Immune Responses Without Infection

I. The four types of hypersensitivity

A. Type I -

Immediate hypersensitivity (atopic allergy and anaphylaxis)- mediated by mast cells and IgE

B. Type II -

IgG mediated effects against cell-bound antigens

C. Type III -

IgG mediated effects against soluble antigens- immune complex mediated

D. Type IV -

T-cell effects - delayed type hypersensitivity DTH

II. Atopic Allergy

A. Allergen -

an antigen, usually airborne, that stimulates IgE immunity - it is not known why some individuals are allergic to some substances and others are not. MHC may play a role

B. Sensitization -

no allergic response made the first time one is exposed to allergen - specific IgE is produced that binds to mast cells. Further exposure will cause symptoms

C. Desensitization -

injection of small amounts of allergen stimulates IgG and IgA, which bind to allergen before it can interact with mast cell-bound IgE - can moderate allergic symptoms

D. Features of allergens -

body exposed to very small concentrations of allergens, which favors TH2 helper T-cell response and antibody production - allergens are highly soluble and stable protein antigensthat can bind to MHC Class II - examples are bee venom and ragweed pollen.

E. Individuals with high levels of worm-specific IgE are less prone to other allergies -

the IgE to the worms fills up most of the Fc receptors on the mast cells (immune deviation)

F. MHC Class II phenotype also important -

statistical correlation between MHC and propensity toward certain allergies

G. Systemic anaphylaxis -

when allergen is given systemically to a sensitized individual, disseminated mast cell activation leads towidespread vasodilation, constriction of the airways, and epiglottal swelling called anaphylactic shock. Example is bee sting or reaction to penicillin. Anaphylaxis can be fatal if epinephrine (vasoconstrictor)is not administered

H. Wheal and flare -

when small doses of allergen are injected into skin - local vasodilation and increased vascular permeability causes a raised, liquid filled area (edema) surrounded by a red zone - used by allergists to determine what a patient is allergic to (skin testing)

I. Inhaled allergen -

allergic rhinitis (runny nose, etc.) and allergic asthma (bronchial constriction, making breathing difficult)

J. Ingested allergen -

food allergies, can cause vomiting and diarrhea by inducing smooth muscle contraction - can also cause urticaria (hives, red swellings beneath the skin)

K. Treatment with anti-histamines -

works for allergic rhinitis,but not for allergic asthma, where the bronchial passageways are chronically inflamed - asthma can be treated with inhaled corticosteroids (e.g., epinephrine)

III. Type II and Type III hypersensitivity - mediated by IgG

A. Type II -

antibody binds to surface of a cell, such as a red blood cell, which is then destroyed by activated complement

B. Type III -

small immune complexes (Ag + Ab) can aggregateand deposit on blood vessel walls - when this occurs, complement is activated, leading to increased vascular permeability and eventually to blood-vessel occlusion by cells and platelets

IV. Type IV - Delayed Type Hypersensitivity

A. Example: the tuberculin test -

small amount of protein extract (PPD - purified protein derivative) from M. tuberculosis is injected into the skin. Inflammatory TH1 T-cells enter site of injection. These T-cells recognize Ag/Class II MHC on antigen- presenting cells and release inflammatory cytokines. This increases vascular permeabilityand recruits neutrophils and then macrophages to the site. This leads to a reddish, induration (hard swelling) at the site. This reaction takes 24-48 hr to occur.

B. Contact sensitivity -

poison ivy venom binds covalently to host proteins, forming new antigens that lead to a DTH reaction. Jewelry with nickel in it can do this also

V. Autoimmune diseases -

how these diseases are triggered is not known. Immune responses to infectious agents may play a role.

A. Association between MHC genotype and autoimmune disease -

there is a statistical correlation

B. Damage can be caused by antibodies or T-cells

C. Graves disease -

antibody to the thyroid stimulating hormone receptor in thyroid - stimulates high thyroid hormone levels

D. Myasthenia gravis -

antibody to the acetylcholine receptor found in neuromuscular junctions. Leads to muscle weakness and death

E. Systemic lupus erythematosus -

immune complexes are made to nucleic acid/protein complexes - these can deposit in the glomerulus and cause kidney damage - more common in women - characteristic symptom is a butterfly-shaped facial rash.

F. Rheumatoid arthritis -

inflammatory T-cells specific for joint antigens - joints swell painfully, leading to decrease in joint flexibility

G. Insulin-dependent (juvenile) diabetes -

cytotoxic T-cells specific for surface proteins of the beta cells of the pancreas. This prevents these cells from producing insulin

VI. Transplant rejection -

responses to alloantigens

A. Types of grafts

1. Autograft -

within the same individual - no rejection

2. Syngeneic -

between genetically identical individuals (inbred mice or identical twins) - no rejection

3. Allogeneic -

between unrelated individuals of the same species differences in MHC molecules can cause rejection (days)

4. Xenogeneic-

between different species - hyperacute graft rejection (hours) - caused by antibodies against endothelial cells of domestic animals binding to the graft, which initiates the complement and clotting cascades.

B. Graft rejection

1. Primarily mediated by T-cells -

cytotoxic T-cell, inflammatory TH1 T-cells, or both

2. First set rejection -

takes about 11-15 days

3. Second set rejection -

if try to graft same individual with tissue from the same donor, rejection is more rapid (6-8 days) - mechanism due to immunological memory, since third party grafts are rejected no faster than first set rejection.

C. Tissue typing -

the exact nature of T-cell responses to non-self MHC is not clear, but trying to match MHC molecules between donor and recipient significantly improves success rate.However, it is extremely difficult to find exact MHC match between unrelated individuals.

D. Routinely transplanted organs -

kidney and corneal transplants survive the best - transplants use immunosuppressive, anti-rejection drugs such as FK-506 and cyclosporin A, which inhibit T-cell activation.

E. The fetus is an allograft that is not rejected -

fetus has paternal MHC and/or minor histocompatibility molecules that are different from those of the mother - one reason that fetus is not rejected is that the mother's cellular immune response can not cross the placenta, making the uterus an immunologically privileged site. Other privileged sites include the brain, eye, and testes. We make no response to antigens present in these sites, either.