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Aims • Compare and contrast the ABO and Rho(D) alloantigens. • Describe an Arthus reaction. • List the cells involved in a DTH response. • Describe ocular immune privilege • Describe the role Anterior Chamber Associated Immune Deviation (ACAID) is believed to play in an ocular immune response. • Readings: Abbas & Lichtman, Chapter 11 Blood Group Antigens Type A Type O Type B Red Cell Membrane • There are numerous blood group antigens – ABO system • Glycosphingolipids – Terminal sugars are galactose (B) & N-acetylgalactosamine (A) • present on the surface of RBCs • 80% of individuals also secrete these molecules in their saliva, sweat and other secretions • three alleles (A,B,O) Adapted from Roitt’s Essential Immunology 15-15 ABO system • Human serum usually contains isohemagglutinins which are antibodies against blood group antigens – IgM Genotype Phenotype Frequency Isohemagglutinins AA, AO A 42% anti- B BB, BO B 8% anti- A, AB AB 3% None OO O 47% anti-A, anti-B ABO Transfusion Reactions • Mediated by isohemagglutinins – Mediated by IgM (highly efficient C’ fixing antibody isotype) • Systemically administered antigen • Reaction Results in: – – – – Massive release of anaphylatoxins Damaged RBCs Free heme complex in circulation Fever, chills, angina, hypotension, shock, DIC, renal failure. – Fatal in 10-40% occurrences. Rh (D) System • Rh antigens are __________________________ • No naturally occurring antibodies to Rh antigens • Rh antigens are sparse and widely scattered in the RBC membrane • Not found on other body cells or fluids Rh (D) System • Consist of three genes (CDE) that are closely linked and inherited as a group Father cde CDe Mother CDE CDE/cde (Rh+ ) CDE/CDe (Rh+) CdE CdE/cde (Rh_) CdE/CDe (Rh+) • Gene “D” is the most clinically important and its presence confers Rh+ phenotype (~85% of individuals are Rh+). • ABO and RhD are not the only relevant antigens on RBCs! Hemolytic Disease of the Newborn (HDN) • erythroblastosis fetalis • anemia and jaundice – RBC destruction • leukopenia and thrombocytopenia – RBC replacement • hepatomegaly/splenomegaly – RBC clearance • ascites and edema • petechia Hemolytic Disease of the Newborn (HDN) • Erythrocytes from RhD+ fetus leak into the maternal circulation usually during birth. Adapted from Roitt’s Immunology 22-7 Hemolytic Disease of the Newborn (HDN) • Stimulating the production of antiRhD antibody of the IgG class postpartum. Adapted from Roitt’s Immunology 22-7 Hemolytic Disease of the Newborn (HDN) • During subsequent pregnancies, anti-RhD IgG antibodies are transferred across the placenta into the fetal circulation. • If the fetus is again RhD+ the antibodies cause erythrocyte destruction. Next Pregnancy Adapted from Roitt’s Immunology 22-7 Prevention of HDN • Prenatal typing of parents • Administer RhoGam (antiRhD, IgG) within 72 hours of birth if Rh-incompatible • MicRhoGam – smaller doses at 28+ weeks • RhoGam binds fetal Rh+ RBCs and removes them from the maternal circulation prior to initiating an immune response. • If HDN is present – exchange transfusion with O neg. blood RhoGam Adapted from Roitt’s Immunology 22-7 Type III Hypersensitivity • Involves soluble antigen • Immune complex-mediated Abbas & Lichtman’s Basic Immunology 11-7B Type III Hypersensitivity • Arthus reaction • Persistent low-grade infection. – Weak antibody response and chronic immune-complex formation (malaria). • Autoimmune disease. – Constant formation of autoantibody to a self-antigen and prolonged immune-complex formation (Systemic Lupus erythematosus). • Inhalation of antigenic material. – Immune-complex formation in the lung following repeated inhalation of mold, plant, or animal (Farmer’s lung) antigens. Type III Hypersensitivity Mechanism • Immune complexes can bind to ________________ receptors on basophils and platelets resulting in increased blood vessel permeability due to the release of vasoactive amines (histamine). Adapted from Roitt’s Immunology 23-5 Arthus Reaction • Example: Deltoid muscle soreness following tetanus booster. • Localized deposition of insoluble IC. • Sensitization – usually a result of secondary immunization – usually high levels of IgG • Reaction – localized either i.d. or i.m. • Time of onset – earliest reactions are 1-2 hours after injection. – depends on the amount of Ag and Ab available for complexing. • Duration – depend upon severity Arthus Reaction • Clinical manifestations – Local swelling, erythema, edema. – If severe, could yield hemorrhage and necrosis erythema necrosis edema Arthus Reaction • Histology – acute inflammation (neutrophil accumulation) – thrombus formation. dermis perivascular cuffing (neutrophils extravasating) capillary Type IV “Delayed Hypersensitivity” • Takes longer than 12 hours to develop. • Cell-mediated immune response. – Involving T cells. • Three types: – Contact – Tuberculin – Granulomatous Abbas & Lichtman’s Basic Immunology 11-11A Contact “Delayed Hypersensitivity” • Primarily a epidermal reaction. • Due to the hapten (nickel) in the watch buckle. • Haptens are small molecules which by themselves cannot be antigenic, but they bind to proteins to become antigenic. Contact Mechanism • Langerhans’ cells – principal APC – Express MHC class II, and receptors for Fc and complement. • 2 stages – Sensitization • produces memory T cells. • 10-14 days. – ____________________ • recruitment of T helper cells and monocytes. Adapted from Roitt’s Immunology 24-4 Contact Mechanism: Sensitization • Haptens enter the epidermis, combine with a carrier protein, and then are phagocytized by Langerhans’ cells. • The Langerhans’ cells migrate to a regional lymph node and present the Hapten-peptide in MHC class II to CD4+ T cells. • Resulting in a population of memory CD4+ T cells. Adapted from Roitt’s Immunology 24-4 Contact Mechanism: Elicitation • Langerhans’ cells present haptenpeptide in MHC class II to CD4+ T cells. • CD4+ T cells secrete cytokines (IFNg). • Keratinocytes release cytokines (IL-1 and IL6). • CD4+ T cells and macrophages are attracted to the site. Adapted from Roitt’s Immunology 24-5 Tuberculin-Type “Delayed Hypersensitivity” • Premise for your TB test. • Similar to contact hypersensitivity in that the Langerhans’ cell presents antigen to CD4+ T cells. • The resulting IFNg activates macrophages to make TNFa and IL-1. • Adhesion molecules are made and leukocyte extravasation occurs. • Inflammation and edema. 80-90% macrophages Adapted from Roitt’s Immunology 24-9 Granulomatous-Type “Delayed Hypersensitivity • Usually results from a microorganism persisting within a macrophage. • Can also form from a foreign body (talc) that cannot be phagocytized by macrophages. • Result in the formation of granulomas containing giant cells and epitheloid cells derived from macrophages. Immune Privilege • Sites in the body that are inaccessible to or that actively suppress immune responses. • Examples include: – The anterior chamber of the eye – The testes – The ___________________________ Why is the Anterior Chamber of the Eye Immune Privileged? • There is a need to protect the delicate visual axis from the sight-destroying potential of immunogenic inflammation. Proof of Ocular Immune Privilege • Genetically incompatible tumor cells transplanted into the anterior chamber can often grow into tumors, whereas the same cells do not form tumors when injected subcutaneously. • Cornea transplants do not require tissue matching or immunosuppressive therapy. Ocular Immune Privilege • Passive factors – Blood-ocular barriers (capillaries of the iris and retina) – Lack of lymphatic drainage – ______________________________________ MHC class I and II expression – APC without Class II MHC Ocular Immune Privilege • Active factors – the presence of inhibitory cytokines • TGFb • IL-10 • MIF – the expression of FasL resulting in apoptosis of Fas expressing T cells. Anterior Chamber Associated Immune Deviation (ACAID) Immune Privilege Due to ACAID • Selective suppression of effectors of immunogenic inflammation – delayed hypersensitivity (Type IV) T cells – complement-fixing antibodies (IgG and IgM) • Preservation of other effectors cells – cytotoxic T cells – non-complement fixing antibodies (IgA) Immune Privilege Due to ACAID • ACAID is initiated by an antigen-specific signal generated within the anterior chamber via intraocular dendritic cells and macrophages. • Under the influence of immunoregulatory factors (____________________________________) in aqueous humor, these cells: – capture antigen – process it uniquely – Do not secrete IL-12 or express CD40 – migrate across the trabecular meshwork into the blood and then to the spleen. Immune Privilege Due to ACAID • In the marginal zone of the spleen, the APC present antigen to T cells in an environment that results in them differentiating into T regulatory cells (Treg). • Tregs prevent type IV delayed hypersensitivity reactions (CMI) from occurring and prevent B cells from making antibody that activates complement cascade. Next Time • Immunizations • Diagnostic Tests Objectives 1. Compare and contrast the ABO and Rh(D) alloantigens. 1. Role in HDN 2. Describe Type III Hypersensitivity reaction. 1. Arthus reaction. 3. Describe Type IV Hypersensitivity reaction. 1. List the different types and cells involved in this response. 4. Describe ocular immune privilege 5. Describe the role Anterior Chamber Associated Immune Deviation (ACAID) is believed to play in an ocular immune response.