,parasites
 Artificially by immunization
 Contact with many sensitizing chemicals on
  the skin leading to contact dermatitis
   sensitizing Ags are usually haptens which
  complex with skin protein carrier molecules
Type IV Hypersensitivity


 Diagnostic tests in vivo include delayed
 cutaneous reaction (e.g. Montoux test)
 and patch test (for contact dermatitis).
  Table 4: Comparison of Different Types of hypersensitivity


characteristics    type-I             type-II              type-III          type-IV
                   (anaphylactic)     (cytotoxic)           (immune          (delayed type)
                                                           complex)
antibody           IgE                IgG, IgM             IgG, IgM          None
antigen            Exogenous          cell surface         Soluble           tissues & organs

response time      15-30 minutes      minutes-hours        3-8 hours         48-72 hours

Appearance         wheal & flare      lysis and necrosis   erythema and      erythema and
                                                           edema, necrosis   induration

Histology          basophils and      antibody and         complement and    macrophages and
                   eosinophil         complement           neutrophils       T cells

transferred with   Antibody           Antibody             Antibody          T-cells

examples           allergic asthma,   erythroblastosis     SLE, farmer’s     tuberculin test,
                   hay fever          fetalis,             lung disease      poison ivy,
                                      Goodpasture’s                          granuloma
                                      nephritis