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Immunology Immunologic Disorders Chapter 18 Nester 4th. Ed. Immunological Disorders The immune system is incredibly efficient. It protects us from microorganisms, larger parasites and viruses. Without immunity we would all die. Immunological Disorders Sometimes immunity works to eliminate the Ag but inappropriately. Hypersensitivity (tissue damage) Autoimmune disease Sometimes it does not work, or some piece is missing. Immunodeficiency diseases Hypersensitivity An exaggerated immune response An inappropriate immune response Occurs in two stages, a sensitization stage and then the hypersensitivity reaction 4 categories (Table 18.1) Based on the parts of the immune system involved Based on the speed of the response Type I Hypersensitivity Mechanism Sensitization first exposure to antigen in which IgE is produced Triggering second or any subsequent exposure to Ag after sensitization Figure 18-1, page 445 Type I Hypersensitivity Figure 18.1 IgE bound on the surface of mast cells Chemical mediators histamine, serotonin, leukotrienes, bradykinins all lead to: • • • • inflammation smooth muscle contraction leading to airway constriction smooth muscle contraction of the GI tract smooth muscle contraction of vessels Type I Hypersensitivity Localized Type I Hypersensitivity reactions Also known as atopic reactions or as allergies Allergic rhinitis hay fever itching, teary eyes, sneezing, runny nose histamine activity is blocked by anti-histamine Type I Hypersensitivity Localized Type I Urticaria hives wheals, itchy red swellings one consequence of food allergies histamine activity is blocked by anti-histamine Figure 18- 2 Type I Hypersensitivity Localized Type I Food allergies shell fish, wheat, milk protein, etc. diarrhea painful cramping hives anti-histamine helps as stated previously Type I Hypersensitivity Localized Type I Asthma mostly airborne allergens Leukotrienes, prostaglandins and protein cytokines are the main mediators anti-histamine will not work Type I Hypersensitivity Why do we have IgE? Mucous membranes have many B-cells committed to making IgA and IgE people with allergies have more IgE producing cells than other people both of these Ab are needed for protection against certain bacteria and definitely parasites Type I Hypersensitivity The tendency to have allergies is inherited. About 20-30 % of the U.S. population has Type 1 allergies. There is a direct correlation in increasingly large allergic populations and pollution in the western world. Type I Hypersensitivity Immunotherapy Desensitization or hyposensitization Inject very small doses of allergen Do this over a period of months Gradually increase the dose with time Increases IgG response Increases Ts cells Decreases IgE production Figure 18.2 Figure 18-3, page 445 Type I Hypersensitivity Immunotherapy Antibodies to IgE (anti-IgE) Monoclonal antibody produced in mouse Hybrid recombinant molecule rhuMab (recombinant human Monoclonal antibody) Type I Hypersensitivity Generalized Type I hypersensitivity is anaphylaxis (shock)- rare, serious Systemic release of histamine and other mediators Extensive blood vessel dilation Decreased organ perfusion Blood pressure drops dramatically leading to shock Fatal in minutes Bee venom, penicillin (hapten) injection, peanuts Angioedema in anaphylaxis Edema of Anaphylaxis Type II Hypersensitivity Table 18.1 Response is to a cellular antigen Foreign antigen Haptens (some drugs bind to RBC’s) Mechanisms Cytotoxic by opsonization or ADCC Cytolytic by complement fixation Stimulation or inhibition of cell function Figure 16.16 Type II Hypersensitivity Transfusion reaction Normal RBC’s have many antigens 600 known Ag’s 23 major blood groups ABO blood group is of most concern Type II Hypersensitivity Transfusion reaction ABO system (Table 18.2) genes on chromosome 9 A gene product makes A antigen B gene product makes B antigen O gene makes neither AB gene makes A and B antigen Naturally occurring IgM antibodies If an ABO mismatch occurs, IgG is made to the Ag Blood Group Antigens Antibodies Can give blood to Can receive blood from A A B A and AB A and 0 B B A B and AB B and 0 AB A and B None AB AB, A, B, 0 0 None A and B AB, A, B, 0 0 Type II Hypersensitivity Hemolytic disease of the newborn Rhesus (Rh) blood group Rh+ = D antigen on RBC’s Rh- = D antigen is missing from RBC’s Figure 18.4 Type II Hypersensitivity Hemolytic disease of the newborn Disease not usually seen until shortly after birth mother’s enzymes that removed toxic products of RBC destruction are gone 36 hours jaundice severe anemia brain damage death Type II Hypersensitivity Hemolytic disease of the newborn Treatments exchange transfusions light treatment • detoxifies the RBC breakdown products • 420-480 nm (in the ultra violet range) RhoGam - anti-Rh antibodies • given to mom within a few hours of abortion or delivery • 24-48 hours is OK but not preferable Type II Hypersensitivity Cytotoxic effect by alteration in cell function Stimulation of cell function Grave’s disease of the thyroid gland • Autoantibody binds to a receptor on the outside of the cell and increases activity causing hyperthyroidism Inhibition of cell function Myasthenia gravis • Autoantibody against the acetylcholine receptor on the motor end plate causes muscle weakness Grave’s disease Myasthenia Gravis Type III Hypersensitivity Immune complex formation Mechanism- Figure 18-5 Blood clotting Attracts neutrophils Type III Hypersensitivity Immune complex formation Mechanism- Figure 18-5 Localized reaction- Arthus reaction Antigen is present in excess over antibody Produce large complexes that don’t travel far in circulation Example is Hypersensitivity pneumonitis such as Farmer’s Lung. Type III Hypersensitivity Generalized reaction is serum sickness Small soluble complexes since antigen is in excess over antibody Most often occurs in response to exposure to an injected foreign protein or to the continual exposure to an endogenous antigen such as in autoimmune diseases Type III Hypersensitivity Serum sickness mechanism Deposited in small vessels Response is seen a week to 10 days following injection of a foreign antigen Glomerulonephritis Arthritis Skin rash Disseminated intravascular coagulation Fever Lymphadenopathy Type IV Hypersensitivity Delayed hypersensitivity Slow developing response to antigen Reaction peaks at 2 to 3 days Cell mediated response T cells are responsible Occurs anywhere in the body Tuberculin skin test (Figure 18.8) Protein Ag from Mycobacterium tuberculosis Induration occurs if the person has Ab to the Ag Induration Sensitized T cells with specific antigen Followed by release of cytokines and influx of macrophages Figure 18-7, page 450 Type IV Hypersensitivity Contact dermatitis Poison ivy, poison oak (Figure 18.7) oils of plants induce the allergy Nickel, chromium salts Haptens (Figure 18.8) Detected by a patch test Type IV Hypersensitivity In infectious diseases Leprosy Tuberculosis Leishmaniasis Herpes simplex Hepatitis B Fungus diseases Type IV Hypersensitivity Transplant rejection MHC molecules antigens are involved Tissue typing looks for a match of Ag’s between the donor and the recipient. Immunosuppression is needed in most transplant situations cyclosporin • suppresses T-cells but does not kill them • has no effect on B-cells • leaves most parts of the immune system intact Autoimmune disease Occurs when recognition of self breaks down Multiple possible reasons certain bacteria and viruses have Ag’s similar to some of ours tissue damage that results in the release of self Ag’s Examples - Table 18.6 Autoimmune disease Myasthenia gravis Ab forms to the acetylcholine receptor Ab blocks the receptors at the neuromuscular junction immune complexes have been found at these junctions results in muscle weakness babies with maternal Ab also suffer muscle weakness temporarily Autoimmune disease Sympathetic ophthalmia penetrating wound in one eye produces blindness in the healthy eye Type IV hypersensitivity Autoimmune disease Feeding or oral tolerance - ingestion of Ag induces tolerance Local intestinal immune response with release of cytokines Down-regulation of antigen receptors Deletion of immune cells rheumatoid arthritis - collagen multiple sclerosis - myelin basic protein Immunodeficiency Body can’t make or sustain an adequate immune response. Primary - congenital result from genetic or developmental abnormalities Secondary - acquired result of malignancies, advanced age, certain infections, immunosuppressive drugs, malnutrition. Primary - congenital Severe combined immunodeficiency SCID 1 in 500,000 live births no B or T cells die at an early age without a bone marrow transplant Infantile X-linked agammaglobulinemia (Burton’s agammaglobulinemia) boys cannot make immunoglobulins fine until maternal antibody is gone Staphylococcal and Streptococcal infections Primary - congenital DiGeorge’s syndrome no thymus therefore no T-cells susceptible to eukaryotic pathogens, viruses, fungi, intracellular bacteria, fungi Selective IgA deficiency most common primary immunodeficiency repeated bacterial infections 1 in 333 to 700 people Primary - congenital Complement deficiencies no C3 - infections with bacteria with capsules and pyogenic bacteria no C5,6,7,8 - more infections with Neisseria Chediak-Higashi disease the lysosomes of phagocytes lack some enzymes phagocytized bacteria are not killed Secondary - acquired Malnutrition Lymphoid malignancies Leukemia Hodgkin’s disease Infections AIDS caused by HIV Secondary - acquired Measles virus kills many lymphoid cells Syphilis, leprosy, and malaria affect T-cells and macrophages In multiple myeloma, one B-cell clone multiplies out of control makes one kind of Ab in such great quantities that other Ab needed to fight infection are not made