Objectives Hypersensitivity I & II Ch.

18-19
March 6th, 2006 Ricky Chang 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 selfexcessive responses to against foreign ag, ag, such as microbes and allergens

Hypersensitivity
Common cause is failure of self-tolerance, 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

Type I (Immediate)
1) 2) 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)

3)

Mast Cell

4)

Basophil
5)

Type I Mediators and Effects

Mediator Release from Mast Cells 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-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!

Activation of Mast Cells

IgE from B-cells binds to FcRI on mast-cells - is the heavy chain responsible for IgE isotype switching FcRI on mast-cells cross-links with Agbounded IgE and induces degranulation of mediators

Activation of Mast-cells
Cross-linking

Cross-linking of FcRI to IgE bounded to Ag Degranulation of Mediators

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 Bcells 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

1) Connective tissue mast cells (CTMCs) 2) 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 Crohns 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) FcRI (high affinity): Expressed on mast cells and basophils 2) FcRII (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

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

Antihistamines
Nausea,vertigo,motion sickness H1 Antagonists

-Cyclizine -Dimenhydrinate -Diphenhydramine (Benadryl, Tylenol PM) -Meclizine

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

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 receptormediated 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: 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

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