Hypersensitivity I

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Hypersensitivity I IICh. 18-19

• March 6th, 2006
• Ricky Chang

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Objectives

• Know the mechanism of Type I hypersensitivity
• Know the mediators of Type I hypersensitivity
• Know the diseases associated with Type II
  hypersensitivity

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Hypersensitivity

• Adaptive immunity is important against microbial
  infections, but it is also capable of causing
  tissue injury and disease (autoimmune diseases)
• Occurs when immune responses are directed against
  self-ag and also from uncontrolled or excessive
  responses to against foreign ag, such as microbes
  and allergens

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Hypersensitivity

• Common cause is failure of self-tolerance, which
  ensures that individuals do not respond to their
  own antigens
• Leads to tissue injury that occurs in autoimmune
  diseases due to the same effector mechanisms used
  to protect against microbes

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Hypersensitivity

• Type I IgE antibodies bind to Fc receptors on
  mast cells. IgE induces mast cell degranulation
  and release inflammatory mediators
• Type II Ab mediated immune response against self
  antigen or foreign antigen (ie ag on transfused
  RBC)
• Type III Immune complexes are deposited in
  tissue
• Type IV T-cell mediated response where Ag
  sensitized T-cells release lymphokines

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Hypersensitivity
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Hypersensitivity
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Roles of Mast Cells

• Part of connective tissue (contains granules of
  histamine and heparin)
• Allergic diseases (asthma,eczema,itch)
• Anaphylaxis (systemic shock to allergens such as
  bee sting,nuts,drugs)
• Autoimmune disorders/Acute or chronic
  inflammation (MS, Rheumatoid arthritis)
• Wound healing
• Innate response for clearing bacteria and viruses
  

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Mast Cell
Basophil
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Type I (Immediate)

1. Ag/allergen stimulate CD4?Th2
2. Th2 releases IL-4, which promote B-cells specific
   for that Ag to differentiate into IgE producing
   cells
3. Circulating IgE binds to Fc receptors on mast
   cells and basophils
4. Elicits a transduction event to release mediators
   stored in granules (Degranulation)
5. Immediate hypersensitivity response (5-10 minutes)

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Mediator Release from Mast Cells
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Type I Mediators and Effects
Figure19.3
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Type I Mediators and Effects
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IgE-Mediated Allergic Reactions
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Type I Mast Cells

• Type I reaction is dependent upon the specific
  triggering of IgE-sensitized mast-cells by
  allergen (Ag)
• Ag enter via mucosal surfaces and are taken up by
  APC
• Th2 cells release IL-4 to facilitate the B-cell
  proliferation and differentiation, producing IgE
  specific for the allergen
• REMEMBER THIS IS A TH2 RESPONSE!

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Activation of Mast Cells

• IgE from B-cells binds to Fc?RI on mast-cells
• -? is the heavy chain responsible for IgE
  isotype switching
• Fc?RI on mast-cells cross-links with Ag-bounded
  IgE and induces degranulation of mediators

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Cross-linking of Fc?RI to IgE bounded to Ag
Degranulation of Mediators
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Activation of Mast-cells
Cross-linking
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Mast-Cell Mediators

• Inflammatory Mediators released
• -Histamine
• -Proteases (tryptase or chymase), acid
  hydrolases
• -Proteoglycans (heparin, chondroitin sulfate)

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Mast Cells Lipid Mediators

• Prostaglandins D2
• Leukotrienes C4, D4, E4
• Platelet-activating factor

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Mast-Cells Cytokines

• IL-3 Promote mast cell proliferation
• IL-4, IL-5 Promote Th2 differentiation and IgE
  AB production
• TNF-?, MIP-1? Enhance inflammatory reaction

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Allergen Induced Hypersensitivity

• Allergen are antigens that induce production of
  specific IgE AB
• Examples plant pollens, dust, animal hair,
  animal anti-serum, insect venom, chemicals, and
  foods
• Once the allergen reaches the sensitized mast
  cells, the allergen crosslinks the surface-bound
  IgE? ?intracelluar Ca2 and triggers
  degranulation of mediators

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Atopy

• Atopy Describes individuals that produce IgE AB
  in response to various environmental Ag and
  develop immediate hypersensitivity (Type I)
  responses.(Asthma, eczema, hay fever, and
  urticaria)
• These individuals normally have a strong family
  history (autosomal transmission of atopy)

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Atopy

• HLA vs. Allergen Responsiveness
• -Some allergens response have a relationship to
  HLA
• -HLA-DR2 and HLA-A2 high responder to low dos
  of ragweed
• -HLA-B8 high responder to ragweed and also
  associated to other forms of hyperimmunity
  (autoimmunity)

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IgE

• IgE blood concentrations are often increased in
  allergic disease and are grossly elevated in
  parasitic infections
• IL-4 promote B-cells to differentiate into
  IgE-producing specific cells

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Eosinophil

• Th2 produce IL-5 Promotes the synthesis and
  secretion of IgA from B-cells and also important
  in stimulating eosinophil development and
  activation
• IL-4 and IL-5 production by Th2 cells may account
  for the eosinophilia seen in type I
  hypersensitivity and parasitemia

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Two Types of Mast Cells

• Connective tissue mast cells (CTMCs)
• Mucosal mast cells (MMC)

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Connective Tissue Mass Cells

• CTMCs are found most in blood vessels but vary in
  size and number of granules at different regions
  of the body
• Diseases such as Crohns disease, ulcerative
  colitis, and RA all present with increase in CTMCs

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Types of Fc Receptors for IgE

• There are two types of receptors for IgE
• 1) Fc?RI (high affinity) Expressed on mast
  cells and basophils
• 2) Fc?RII (low affinity) Expressed by
  lymphocytes

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Mast Cells Activation

• Cross-linking can be artificially induced with
  lectins such as PHA (Polyhydroxyaldehyde) and
  ConA
• These carbohydrates cross-link with IgE and cause
  degranulation
• This explains urticaria in individuals allergic
  to fruits (ie strawberries-contain large amt of
  lectin

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Degranulation

• C products of C3a and C5a are very active in
  degranulating mast cells
• Compounds that affect Ca2 influx into mast cells
  can induce degranulation
• Drugs such as morphine, codeine, synthetic ACTH
  can create clinical manifestations related to
  mast cells

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Modulation of Mast Cells
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Therapy for Allergy

• 1) Agents that increase intracellular cAMP
  (?-agonist)-inhibits contraction
• -Theophyllines Prevents cAMP degradation
• 2) Blocking mediator release, such as sodium
  cromolyn mechanism not clear, but seem to
  antagonize IgE-induced mediator release.

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Therapeutics

• Direct Inhibitors
• -Theophyllines, Xanthines
• -Sodium cromolyn
• -Epinephrine
• -PGE1, PGE2
• Indirect Inhibitor
• -Glucocorticoids

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Histamine Receptors

• H1
• Bronchial constriction
• Musous secretion
• Intestinal smooth muscle contraction
• Itching and pain at sensory nerve endings

• H1 and H2
• Reduces BP
• Increase permeability in skin
• H2
• - Gastric secretion in stomach

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Antihistamines

• Nausea,vertigo,motion sickness
• -Cyclizine
• -Dimenhydrinate
• -Diphenhydramine (Benadryl, Tylenol PM)
• -Meclizine

• H1 Antagonists
• -Promethazine (Phenergan)
• -Cetirizine (Zyrtec)
• -Desloratadine (Clarinex)
• -Fexofenadine (Allegra)
• -Loratadine (Claritin)

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Type II Hypersensitivity
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Type II

• Antibodies are directed against ag on particular
  cells/tissue or extracellular matrix, causing
  damage (ie RBC transfusion)
• These cell- or tissue-specific Ab cause diseases
  
• -Myasthenia Gravis Ab blocks Ach-binding and
  cause muscle weakness and paralysis
• -Graves Disease Ab stimulate TSH and casue
  hyperthyroidism)

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Type II
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Type II

• Type II causes disease by 3 mechanism
• 1) Opsonization and phagocytosis of cells
• 2) Complement and Fc receptor-mediated
  inflammation and tissue injury
• 3) Interference of normal cellular function by
  binding to important molecules or receptors

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Reaction Against RBCs and Platelets

• Transfusion Reactions There are 200 genetic
  variant of the RBC, but the ABO is the main
  designation
• The Rh system is also important because its cause
  of hemolytic disease in the newborn

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Reaction Against RBCs and Platelets
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Reaction Against RBCs and Platelets

• Hemolytic disease of the newborn (2nd born)
• -RhoGam Its an Anti-Rh Antibody given to
  mother after the first born to prevent future
  complications in later newborns
• Autoimmune Hemolytic Anemia
• -When provoked by allergic reactions to certain
  drugs, including Penicillin, quinine, and
  sulphonamides

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Idiopathic Thrombocytpenic Purpura (ITP)

• Autoantibody to platelets from the rapid removal
  of platelets from circulation
• Most often develop in women after bacterial or
  viral infections
• Associated with autoimmune disease Systemic Lupus
  Erythematosus (SLE)

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Type II Mediated Autoimmune Diseases

• Myasthenia Gravis
• Graves Disease
• Insulin-resistance Diabetes
• Hemolytic Anemia
• Rheumatoid Arthritis

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Advise of the Day
TYPE III Type IV..To Be Continued