HYPERSENSITIVITY REACTIONS

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HYPERSENSITIVITY REACTIONS
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• Hypersensitivity refers to undesirable (damaging,
  discomfort-producing and sometimes fatal)
  reactions produced by the normal immune system
• Hypersensitivity reactions require a
  pre-sensitized (immune) state of the host

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CLASSIFICATION

• TYPE I IMMEDIATE, ATOPIC, ANAPHYLLACTIC
• TYPE II ANTIBODY DEPENDANT
• TYPE III IMMUNE COMPLEX
• TYPE IV CELL MEDIATED / DELAYED TYPE OF
  HYPERSENSITIVITY
• TYPE V - STIMULATORY

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Type 1 Immediate Hypersensitivity Reaction

• Mediated by IgE antibody to specific antigens
• Mast cells stimulated and release histamine
• Reaction within one hour of exposure
• Examples
• Anaphylaxis (e.g. Penicillin)
• Urticaria
• Angioedema
• Atopic Allergy

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Type 2 Cytotoxic Antibody Reaction

• Mediated by IgG and IgM to specific antigens
• Examples
• Transfusion Reaction
• Rhesus Incompatibility (Rh Incompatibility)
• Mycoplasma pneumoniae related cold agglutinins
• Hashimoto' Thyroiditis
• Good pasture's Syndrome
• Delayed transplant graft rejection

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Type 3 Immune Complex Reaction

• Antigen-antibody complexes deposit in tissue
• Reaction within 1-3 weeks after exposure
• Examples
• Systemic Lupus Erythematosus
• Erythema Nodosum
• Polyarteritis nodosa
• Arthus Reaction (e.g. Farmer's Lung)
• Rheumatoid Arthritis
• Elephantiasis (Wuchereria bancrofti reaction)
• Jarisch-Herxheimer Reaction
• Serum Sickness

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Type 4 Delayed-Type Hypersensitivity

• Mediated by T-Lymphocytes to specific antigens
• Involves major histocompatibility complex (MHC)
• Reaction within 2-7 days after exposure
• Examples
• Mantoux Test (PPD)
• Allergic Contact Dermatitis (e.g. Nickel allergy)
  

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Other allergy mediated reactions

• Stimulatory Hypersensitivity
• Humoral antibody activates receptor sites
• Example Thyrotoxicosis (TSH autoantibodies)
• Fas/Fas ligand-induced apoptosis
• Example Stevens Johnson Syndrome
• T-Cell activation
• Example Sulfonamide induced Morbilliform rash

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TYPE I HYPERSENSITIVITY REACTION

• Type 1 hypersensitivity is an allergic reaction
  provoked by re-exposure to a specific type of
  antigen referred to as an allergen
• Exposure may be by ingestion, inhalation,
  injection, or direct contact
• The difference between a normal immune response
  and a type I hypersensitive response is that
  plasma cells secrete IgE
• This class of antibodies binds to Fc receptors on
  the surface of tissue mast cells and blood
  basophils

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• The mechanism of reaction involves preferential
  production of IgE, in response to certain
  antigens (allergens).
• IgE has very high affinity for its receptor on
  mast cells and basophils.
• A subsequent exposure to the same allergen cross
  links the cell-bound IgE and triggers the release
  of various pharmacologically active substances
• Cross-linking of IgE Fc-receptor is important in
  mast cell triggering.
• Mast cell degranulation is preceded by increased
  Ca influx, which is a crucial process
  ionophores which increase cytoplasmic Ca also
  promote degranulation, whereas, agents which
  deplete cytoplasmic Ca suppress degranulation.

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Pharmacologic Mediators of Immediate
Hypersensitivity 

• Preformed mediators in granules
• Histamine - bronchoconstriction, mucus secretion,
  vasodilatation, vascular permeability
• Tryptase proteolysis
• Kininogenase - kinins and vasodilatation,
  vascular permeability, edema
• ECF-A (tetrapeptides)attract eosinophil and
  neutrophils 

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Newly formed mediators

• Leukotriene- B4 basophil attractant
• leukotriene C4, D4 - same as histamine but 1000x
  more potent
• prostaglandins D2 - edema and pain
• PAF - platelet aggregation and heparin release
  microthrombi 

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• Diagnostic tests for immediate hypersensitivity
  include
• skin (prick and intradermal) tests
• measurement of total IgE and specific IgE
  antibodies against the suspected allergens
• Total IgE and specific IgE antibodies are
  measured by a modification of enzyme immunoassay
  (ELISA)
• Increased IgE levels are indicative of an  atopic
  condition, although IgE may be elevated in some
  non-atopic diseases (e.g., myelomas, helminthic
  infection, etc.)

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Intradermal skin test with multiple positive
allergen responses 
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TYPE 2 HYPERSENSITIVITY REACTION

• Mechanism
• Either IgG or IgM is made against normal self
  antigens as a result of a failure in immune
  tolerance or a foreign antigen resembling some
  molecule on the surface of host cells enters the
  body and IgG or IgM made against that antigen
  then cross reacts with the host cell surface.

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• The binding of these antibodies to the surface of
  host cells then leads to
• opsonization of the host cells whereby phagocytes
  stick to host cells by way of IgG, C3b, or C4b
  and discharge their lysosomes

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Opsonization During Type-II Hypersensitivity,
Step-1

• The Fab of IgG reacts with epitopes on the
  host cell membrane. Phagocytes bind to the Fc
  portion

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Opsonization During Type-II Hypersensitivity,
Step-2

• Phagocytes binding to the Fc portion of the IgG
  and discharge their lysosomes causing cell lysis.
  

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IgG reacts with epitopes on the host cell
membrane. Phagocytes then bind to the Fc portion
of the IgG and discharge their lysosomes.
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• activation of the classical complement pathway
  causing MAC lysis of the cells

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MAC Lysis During Type-II Hypersensitivity, Step-1

• IgG or IgM reacts with epitopes on the host
  cell membrane and activates the classical
  complement pathway. Membrane attack complex (MAC)
  then causes lysis of the cell.

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MAC Lysis During Type-II Hypersensitivity, Step-2

• Membrane attack complex (MAC) then causing lysis
  of the cell.

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IgG or IgM reacts with epitopes on the host cell
membrane and activates the classical complement
pathway. Membrane attack complex (MAC) then
causes lysis of the cell.
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• ADCC destruction of the host cells whereby NK
  cells attach to the Fc portion of the antibodies.
• The NK cell then release pore-forming proteins
  called perforins and proteolytic enzymes called
  granzymes.
• Granzymes pass through the pores and activate the
  enzymes that lead to apoptosis of the infected
  cell by means of destruction of its structural
  cytoskeleton proteins and by chromosomal
  degradation.

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ADCC-Induced Apoptosis by NK Cells During Type II
Hypersensitivity, Step-1
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ADCC-Induced Apoptosis by NK Cells During Type II
Hypersensitivity, Step-2
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ADCC-Induced Apoptosis by NK Cells During Type II
Hypersensitivity, Step-3
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ADCC Destruction During Type-II Hypersensitivity
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ADCC Apoptosis by NK Cells During Type II
Hypersensitivity
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Type II Hypersensitivity Reaction

• Type II hypersensitivity affects a variety of
  organs and tissues
• The antigens are normally endogenous, although
  exogenous chemicals (haptens) which can attach to
  cell membranes can also lead to type II
  hypersensitivity
• Drug-induced hemolytic anemia, granulocytopenia
  and thrombocytopenia are such examples
• The reaction time is minutes to hours
• Type II hypersensitivity is primarily mediated by
  antibodies of the IgM or IgG classes and
  complement
• Phagocytes and K cells may also play a role (ADCC)

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• Diagnostic tests include detection of circulating
  antibody against the tissues involved and the
  presence of antibody and complement in the lesion
  (biopsy) by immunofluorescence.

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• The staining pattern is normally smooth and
  linear, such as that seen in Good pasture's
  nephritis (renal and lung basement membrane)

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pemphigus (skin intercellular protein, desmosome)
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