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Hypersensitivity I & II Ch. 18-19 . March 6th, 2006 Ricky Chang. Objectives. Know the mechanism of Type I hypersensitivity Know the mediators of Type I hypersensitivity Know the diseases associated with Type II hypersensitivity. Hypersensitivity.

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Hypersensitivity I & II Ch. 18-19

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Hypersensitivity I & IICh. 18-19

March 6th, 2006

Ricky Chang


Objectives

  • Know the mechanism of Type I hypersensitivity

  • Know the mediators of Type I hypersensitivity

  • Know the diseases associated with Type II hypersensitivity


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


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


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


Hypersensitivity


Hypersensitivity


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


Mast Cell

Basophil


Ag/allergen stimulate CD4+Th2

Th2 releases IL-4, which promote B-cells specific for that Ag to differentiate into IgE producing cells

Circulating IgE binds to Fc receptors on mast cells and basophils

Elicits a transduction event to release mediators stored in granules (Degranulation)

Immediate hypersensitivity response (5-10 minutes)

Type I (Immediate)


Mediator Release from Mast Cells


Type I Mediators and Effects

Figure19.3


Type I Mediators and Effects


IgE-Mediated Allergic Reactions


Type I: Mast Cells

  • Type I reaction is dependent upon the specific triggering of IgE-sensitizedmast-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!


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


Cross-linking of FcRI to

IgE bounded to Ag

Degranulation of Mediators


Activation of Mast-cells

Cross-linking


Mast-Cell Mediators

  • Inflammatory Mediators released

    -Histamine

    -Proteases (tryptase or chymase), acid hydrolases

    -Proteoglycans (heparin, chondroitin sulfate)


Mast Cells: Lipid Mediators

  • Prostaglandins D2

  • Leukotrienes C4, D4, E4

  • Platelet-activating factor


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


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 Ca+2 and triggers degranulation of mediators


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)


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)


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


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


Two Types of Mast Cells

  • Connective tissue mast cells (CTMCs)

  • Mucosal mast cells (MMC)


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 Crohn’s disease, ulcerative colitis, and RA all present with increase in CTMCs


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


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


Degranulation

  • C’ products of C3a and C5a are very active in degranulating mast cells

  • Compounds that affect Ca+2 influx into mast cells can induce degranulation

  • Drugs such as morphine, codeine, synthetic ACTH can create clinical manifestations related to mast cells


Modulation of Mast Cells


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.


Therapeutics

  • Direct Inhibitors

    -Theophyllines, Xanthines

    -Sodium cromolyn

    -Epinephrine

    -PGE1, PGE2

  • Indirect Inhibitor

    -Glucocorticoids


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

Histamine Receptors


Nausea,vertigo,motion sickness

-Cyclizine

-Dimenhydrinate

-Diphenhydramine (Benadryl, Tylenol PM)

-Meclizine

H1 Antagonists

-Promethazine (Phenergan)

-Cetirizine (Zyrtec)

-Desloratadine (Clarinex)

-Fexofenadine (Allegra)

-Loratadine (Claritin)

Antihistamines


Type II Hypersensitivity


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)


Type II


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


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


Reaction Against RBCs and Platelets


Reaction Against RBCs and Platelets

  • Hemolytic disease of the newborn (2nd born)

    -RhoGam: It’s 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


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)


Type II Mediated Autoimmune Diseases

  • Myasthenia Gravis

  • Graves’ Disease

  • Insulin-resistance Diabetes

  • Hemolytic Anemia

  • Rheumatoid Arthritis


Advise of the Day

TYPE III & Type IV..To Be Continued…


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