immunology

1. Hypersensitivity Reactions, Allergies, chronic inflammation immunology

2. Hypersensitivity – responding inappropriately to an antigen • Inflammatory response can have deleterious effects • Tissue injury • Disease • death

3. Hypersensitivity Reactions • May develop in course of humoral OR cell-mediated response • Immediate hypersensitivity • Anaphylactic • Antibody-antigen complexes • Manifests in minutes • Delayed-type hypersensitivity • May occur in days

5. Type I – IgE-Mediated Hypersensitivity • Induced by antigens referred to as allergens • Induces humoral response but induces high secretion of IgE • Fc portion of IgE binds with Fc receptors on mast cells and basophils • Degranulation occurs

7. Type 1 • Common components • Allergens • Atopy – hereditary predisposition to development of immediate hypersensitivity reactions to common antigens • Allows nonparasitic antigens to induce IgE response • IgE • Normally lowest of all antibody classes in serum • Half-life is 2-3 days but once bound to mast cells or basophils, can last for weeks • Mast cells and basophils • IgE binding receptors • High affinityFcεRI(mast cell,basophil,eosinophil,momncytes,platelets) • Low affinityFcεRII CD23(activated B-cell & various cell type) • Soluble & membrane forme • Atopic individuals have higher amount of soluble IgE receptor that has been shown to increase IgE production by B cells

9. Pharmacologic agents that mediate Type I • Primary mediators • Made before and stored in granules • Histamine, proteases, eosinophil chemotactic factor, heparin • Secondary mediators • Synthesized after • Platelet-activating factor, leukotrienes, prostaglandins, bradykinins, some cytokines and chemokines

11. Histamine • Formed by decarboxylation of amino acid Histidine • Major component of granules • Effects observed in minutes • Contraction of smooth muscle (intestinal and bronchial), increase permeability of venules, increased mucus secretion by goblet cells

12. Leukotrienes and prostaglandins • Effects longer to become apparent • Effects longer lasting than histamine • Bronchoconstriction, vascular permeability, mucus production • Cytokines and Chemokines • like ( IL-4, IL-5, IL-8, IL-13, GM-CSF, and TNF-α) alter the local microenvironment and lead to the recruitment of inflammatory cells such as neutrophils and eosinophils

13. Type I Hypersensitivities Are Characterized by Both Early and Late Responses • The early response occurs within minutes of allergen exposure and result from mast cell degrnulation of histamine, leukotrienes, and prostaglandins. • hours after the immediate phase ,mediators released during the course of the reaction induce localized inflammation, called the late-phase reaction • Third phase starts around 3 days post antigen challenge and peaks at day 4 multiple granulocyte subsets can cooperate in the induction of chronic allergic inflammation

14. Cytokines released from mast cells, particularly TNF- α and IL-1, increase the expression of cell adhesion molecules on venular endothelial cells, • thus facilitating the influx of neutrophils, eosinophils, and T H 2 cells that characterizes this phase of the response. Eosinophils play a principal role in the late-phase reaction. • Eosinophil chemotactic factor, released by mast cells during the initial reaction, attracts large numbers of eosinophils to the affected site. • Cytokines released at the site, including IL-3, IL-5, and GM-CSF, contribute to the growth and differentiation of these cells, which are then activated by binding of antibody-coated antigen.

15. This leads to degranulation and further release of inflammatory mediators that contribute to the extensive tissue damage typical of the late-phase reaction. • Neutrophils, another major participant in late-phase reactions, are attracted to the site of an ongoing type I reaction by neutrophil chemotactic factor released from degranulating mast cells. • Once activated, the neutrophils release their granule contents, including lytic enzymes, platelet-activating factor, and leukotrienes.

16. massive eosinophil infiltration but, in contrast to the second phase, requires the presence of basophils. • cytokines and proteases released from basophils act on tissue-resident cells such as fibroblasts. • These fibroblasts then secrete chemokines that are responsible for the recruitment of larger numbers of eosinophils and neutrophils to the skin lesion. • Subsequent degranulation of the eosinophils and neutrophils adds to the considerable tissue damage at the site of the initial allergen contact. These experiments illustrate how [multiple granulocyte subsets can cooperate in the induction of chronic allergic inflammation.]

18. Type 1 can be systemic or localized • Systemic anaphylaxis • Quick, can be fatal • Antigens like :venom from bee, wasp, hornet, and ant stings; drugs such as penicillin, insulin, and antitoxins; and foods such as seafood and nuts. • Respiration labored, blood pressure drops, bronchiole constriction, edema, shock • Epinephrine treats, relaxes smooth muscle and increases cardiac output (prevents vascular collapse)

19. Type 1 can be systemic or localized • Localized Hypersensitivity Reactions (Atopy)is limited to a specific target tissue or organ • Allergic Rhinitis • Most common, “hay fever” • Tearing, runny nose, sneezing, and coughing • Asthma • Triggered like hay fever but doesn’t happen in nasal cavity, happens in lower respiratory tract • Food allergies(cow’s milk, eggs, peanuts, tree nuts, soy, wheat, fish, and shellfish) • food allergens are water-soluble glycoproteins stable to heat, acid, digest slowly. • cross-linking of IgE on mast cells along gastrointestinal tract induce localized smooth muscle contraction and vasodilation and thus such symptoms as vomiting or diarrhea • Atopic dermatitis • Allergic eczema • develops erythematous (red) skin • Eruptions skin lesions in atopic dermatitis contain T H 2 cells and an increased number of eosinophils (unlike DTH,TH1)

21. Clinical Methods to detect Type 1 • Skin testing • small amounts of potential allergens are introduced at specific skin, • Thirty minutes later, the sites are reexamined, redness and swelling • Checking serum level of IgE • using ELISA or Western blot technologies

22. Control of Type 1 • Avoiding contact • Immunotherapy • Subcutaneous injections of allergens(Hyposensitization) • Causes shift to IgG production instead of IgE • Monoclonal anti-human IgE • Drug therapies

23. Antibody-Mediated (Type II) Hypersensitivity Reactions • Antibody bound to a cell-surface antigen can induce death of the antibody-bound cell by three distinct mechanisms: • First, certain immunoglobulin subclasses can activate the complement system, creating pores in the membrane of a foreign cell. • Secondly, antibodies can mediate cell destruction by antibody dependent cell-mediated cytotoxicity (ADCC), in which cytotoxic cells bearing Fc receptors bind to the Fc region of antibodies on target cells and promote killing of the cells. • Finally, antibody bound to a foreign cell also can serve as an opsonin, enabling phagocytic cells with Fc or C3b receptors to bind and phagocytose the antibody-coated cell.

24. Type II – Antibody-Mediated Cytotoxic Hypersensitivity • Transfusion Reactions • antigens that are associated with the blood types are identified as A, B, and H, • Individuals have antibodies to blood types not their own and adults possess IgM antibodies to those Ag. • Antibodies directed toward ABH antigens are termed isohemagglutinins • Antibody attaches to RBC and initiates complement system to lyse RBC • After lysis: • Hemoglobin detected in plasma, starts to filter through kidneys and found in urine (hemoglobinuria) • Hemoglobin converted to bilirubin – toxic at high levels • Fever, chills, blood clotting

25. Type II – Antibody-Mediated Cytotoxic Hypersensitivity • Hemolytic disease of newborn • Rh+ fetus, Rh- mother • IgG antibodies cross placenta(memory) • Some of these antibodies may be anti-Rh antibodies • Can have severe consequences • Antibodies against ABO blood groups produce less consequences, can be easily treated • Rhogam shot • Given to mother • Anti-Rh antibodies bind to fetal cells that might have entered mother’s system during birthing process, facilitates clearing before there is a B cell response

27. Type II – Antibody-Mediated Cytotoxic Hypersensitivity • Hemolytic Anemia Can Be Drug Induced • Certain antibiotics (e.g., penicillin, cephalosporins, and streptomycin), as well as other well-known drugs • adsorb nonspecifically to proteins on red blood cell membranes, forming a drug protein complex • induce formation of antibodies • inducing complement-mediated lysis • progressive anemia

28. Type III – Immune complex-mediated hypersensitivity • Complexing of antigen plus antibody facilitates phagocytosis and clearing of antigen • Large amounts of these complexes can lead to tissue damage & Type III hypersensitivity

29. Conditions associated with the initiation of a type III response include : • the presence of antigens capable of generating particularly extensive antigen-antibody lattices, • a high intrinsic affinity of antigens for particular tissues, • the presence of highly charged antigens (which can affect immune complex engulfment) and • a compromised phagocytic system.

30. Mechanisms • Immune complexes bind to mast cells, neutrophils, and macrophages via Fc receptors, triggering the release of vasoactive mediators and inflammatory cytokines, which interact with the capillary epithelium and increase the permeability of the blood vessel walls. • Immune complexes then move through the capillary walls and into the tissues where they are deposited and set up a localized inflammatory response. • Complement fixation results in the production of the anaphylatoxin chemokines C3a and C5a, which attract more neutrophils and macrophages. • These in turn are further activated by immune complexes binding to their Fc receptors to secrete proinflammatory chemokines and cytokines, prostaglandins, and proteases. • Proteases digest the basement membrane proteins collagen, elastin, and cartilage. • Tissue damage is further mediated by oxygen free radicals released by the activated neutrophils. • In addition, immune complexes interact with platelets and induce the formation of tiny clots.

32. Symptoms induced such as • fever, urticaria (rashes), joint pain, lymph node enlargement, and protein in the urine. • The resulting inflammatory lesion is referred to as vasculitis if it occurs in a blood vessel, glomerulonephritisif it occurs in the kidney, or arthritis if it occurs in the joints.

33. Type III can be localized • Injection of antigen intradermally or subcu into animal that has high level of antibody for that antigen • Arthus reaction • Bug bites

34. Type III can be generalized • Serum sickness • After receiving antiserum (serum from another animal that may contain antitoxins for treatment) • Use of monoclonal antibodies for use of cancer treatment • Patient developed antibody against mouse monoclonal antibody • Autoimmune diseases • Lupus, Rheumatoid arthritis • Drug reactions • Penicillin, sulfonamides • Infectious disease

35. Type IV – Delayed-type Hypersensitivity • Some subpopulations of TH cells encounter antigen, secrete cytokines and induce localized inflammatory response • Most cases are not detrimental(harmful)

37. Cytokine mediated inflammation • In immune-mediated inflammation, TH1 and TH17 cells secrete cytokines that recruit and activate leukocytes. • IL-17, produced by TH17 cells, promotes neutrophil recruitment; (IFN-γ), produced by TH1 cells, activates macrophages; and (TNF) and chemokines, produced by T lymphocytes and other cells, are involved in the recruitment and activation of many types of leukocytes. • Tissue injury results from the products of the recruited and activated neutrophils and macrophages, such as lysosomal enzymes, reactive oxygen species, nitric oxide, and proinflammatory cytokines. • The inflammation associated with T cell–mediated diseases is typically chronic, but bouts of acute inflammation may be superimposed on a background of chronic inflammation. • Delayed-type hypersensitivity (DTH) is an example of such inflammatory reactions.

38. Type IVSensitization phase and Effector phase of DTH

39. A DTH response begins with an initial sensitization by antigen,Followed by a period of at least 1 to 2 weeks during which antigen-specific T cells are activated and clonally expanded. • A variety of antigen- presenting cells (APCs) are involved in the induction of a DTH response, including Langerhans cells and macrophages. These cells pick up antigen that enters through the skin and transport it to regional lymph nodes, where T cells are activated. The vascular endothelial cells express class II MHC molecules and can also function as APCs in the development of the DTH response. • Generally, the T cells activated during the sensitization phase of a traditional DTH response are CD4 +, primarily of the T H 1 subtypes. However, recent studies indicate that T H 17, T H \2, and CD8+cells can also play a role.

40. A second exposure to the sensitizing antigen induces the effector phase, T cells are stimulated to secrete a variety of cytokines, including IFN- γ and Lymphotoxin- α (TNF- β ), which recruit and activate macrophages and other inflammatory cells. • A DTH response normally does not become apparent until an average of 24 hours after the second contact with the antigen and generally peaks 48 to 72 hours after this stimulus. The delayed onset of this response reflects what ??? the time required for the cytokines to induce localized influxes of macrophages and their activation. • By the time the DTH response is fully developed, only about 5% of the participating cells are antigen-specific T H 1 cells; the remainder are macrophages and other innate immune cells.

41. Prolonged DTH can lead to formation of granulomaTuberculosis test is done this way T cell reactions specific for microbes and other foreign antigens may also lead to inflammation and tissue injury. Intracellular bacteria such as Mycobacterium tuberculosis induce strong T cell and macrophage responses that result in granulomatous inflammation and fibrosis the inflammation and fibrosis may cause extensive tissue destruction and functional impairment, typically in the lungs.

42. Many organ-specific autoimmune diseases are caused by interaction of autoreactive T cells with self antigens, leading to cytokine release and inflammation. • rheumatoid arthritis (RA), multiple sclerosis, type 1 diabetes, psoriasis, and other autoimmune diseases • A variety of skin diseases that result from topical exposure to chemicals and environmental antigens, called contact sensitivity, are due to inflammatory reactions, presumably triggered by neoantigens formed by the binding of the chemicals to self proteins. Both CD4+ and CD8+ T cells may be the source of cytokines in contact sensitivity reactions. Examples of contact sensitivity include rashes induced by poison ivy and poison oak (in which T cells react against self proteins that are modified by chemicals made by the plants called urushiols), and rashes induced by contact with metals (nickel and beryllium) and a variety of chemicals, such as thiuram, which is used in the manufacture of latex gloves. Some of these reactions become chronic and clinically are called eczema. • T cell responses against intestinal bacteria are believed to underlie some forms of inflammatory bowel disease.

43. Type IV – contact dermatitis

44. Diseases Caused by Cytotoxic T Lymphocytes CTL • responses to viral infection can lead to tissue injury by killing infected cells, even if the virus itself has no cytopathic effects. • Example of viral infections in which the lesions are due to the host CTL response and not the virus itself include certain forms of viral hepatitis in humans . • CTLs may contribute to tissue injury in autoimmune disorders in which destruction of particular host cells is a prominent component, such as type 1 diabetes, in which insulin-producing β cells in pancreatic islets are destroyed.

45. At present the best way to avoid a DTH response it to avoid the causative antigen. • Once hypersensitivity has developed, topical or oral corticosteroids can be used to suppress the destructive immune response.

46. Chronic Inflammation • Causes: • Infections • Continuing physical damage to tissue • Obesity • autoimmunity

47. Obesity Is Associated with Chronic Inflammation • Chronic Inflammation and Insulin Resistance • A mother has an Rh- and the father an Rh+ blood type.The first baby born to the parents was Rh+ . However, the parents elect for mother not to receive Rhogam. Are all future babies of this couple at risk for type II hypersensitivity reactions? Why?/Why not?