Hypersensitivity reactions

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Hypersensitivity reactions
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The immune system is concerned with protection of
the host against foreign antigens, particularly
infectious agents.

• Inappropriate immune response may be
• Allergy exaggerated immune response against
  environmental antigens.
• Autoimmunity misdirected immune response against
  the hosts own cells.

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3. Alloimmunity immune response directed
against beneficial foreign tissues e.g. blood
transfusion or organ transplantation.4. Immune
deficiency inability of the immune system to
protect the host.
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Hypersensitivity

• Is an altered immunologic response to an antigen
  that results in tissue damage.

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Hypersensitivity reactions

• Type I immediate (Ig E mediated)
  hypersensitivity
• Type II Tissue specific (cytotoxic)
  hypersensitivity
• Type III immune-complex mediated
  hypersensitivity
• Type IV cell mediated or delayed hypersensitivity

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Type I hypersensitivity
1). Characteristics 2). Components and
cells 3). Mechanism 4). Clinical
examples of type I Hypersensitivity 5).
Therapy for type I Hypersensitivity
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Type I hypersensitivity reactions are the most
common forms of allergic reactions especially
against environmental agents.
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1) Characteristics
Occur and resolve quickly
Mediated by serum IgE
Systemic and regional tissue dysfuntion
Genetic predisposition (atopy)
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2) Components and cells in Type I hypersensitivity

• (Antigen) Allergen
• pollen?dust mite?insects etc
• selectively activate CD4Th2 cells and B
  cells
• Antibody(IgE)
• IgE mainly produced by mucosal B cells
  in the lamina prapria.
• IL-4 is essential to switch B
  cells to IgE production
• Mast cell and basophil
• Eosinophil

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3). Mechanism

• First exposure to allergen
• Allergen stimulates B lymphocytes to form
  antibody (IgE type).
• IgE fixes, by its Fc portion to mast cells and
  basophils.
• Second exposure to the same allergen
• The antigen fixes directly to IgE (which is
  already fixed to mast cell) leading to activation
  and degranulation of mast cells and release of
  mediators

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The biological mediators are
1. Histamine
Vasodilatation and increased vascular
permeability.
2. Leukotrienes
Bronchial smooth muscles contraction
3. Prostaglandin D2
Causes bronchospasm and increased mucin
secretion.
4. Platelet activating factor (PAF)
platelet aggregation, release of histamine,
bronchospasm, increased vascular permeability,
and vasodilation
5. Eosinophil chemotactic factor(ECF-A
6. Bradykinin
Vasodilation
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Immediate Phase Allergic Reaction

• Occurs within seconds to minutes of IgE receptor
  activation (mast cell mediator release) and
  resolving within an hour
• Intense pruritus, edema, erythema

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Late Phase Allergic Reaction

• A delayed inflammatory response (peaking at 4-8
  hrs and persisting up to 24 hrs) following an
  intense acute phase reaction
• Skin erythema, induration, burning
• Lungs airway obstruction poorly responsive to
  bronchodilators
• Nose/eyes erythema, congestion, burning
• Histology infiltration of tissues with
  eosinophils, neutrophils, basophils, monocytes,
  and CD4 T cells as well as tissue destruction,
  typically in the form of mucosal epithelial cell
  damage.

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Clinical examples of type I hypersensitivity
1.  Systemic anaphylaxis a very dangerous
condition
Allergic reactions after injection of drugs
(penicllin)or serum
2. Respiratory allergic diseases
1) Allergic asthmaacute response, chronic
response
2) Allergic rhinitis, Allergic
rhinoconjunctivitis (hay fever
3. Gastrointestinal allergic disease
4. Skin allergy Eczema (atopic dermatitis),
Acute urticaria
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Anaphylaxis

• Systemic form of Type I hypersensitivity
• Exposure to allergen to which a person is
  previously sensitized
• Allergens
• Drugs penicillin
• Serum injection anti-diphtheritic or
  anti-tetanic serum
• anesthesia or insect venom
• Clinical picture
• Shock due to sudden decrease of blood
  pressure, respiratory distress due to
  bronchospasm, cyanosis, edema, urticaria
• Treatment corticosteroids injection,
  epinephrine, antihistamines

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Atopy

• There is a strong familial predisposition to
  type I hypersensitvity reaction.
• The predisposition is genetically determined
• Atopic individuals have higher quantities of
  IgE antibodies and higher concentration of Fc
  receptors on mast cells.
• The airways and skin are commonly affected.
• Allergens
• Inhalants dust mite, pollens, mould
  spores.
• Ingestants milk, egg, fish, chocolate
• contactants wool, nylon, animal fur.

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Methods of diagnosis

• 1) History taking for determining the allergen
  involved
• 2) Skin tests
• Intradermal injection of battery of different
  allergens
• A wheal and flare (erythema) develop at the
  site of
• allergen to which the person is allergic
• 3) Determination of total serum IgE level-
• Radioimmunosorbent test (RIST)
• 4) Determination of specific IgE levels to the
  different allergens- Radioallergosorbent test
  (RAST)

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Skin test
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Management

• 1) Avoidance of specific allergen.
• 2) Hyposensitization
• Minute quantities of the responsible allergen is
  injected in increasing doses over a long peroid.
• 3) Drug Therapy
• corticosteroids injection, epinephrine,
  antihistamines

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2. Type II Hypersensitivity (Cytotoxic or
Cytolytic Reactions)
1. Characteristic features
2. Mechanism of Type II Hypersensitivity
3. Common diseases of Type II Hypersensitivity
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1. Characteristic features

Primed IgG or IgM
Antigen or hapten on membrane
Injury and dysfunction of target cells
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Type II Hypersensitivity ReactionsMechanisms of
Tissue Damage

• An antibody (Ig G or Ig M) reacts with
• antigen on the cell surface
• This antigen may be part of cell membrane
• or circulating antigen (or hapten) that
• attaches to cell membrane

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Mechanisms of type II hypersensitivity
reactions

• Complement-mediated cell lysis.
• Complement fixation to antigen antibody
  complex on cell surface. The activated complement
  will lead to cell lysis.
• Phagocytosis mediated cell lysis.
• Phagocytosis is enhanced by the antibody
  (opsinin) bound to cell antigen leading to
  opsonization of the target cell

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• Antibody-dependent cell-mediated cytotoxicity
  (ADCC)
• - Antibody coated cells e.g. tumor cells, graft
  cells or infected cells can be killed by cells
  possess Fc receptors.
• Antibody mediated cellular dysfunction
• The antibody does not destroy the cell but attach
  certain receptor to either block them (myasthenia
  gravis) or stimulate them (Graves disease).

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Clinical examples of type II hypersensitivity
reaction

• 1) Incompatible blood transfusion due to ABO
  incompatibility
• 2) Rh-incompatability (Haemolytic disease of the
  newborn)
• 3) Autoimmune hemolytic anaemia.
• 4). Autoimmune thrombocytopenic purpura.
• 5). Myasthenia gravis.
• 6). Gravis disease.
• 7). Insulin-resistant diabetes mellitus.

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• 8). Graft rejection cytotoxic reactions
• In hyperacute rejection the recipient already
  has performed antibody against the graft
• 9). 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

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3. Type III (Immune complex-mediated
hypersensitivity reactions. 1.
Characteristics 2. Mechanism of type III
hypersensitivity 3. Clinical examples of
type III hypersensitivity
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1. characteristics Free Ag Primed Ab
forming larger immune complexs

Deposit in tissue or blood vessel wall  

complement activation
and subsequent Inflammation
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• 2. Mechanism of type III hypersensitivity
• Immune complex activate Complement system
• Split products-C3a, C4a,C5a.
• C3a, C4a, C5a are chemotactic for Neutrophils.
• Neutrophils attempt to phagocytose the immune
  complex which is often unsuccessful because the
  complexes are bound to a large areas of tissue.
• During this attempts, release of large
  quantities of lysosomal enzymes causing tissue
  damage and inflammation.

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Arthus reaction

• Caused by repeated local exposure to an antigen
  that reacts with preformed antibody and forms
  immune complexes in the walls of the local blood
  vessels.
• The symptoms appear within 1 hour after injection
  and the peak 6-12 hours later.
• Lesions include edema, hemorrhage, clotting and
  tissue necrosis.

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Serum sickness

• Is a protoype of systemic immune complex
  hypersensitivity reaction.
• The immune complex circulate in the blood and
  deposit in blood vessels (vascultitis), joint
  (arthritis) and kidney (glomerulonephritis)
  associated with fever, rash and lymphadenopathy.
• Serum sickness was initially described as a
  complication of therapeutic administration of
  horse serum that contains anti-tetanic Abs.
• Serum sickness reactions can be caused by
  repeated intravenous administration of other
  antigens such as drugs.

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TYPE IV (cell mediated) hypersensitivity

• Whereas types I, II and III mediated by antibody,
  type IV mediated by T lymphocytes (cytotoxic T
  cells or cytokine-producing Th1 cells).
• Develops after 48-72 hrs of second exposure to
  antigen in a sensitized individual.
• Some subpopulations of activated TH cells
  encounter certain types of antigens, they secrete
  cytokines that induce a localized inflammatory
  reaction- delayed-type hypersensitivity (DTH).
• The reaction is characterized by large influxes
  of nonspecific inflammatory cells, macrophages.

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• A prolonged DTH response leads to destructive
  inflammatory response with development of
  granulomatous reaction.
• A granuloma develops by continuous activation of
  macrophages.
• Giant cells displace the normal tissue cells,
  forms palpable nodules, and release high
  concentrations of lytic enzymes, which destroy
  surrounding tissue.

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PHASES of DTH response

• Sensitization phase
• Activation of TH cells by Antigen presenting
  cells (APC) e.g Langerhans cells Macrophages
• Proliferation TH 1 subtype occurs.
• Effector phase
• TH 1 secrete cytokines , IL2, TNFß
• Recruitment activation of Macrophages

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• 3. Clinical examples of type IV hypersensitivity
• 1) Tuberculin test a skin test for T.B
• 2) Contact dermatitis
• caused by Paint, drug leading to appearance
  of red rash, papula, water blister, dermatitis
• 3) Graft rejection after organ transplantation
• 4) Immune response in local tumor mass

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Summary
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Gell and Coombs classification of
hypersensitivity reaction

• Type Description Time Mechanism,
  Typical manifestation
• Type I IgE-mediated 2-3min Ag induce
  cross-linkage Systemic anaphylaxis
• hypersensitivity of IgE
  bound to mast cells Localized anaphylaxis
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  or basophils with release -Hay fever, Asthma,
• 
  of vasoactive mediators Hives, Food
  Allergy
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  Eczema.
• Type II Ab-mediated 5-8h Ab directed
  against cell- Blood-transfusion
• cytotoxic
  surface Ags mediates cell reactions.
• hypersensitivity
  destruction via C activation Erythroblastosis
  fetalis
  Autoimmune hemolytic anemia.

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Gell and Coombs classification of
hypersensitivity reaction

• Type Description Time Mechanism
  Typical Manifestations
• TypeIII Immune complex 2-8h Ag-Ab
  complexes Localized Arthus
• -mediated
  deposited in various reaction
• hypersensitivity
  tissues induce C acti- Generalized reactions
• 
  vation and an ensuing Serum sickness,
• 
  inflammatory response Glomerulonephritis
• 
  
  Rheumatoid arthritis
• 
  SLE
• Delayed reactions
• Type IV cell-mediated 24-72h Sensitized
  TDTH cells Contact dermatitis,
• hypersensitivity
  release cytokines that Tuberculous lesions,
• 
  activate Macrophages, Graft rejection.
• 
  which mediate direct
• 
  cellular damage.