These lecture notes will provide an outline of information from the lectures. They are not complete. They should be used to help follow the lecture and as a guideline for information I think is important. You will need to fill in the gaps.

Chapter 20

These notes were updated March 26, 2001, and are ready for printing by Spring 2001 Med Micro. students.

Hypersensitivity

A state of increased sensitivity to an antigen, arising from a previous exposure to that antigen

I. Hypersensitivity A. Triggered by initial exposure to an antigen 1. Individual is sensitized B. Subsequent exposure to that same antigen leads to a reaction
C. May be immediate (antibody-mediated)
D. May be delayed (cellular-mediated)
E. Four classifications 1. Type I anaphylactic (immediate)
2. Type II cytotoxic (immediate)
3. Type III immune complex (immediate)
4. Type IV cellular (delayed) II. Type I A. Begins with initial exposure to an allergen 1. Allergens are antigenic substances that cause allergies
2. Examples of allergens are bee venom, penicillin, peanuts, and shell fish
3. This first dose is called the sensitizing dose B. Immune system responds
C. B lymphocyte becomes plasma cell and produces IgE antibody
D. IgE antibody enters circulation and attaches to the surface of mast cells and basophils 1. This is called sensitization E. A subsequent exposure to the allergen occurs 1. The allergen attaches to the IgE antibody molecules already present on the mast cells and basophils
2. When allergen attachment causes a bridging effect between adjacent IgE antibodies, the mast cell or basophil is triggered to release its granules (due to adenyl cyclase inhibition, which reduces cAMP and granules release), which contain histamine a) The histamine causes the release of leukotrienes, prostaglandins, and lymphokines
b) Histamines: dilate and increase permeability of capillaries (1) Edema
(2) Erythema c) Leukotrienes: Prolonged smooth muscle contractions (1) Bronchial tube spasm
(2) Intense abdominal muscle spasm d) Prostaglandins: Constrict bronchial tubes F. Overall effects: 1. Dilation of capillaries
2. Swelling
3. Mucus secretion
4. Smooth muscle contraction
5. Shock
6. Death G. Summary of Type I Hypersensitivity 1. Range of effect: systemic to localized a) Systemic: anaphylactic shock
b) Localized: asthma; hay fever; hives; food allergies (atopic diseases) 2. Cause: mediator substances emitted by granules
3. To prevent: a) Avoid allergen
b) Desensitization (1) Injection of antigen in the hopes that IgG antibodies are produced that will bind to antigen and block it (neutralize it) before it reaches sensitized mast cells/basophils (with IgE) 4. Treatment: a) Adrenaline for anaphylaxis (increases adenyl cyclase, leading to cAMP increase, which inhibits granule release)
b) Aminophylline (theophylline), benadryl, antihistamines, decongestants, steroids III. Type II A. This is a cytotoxic (cell-damaging) reaction that occurs when IgG antibodies react with antigens on the surfaces of red blood cells
B. Complement is often activated as a result
C. IgM may also be involved
D. Includes conditions resulting in damage to non-RBCs as well (p. 652) 1. There are "naturally-occurring" antibodies to certain antigens found on red blood cells
2. Other types of cytotoxic antibodies are not formed until after an initial exposure to a blood cell antigen a) Through a transfusion
b) Through pregnancy (fetal-maternal bleeding is not an uncommon event, especially at delivery when maternal/fetal blood may mix) 3. Review of the Rh Genotype a) Rh positive (1) Person's red blood cells contain the D (Rh) antigen
(2) That person may be heterozygous or homozygous (a) This person does not have and never will develop anti-Rh antibodies b) Rh negative (1) Person's red blood cells do not contain the D (Rh) antigen
(2) That person is always homozygous 4. Rh negative mother marries Rh positive father a) Father is either heterozygous (Dd) or homozygous (DD)
b) Mother is dd (Rh negative)
c) You do the math: (1) If Dad is heterozygous, half of the children will be Rh positive
(2) If Dad is homozygous, ALL of the children will be Rh positive
(3) If mom's fetus is Rh positive, she will probably be exposed to that antigen, be stimulated, be sensitized, and produce anti-Rh antibodies
(4) This happens late in the pregnancy, so the first baby is usually fine
(5) Any subsequent Rh positive fetuses will cause a secondary (anamnestic) response in Mom (a) She produces anti-Rh antibodies (IgG)
(b) Because they are IgG, they cross the placenta, bullets seeking their target
(c) Like a lock and key, they attach to all cells carrying the Rh antigen
(d) Complement's classical pathway is launched (Ag/Ab complex)
(e) C3 is activated and the red blood cells are destroyed
(f) This is called Hemolytic Disease of the Newborn (Erythroblastosis fetalis) E. Summary of Type II Hypersensitivity 1. Range of effect: systemic a) Hemolysis of red blood cells
b) Release of histamine
c) Flushing of face, chest and back pain, chills, fever
d) Increased pulse
e) Oozing/bleeding at surgical site
f) Kidney failure
g) Heart failure
h) Death 2. To prevent: a) Use type-compatible blood for transfusion
b) High standards for labeling patient samples and actual transfusion process, to include monitoring of patient's vital signs during transfusion process
c) RhoGam for Rh negative mothers 3. Treatment: a) HDN: intrauterine transfusion before birth, exchange transfusion after birth
b) Transfusion reaction: immediate cessation of transfusion; treatment of symptoms F. Non-RBC Cytotoxic Reactions Due to Autoimmunity 1. Target is the platelet (can also be the WBC) a) Result is thrombocytopenic purpura (or agranulocytosis), due to autoimmune disease 2. Cause is a small drug molecule, hapten, that coats the platelets, resulting in an antigenic substance
3. Antibodies are produced, activating complement a) Platelets are subsequently destroyed 4. Take patient off the drug and support until platelets are back to normal G. Other Type II Autoimmune Disorders 1. Involve antibody reactions to cell-surface antigens of the host
2. Goodpasture Syndrome a) Antibodies combine with antigens on the membranes of glomeruli in kidneys
b) This binding activates complement, which destroys the glomerular membranes
c) Results in kidney failure 3. Graves' disease: a) Antibodies attach to receptors on thyroid gland cells that normally are the target cells of TSH produced by pituitary gland
b) Thyroid is now stimulated to produce increased amounts of thyroid hormones 4. Hashimoto's Disease a) Antibodies attack thyroid gland cells, causing destruction of thyroid 5. Myasthenia gravis: a) Antibodies coat acetylcholine receptors at junctions at which nerve impulses reach the muscles
b) After a while, muscles controlling diaphragm and rib cage fail to receive necessary nerve signals, causing weakness, fatigue, respiratory arrest and death IV. Type III A. This is caused by a hypersensitivity to an IMMUNE COMPLEX
B. It develops when mostly IgG (some IgM) antibodies combine with antigens to form aggregates (bunches) called immune complexes 1. The antigens are soluble proteins or nucleic acids a) Some are bacterial or viral; others are endogenous 2. These aggregates accumulate in the blood vessels or along the surface of tissues, especially in the basement membrane
3. They cause complement to be activated (classical pathway)
4. Chronic inflammatory process takes place, which is often destructive to host, resulting in tissue damage C. Summary of Type III Hypersensitivity 1. Range of effect: systemic to localized
2. Systemic: SLE (autoimmune)
3. Localized: glomerulonephritis, rheumatic fever, rheumatoid arthritis (autoimmune); Arthus reactions
4. To prevent: a) The pathogenesis of autoimmunity involves immunologic, genetic, and viral factors that are presently poorly understood
b) In many of these, there is a failure of the regulatory mechanism that sustains self-tolerance
c) Complete antimicrobial treatment protocol for bacterial infections 5. Treatment: Steroids V. Type IV A. This is a CELLULAR hypersensitivity that is an exaggeration of cell-mediated immunity
B. It is a delayed reaction whose maximal effect is not seen until 24-72 hours later
C. It is characterized by a thickening and drying of the skin tissue (called induration) accompanied by a surrounding zone of erythema (redness)
D. The two major forms of type IV hypersensitivity are infection allergy and contact dermatitis 1. Infection Allergy a) Stimulating agent: certain microbes (1) Stimulating microbes include: (a) M. tuberculosis
(b) M. leprae
(c) Brucella abortus
(d) Fungi that cause blastomycosis, histoplasmosi, candidiasis
(e) Viruses that cause smallpox and mumps
(f) Tuberculin skin test takes advantage of this (i) PPD of M. tuberculosis intradermally injected
(ii) If previously sensitized, vesicle, erythema, induration develop b) Macrophage phagocytizes antigen, releasing lymphokines (1) T cell arrives and is presented with processed antigens
(2) T cell proliferates into Tc and memory cells (3) Upon subsequent exposure, a cell-mediated hypersensitivity reaction may result

(4) Memory cells activate T cells
(5) Destructive cytokines released
(6) Inflammation occurs 2. Contact Dermatitis a) Usually caused by haptens combining with proteins found in the skin (1) Haptens include clothing, insecticides, coins, cosmetics, furs, formaldehyde, copper, dyes, bacterial enzymes, poison ivy (urushiol) b) Repeated exposure causes a drying of the skin accompanied by erythema and scaling
c) When a sensitized person touches the hapten, T lymphocytes are stimulated
d) Within 24 hours, a type IV reaction takes place VI. Immune Deficiency Diseases A. Bruton's agammaglobulinemia 1. B lymphocytes do not develop a) Thus, no plasma cells
b) Therefore, no antibodies B. DiGeorge syndrome 1. T lymphocytes do not develop a) Thus, defective cell-mediated immunity C. Severe combined immunodeficiency 1. No B OR T lymphocytes D. There can also be problems with WBCs, complement
E. AIDS 1. Viral (HIV is etiologic agent)
2. CD4 cells (helper T lymphocytes) are decreased a) HIV infects the helper T lymphocyte (CD4) (1) This damages cell-mediated immunity
(2) This alters antibody-mediated immunity 3. As long as CD4 count remains stable, AIDS does not develop a) Once CD4 counts drop, both cell-mediated (of course) and humoral (why?) immunity are affected
b) CD4/CD8 ratio (helper to suppressor cells) is reversed from 2:1 to 1:2 4. Use standard precautions to avoid transmission VII. Transplantation Immunology A. Autografts, isografts, allografts, xenografts 1. If host views transplanted tissue as nonself, rejection occurs a) Cytotoxic T lymphocytes (with help from helper T-lymphocytes) attack and destroy transplanted cells
b) OR, helper T-lymphocytes may release lymphokines that cause phagocytes to invade the graft tissue (1) Phagocytes eat the tissue (secreting lysosomal enzymes that cause digestion and cell death to occur) 2. To prevent: Suppress immune system using anti-rejection drugs (e.g., cyclosporine A, FK506) B. Graft-versus-host-disease (GVHD) 1. BIG deal
2. If transplanted tissue (especially bone marrow) contains immunocompetent cells from the DONOR, they can mount a cell-mediated immune response AGAINST the host! VIII. Immune System and Cancer A. Host resistance to tumor cells depends on immunological surveillance 1. This is an ongoing function of cytotoxic T lymphocytes B. Tumor cells are antigenically different from host's normal cells 1. T lymphocytes destroy these cells

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