Immunological Tolerance and Autoimmunity PDF

Chapter 9: Immunological Tolerance and Autoimmunity o Immunological tolerance: unresponsiveness to self-antigens; lack of response to antigens that is induced by exposure of lymphocytes to these antigens - Immunogenic: when lymphocytes are activated to proliferate and to differentiate int...

Chapter 9: Immunological Tolerance and Autoimmunity o Immunological tolerance: unresponsiveness to self-antigens; lack of response to antigens that is induced by exposure of lymphocytes to these antigens - Immunogenic: when lymphocytes are activated to proliferate and to differentiate into effector and memory cells (productive immune response) – normally microbes - Tolerogenic: when lymphocytes are inactivated or killed, resulting in tolerance – normally self-antigens - Failure of self-tolerance is the underlying cause of autoimmune disease - Benefits of inducing tolerance: treat allergies and autoimmune diseases, prevent rejection of organ transplants, gene therapy, stem cell transplantation - Immunological Ignorance: antigen specific lymphocytes do not react, aka ignore presence of an antigen - Central tolerance: immature lymphocytes specific for self-antigens may encounter these antigens in generative lymphoid organs (bone marrow and thymus) and are deleted - Peripheral/secondary tolerance: mature lymphocytes encounter self-antigens in peripheral lymphoid organs/tissues - CD4+ T cells: mediator of virtually all immune responses to protein antigens; induced tolerance in which these cells may be enough to prevent both cell-mediated and humoral immune responses against self-proteins o Autoimmunity: when the immune system attacks the individual’s own cells and tissues o Central T Lymphocyte Tolerance: death of immature T cells and generation of CD4+ regulatory T cells - Negative selection: If an immature T lymphocyte interacts with a self-antigen, it triggers apoptosis and cannot become functionally competent (mature lymphocytes receive signals) - Some immature CD4+ T cells in the thymus don’t die but develops in to regulatory T cells and enter peripheral tissues - Immature lymphocytes may react strongly with an antigen if the antigen is present at high concentrations in the thymus - Self-proteins normally present in peripheral tissues and epithelial cells (thymus) - AIRE (autoimmune regulator): responsible for the thymic expression of peripheral tissue antigens  Mutations in AIRE caused by autoimmune polyendocrine syndrome where peripheral tissue antigens are not expressed in the thymus. Result = immature T cells specific for this antigen are not eliminated and are capable of harming self-antigens o Peripheral T Lymphocyte Tolerance: induced when mature T cells recognize self-antigens in peripheral tissues, leading to functional inactivation (anergy) or death, or when self-reactive lymphocytes are suppressed by regulatory cells (back up mechanism for autoimmunity) - Antigen recognition without costimulation results in T cell anergy or death, or makes T cells sensitive to suppression by regulatory T cells (signal 1 = antigen, signal 2 = expressed on APCs)  Major factor in determining whether T cells are activated or tolerized o Anergy (in T cells): long-lived functional unresponsiveness that is induced when T cells recognize self-antigens. Two mechanisms of anergy are: - 1) abnormal signaling by the TCR complex – TCR loses ability to transmit activating signals - 2) delivery of inhibitory signals from receptors other than the TCR complex – T cells may preferentially engage in the CD28 receptor, CTLA-4 or CD152, or PD-1 (death). Anergic T cells express higher levels of inhibitory receptors o Regulation of T Cell Responses by Inhibitory Receptors: CTLA-4 and PD-1 - CTLA-4: expressed on activated CD4+ T cells and regulatory T cells. Terminates activation of responding T cells and mediates suppressive function of regulatory T cells. Blocks and removes B7 from APCs to reduce costimulation and prevent T cell activation. CTLA-4 has high affinity for B7, meaning when B7 is low, more high-affinity CTLA-4. When B7 is high, more low-affinity CD28 - PD-1: expressed on both CD4+ and CD8+ after antigen stimulation. Has ITIM to deliver inhibitory signals that terminates responses of T cells to self-antigens and chronic infections (mostly virus) - Checkpoint blockade: using inhibitory receptors as a treatment for cancer patients with antibodies that block these receptors. If CTLA-4 or PD-1 are blocked, patients develop autoimmune responses against own tissues (kills tumor?) o Immune Suppression by Regulatory T cells: CD4+ that express CD25 and FoxP3 - Regulatory T cells are CD4+ that express CD25 (alpha chain of IL-2) - Develop in thymus or peripheral tissues after recognizing self-antigens and suppress activation of harmful lymphocytes specific for the self-antigens - FoxP3: transcription factor required for the development and function of regulatory T cells   Mutations: multiorgan autoimmune disease called IPEX - Survival and function of regulatory T cells are dependent on cytokine IL-2  Two opposite roles: promotes immune responses by stimulating T cell proliferation and inhibits immune response by maintaining functional regulatory T cells - TGF-beta: cytokine transforming growth factor that stimulates FoxP3 - Regulatory T cells may suppress immune responses by:  1) Some regulatory cells produce cytokines (IL-10 and TGF-beta) that inhibit activation of lymphocytes, dendritic cells, and macrophages  2) Regulatory cells express CTLA-4, which block/remove B7 on APCs, making APCs incapable of costimulation via CD28 and activating T cells  3) Regulatory T cells (by using IL-2) bind and consume T cell growth factor and reduce availability for responding T cells o Deletion: Apoptosis of Mature Lymphocytes: recognition of self-antigens may trigger apoptosis that results in elimination (deletion) of self-reactive lymphocytes. Two mechanisms: - 1) Antigen recognition induces production of pro-apoptotic proteins in T cells that induce cell death. This induces mitochondrial proteins to activate caspases, cytosolic enzymes that induce apoptosis - 2) Self-antigen recognition may lead to coexpression of death receptors and their ligands. Ligand-receptor interaction generates signals through death receptor that culminates in activation of caspases and apoptosis  Fas (CD95) and Fas ligand (FasL): death receptor-ligand pair involved in self-tolerance; mutation = develop autoimmune diseases with lymphocyte accumulation o Difference between self-antigens and foreign microbial antigens - Self-antigens:  present in thymus, where they induce deletion and generate regulatory T cells  displayed by resting APCs in absence of innate immunity and second signals (favor T cell anergy/death/suppression)  present throughout life and cause prolonged TCR engagement (development of regulatory T cells) - Microbial antigens:  not in thymus; captured from their site of entry and transported to the peripheral lymphoid organs  microbes elicit innate immunity, leading to expression of costimulators and cytokines that promote T cell proliferation and differentiation o B Lymphocyte Tolerance: prevent autoantibody production in self-polysaccharides, lipids, and nucleic acids (T-indie) o Central B Lymphocyte Tolerance: when immature B lymphocytes interact strongly with self-antigens in the bone marrow, the B cells either 1) change their receptor specificity (receptor editing) or 2) are killed (deletion) - Receptor editing: B cells after reacting with self-antigens will reexpress RAG genes, resume Ig light-chain gene recombination, and express new Ig light chain. This new light chain combines with unchanged Ig heavy chain to produce new antigen receptor that is no longer specific for self-antigen. This process reduces the chance of a potentially harmful self-reactive B cell - Deletion: happens when receptor editing fails. The immature B cells die after recognizing self-antigens (similar to negative selection of immature T cells) - Anergy (in immature B cells): B cells specific for antigens with low avidity become functionally unresponsive o Peripheral B Cell Tolerance: mature B lymphocytes that encounter self-antigens in peripheral lymphoid tissues become incapable of responding to that antigen. B cells that do not receive T cell help become anergic and die - During somatic hypermutation of Ig genes in germinal centers, some antigen receptors may be capable of recognizing self-antigens. B cells expressing these receptors die because no follicular T cell help or because they express high levels of Fas and are killed by FasL o Tolerance to Commensal Microbes and Fetal Antigens: products of commensal microbes that live in symbiosis with humans and paternally derived antigens in the fetus; coexistence needed to maintain peripheral tolerance to self-antigens o Tolerance to Commensal Microbes in the Intestines and Skin: microbes reside in intestinal and respiratory tracts and on skin (aid in digestion and absorption of foods, prevent overgrowth of harmful organisms). Mature cells recognize these organisms but do not react against them. This is a result of abundance of IL-10 producing regulatory T cells o Tolerance to Fetal Antigens: paternal antigens in placenta are foreign and must be tolerated by the mother - Peripheral FoxP3+ regulatory T cells: help with tolerance of paternal antigens - Other mechanisms: exclusion of inflammatory cells from the pregnant uterus, poor antigen recognition, and inability to generate harmful Th1 responses in healthy uterus o Autoimmunity: an immune response against self-antigens. Can be organ-specific or systemic. Tissue injury in autoimmune diseases caused by either antibodies against self-antigens or by T cells reacting with self-antigens o Pathogenesis of autoimmunity: developed by inheritance of susceptible genes and environment triggers (infections) o Genetic Factors: attributable to multiple gene loci, with most contribution by MHC genes. An autoimmune disease is more likely to develop in monozygotic (identical) twins - Polymorphisms: variations (basically mutations) in genes that contribute to autoimmune diseases. Same polymorphisms can be associated with different diseases. - Odds ratio or relative risk of HLA-disease association: autoimmune disease risk increases with individuals who inherit particular HLA alleles (though HLA is not the cause of the disease) - Non-HLA polymorphisms are associated with failure of self-tolerance or abnormal lymphocyte activation. This includes:  PTPN22: uncontrolled activation of B and T cells (arthritis, lupus, and T1DM)  NOD-2: causes reduced resistance to intestinal microbes (Crohn’s, IBD)  CD25: influences balance of effector and regulatory T cells  IL-23: promotes proinflammatory Th17  CTLA-4: inhibitory T cell receptor  Mendelian forms of autoimmunity: AIRE, FoxP3, Fas, and CTLA-4 o Role of Infections and other Environmental Influences: infections may activate self-reactive lymphocytes and trigger autoimmune diseases - Microbial nfection in tissue may induce innate immunity response  increased production of costimulators and cytokines by tissue APCs. These APCs may stimulate self-reactive T cells - Molecular mimicry: infectious microbes produce peptide antigens that are similar to and cross react with self- antigens. Immune responses to these peptide antigens may result in autoimmune disease (ex: rheumatic fever) - Innate response to infections can alter chemical structure of self-antigens, which are recognized as nonself and elicit adaptive immune responses - Infections may injure tissues and release antigens that are ignored by immune system  autoimmune reaction against tissues - Normal microbes in gut, skin, etc. may have an effect on health and maintenance of self-tolerance o Lupus (SLE): more common in women; triggered by sunlight in which antibodies are produced against self-nucleic acids and proteins Chapter 10: Immune Responses Against Tumor and Transplants o Cytotoxic T lymphocytes (CTLs): mechanism by which immune system kills both tumor cells and cells of tissue transplants o Is cancer a function of tolerance or ineffective immunity? Both. Ineffective immunity caused by the use of inhibitory molecules produced by tumor and other ideas of immune surveillance and tolerance because MHC doesn't recognize self o Immune surveillance: control and elimination of malignant cells by immune system. Evidence: - 1) Lymphocytic infiltrates around some tumors and enlargements of draining lymph nodes correlate with a better prognosis - 2) Transplants of syngeneic tumors are rejected by animals and are more rapidly rejected if animals had previously been exposed to that tumor. Immunity of tumor transplants can be transferred by lymphocytes from the tumor- bearing animal. - 3) Immunodeficient individuals have an increased incidence of some tumors. - 4) Therapeutic blockades of inhibitory receptors (CTLA-4 and PD-1) lead to tumor remission. o Immune Responses Against Tumors: malignant tumors express various types of molecules that may be recognized by the immune system as foreign antigens (seen as nonself) o Tumor antigens (molecules that may be recognized by the immune system as foreign antigens) - 1. Products of diverse mutated genes - Play no role in tumorigenesis and stimulate adaptive immune response - 2. Product of oncogene or mutated tumor suppressor genes – encode proteins that are seen as foreign - 3. Overexpressed or aberrantly expressed – structurally normal, but elicit abnormal responses - 4. Viral antigens/Oncogenic virus o Immune Mechanisms of Tumor Rejection: main mechanism is killing of tumor cells by CTLs specific for tumor antigens. These tumor antigens are displayed as class I MHC (cross-presentation) and are recognized by class I MHC-restricted CD8+ CTLs, whose function is to kill the cells producing these tumor antigens - CTL responses against tumors are induced by recognition of tumor antigens on host APCs in dendritic cells. APCs ingest the tumor cells and present the antigens to the CTLs  - At the same time, dendritic cells present tumor antigens and may express costimulators that activate T cells - Once CD8+ T cells have differentiated into CTLs, they can kill a tumor cell without costimulation or T cell help o Evasion of Immune Responses by Tumors: immune responses often fail to check for tumor growth because tumors evolve to evade immune recognition or resist immune effector mechanisms (ex. little inflammation and costimulation) - 1) Antigen loss variants: tumors that stop expressing antigens that are the targets of immune attack, which continue to grow and spread because they are not involved in maintaining the malignant properties of the tumor - 2) Some tumors stop expressing class I MHC molecules and cannot display antigens to CD8+ T cells (might be susceptible to NK cells) - 3) Tumors inhibit T cell activation, such as expressing PD-1 or having low B7 levels = high CTLA-4 - 4) Tumors may secrete immunosuppressive cytokines (TGF-beta) or induce regulatory T cells that suppress immune responses o Cancer Immunotherapy: main strategies are to provide antitumor effectors (antibodies and T cells), actively immunize patients against their tumors, and stimulate the patient’s own antitumor immune responses - Passive Immunotherapy: immune effectors are injected into cancer patients  Antibody therapy: monoclonal antibodies bind to tumor antigens and activate host effector mechanisms that destroy tumor cells (ex: antibody specific for CD20 treats B cell tumors). They also work by blocking growth factor signaling (ex: anti-Her2/Neu for breast cancer and anti-EGF-receptor antibody) or by inhibiting angiogenesis (colon cancer)  Adoptive cellular therapy: T lymphocytes (containing tumor-specific CTLs) are isolated from blood or tumor infiltrates of a patient, expanded by culture with growth factors, and injected back into the patient  Chimeric antigen receptors: recognizes a tumor antigen and coupled with intracellular signaling domains is genetically introduced into a patient’s T cells. The cells are expanded ex vivo and transferred back into the patient (works with leukemia) o Stimulation of a Host Antitumor Immune Responses: promoted by vaccination with tumor antigens or by blocking inhibitory mechanisms that suppress antitumor immunity - Vaccination: stimulates active immunity against tumors by vaccinating patients with their own tumor cells or with antigens from those cells. Or a tumor patient’s dendritic cells are expanded and exposed to tumor cells/antigen and used as a vaccine. The dendritic cells hopefully mimic the normal pathway of cross-presentation and generate CTLs against the tumor cells (best results: Hep B and human papillomavirus) - Checkpoint blockade: boost host immune responses against tumors by blocking normal inhibitory signals for lymphocytes and remove the “checkpoints” on immune response (ex. blocking CTLA-4 and PD-1) - Cytokine therapy: treating patients with cytokines that promote leukocyte activation First one was IL-2. o Immune Responses Against Transplants: rejection results from inflammatory reactions that damage transplanted tissues - (in mice) Grafts among members of one inbred strain are affected and grafts from one strain to another are rejected. Conclusion = rejection is controlled by genes, mainly MHC genes - Donor: provides the graft - Recipient/Host: individual whom the graft is placed - Syngeneic: animals identical to one another (and grafts) - Allogeneic/allograft: animals (and grafts) of one species that differ from other animals of the same species (transplants are exchanged between outbred allogenic individuals) - Xenogeneic/xenograft: animals (and grafts) of different species - Allografts and xenografts are always rejected by recipients with normal immune systems - Alloantigens and xenoantigens: antigens that serve as the targets of rejection - Alloreactive and xenoreactive: antibodies and T cells that react against alloantigens and xenoantigens o Transplantation Antigens: antigens of allografts that serve as principal targets of rejection are proteins encoded in MHC - HLA: human leukocyte antigen. Each person expresses six class I MHC alleles (one HLA-1, -B, and -C from each parent) and more than 8 class II MHC alleles (one HLA-DQ and -DP and one/two of -DR from each parent). The chance two siblings will have the same MHC alleles is ¼ - The response to MHC antigens on another individual’s cells is one of the strongest immune responses – many mature T cells will have a high affinity for self MHC displaying foreign peptides (immunologic cross-reaction) - Why recognition of allogenic MHC molecules results in strong T cell reactions  T cells may cross-react with any one allogenic MHC, as long as the MHC molecule resembles complexes of self MHC plus foreign peptides  Self MHC-restricted T cells specific for different peptide antigens may recognize any one allogeneic MHC molecule   A single allogeneic graft cell will express thousands of MHC molecules, which will be recognized as foreign by the recipient’s T cells - Minor histocompatibility antigens: non-MHC antigens that induce graft rejection (proteins differ in sequence between donor and recipient); not as strong as MHC reactions o Induction of Immune Responses Against Transplants: alloantigens from the graft are transported by dendritic cells (costimulator) to draining lymph nodes, where they are recognized by alloreactive T cells. The effector T cells are generated and circulate back to the transplant to mediate rejection - T cells may recognize allogeneic MHC molecules in the graft displayed by donor dendritic cells, or graft alloantigens may be processed and presented by the host’s dendritic cells - Direct Allorecognition: when T cells in the recipient recognize donor allogeneic MHC molecules on graft dendritic cells. This activates alloreactive T cells (CTLs) that recognizes and attacks the cells of the graft (for CTL-mediated acute rejection) - Indirect Allorecognition: when graft cells (alloantigens) are ingested by recipient dendritic cells, and donor alloantigens are processed and presented by the self MHC molecules on recipient APCs. Graft alloantigens are recognized indirectly and rejection of the graft is mediated by alloreactive CD4+ T cells. These T cells enter the graft with host APCs, recognize the graft antigens displayed by the APCs, and secrete cytokines that injure the graft by inflammatory reaction (for chronic rejection) - Blocking costimulation promotes graft survival - Mixed lymphocyte reaction (MLR): an in vitro model of T cell recognition of alloantigens showing how T cells from one individual are cultured with leukocytes of another individual. The responses of the T cells are measured, and the magnitude is proportional to the MHC differences between these individuals (can predict outcomes of graft exchange between the two) - Alloantibodies are mostly helper T cell-dependent high-affinity antibodies – to produce alloantibodies, recipient B cells recognize donor alloantigens and present the antigens to helper T cells, thus initiating the antibody production by B lymphocytes o Immune Mechanisms of Graft Rejection - Hyperacute rejection: occurs within minutes of transplantation and characterized by thrombosis of graft vessels and ischemic necrosis of the graft. Mediated by circulating antibodies that are specific for antigens on graft endothelial cells (binds to graft endothelium and stimulates clotting). May be natural IgM antibodies or antibodies specific for MHC molecules. Usually not a problem because donor and recipient are matched by blood type and recipients are tested for antibodies against cells of the donor - Acute rejection: occurs within days or weeks after transplantation and is the cause of early graft failure because of antibody-mediated injury to graft. Mediated by T cells and antibodies specific for alloantigens on the graft. May be CD8+ CTLs that destroy graft cells or CD4+ cells that secrete cytokines and induce inflammation. - Chronic Rejection: principal cause of graft failure. occurs over months or years (progressive loss of graft function). Causes fibrosis of the graft and graft arteriosclerosis (narrowing of vessels). Believed to be mediated by T cells that react against graft alloantigens and secrete cytokines, which stimulate proliferation of fibroblasts and vascular smooth muscle cells in the graft o Prevention and Treatment of Graft Rejection: immunosuppression to inhibit T cell activation and effector functions. Immunosuppression drugs help with donors that are not HLA-matched, but they are also nonspecific immunosuppression, leading to patients being susceptible to infections (particularly intracellular microbes). Replaces HLA-matching way of organ transplanting - FK506 (calcineurin inhibitor): immunosuppressive drug that blocks phosphatase calcineurin to inhibit NFAT, which is required for the transcription of cytokines in T cells - Rapamycin: inhibits mTOR required for T cell activation - Long term goal: induce immunological tolerance specifically for graft alloantigens so that it won’t shut off other immune responses - Xenotransplantation: possible solution for shortage of suitable donor organs, though it has a high rate of hyperacute rejection. This is because xenografts contain antibodies (natural because does not require prior exposure to xenoantigens) that react with cells from other species and lack proteins that inhibit complement activation o Transplantation of Blood Cells and Hematopoietic Stem Cells - Transfusion: transplantation of blood cells - Blood group antigens: barrier to transfusion; make ABO antigens that are expressed on RBCs, endothelial cells, and others. ABO antigens are carbs that contain a core glycan and may have an additional terminal sugar. A and B  have different terminal sugars, and O has none. Individuals with one antigen are tolerant of that but have antibodies against the other. O makes both anti-A and anti-B antibodies - Transfusion reaction: antibodies react against transfused blood cells expressing the target antigens. Avoided by matching donors and recipients. Blood group antigens do not elicit T cell reactions because they are sugars - Rh antigen: red cell membrane protein that can be the target of maternal antibodies that may attack a developing fetus when the fetus expresses paternal Rh and the mother lacks the protein - Hematopoietic stem cell transplantation: to correct hematopoietic defects, restore bone marrow cells damaged by irradiation and chemo for cancer, and treat leukemias. Bone marrow cells or hematopoietic stem cells from a donor are injected into a recipient. Bone marrow of recipient must be destroyed to create space. Depletion of recipient’s marrow causes deficiency of blood cells. Requires HLA matching to prevent rejection by NK cells - Graft-versus-host disease: mature T cells attack recipient’s tissue. Because HLA matching is always done, this disease is usually directed against minor histocompatibility antigens Chapter 11: Hypersensitivity o Hypersensitivity reactions: when an immune response to an antigen results in sensitivity to challenge with that antigen causing excessive immune response. Occurs in two ways: - Responses to foreign antigens (microbes and noninfectious environmental antigens) - Autoimmunity: responses directed against self-antigens (autologous) as a result of failure of self-tolerance (disorders caused by this = autoimmune disease) o Immediate hypersensitivity (Type 1): caused by the release of mediators from mast cells. Depends on the production of IgE antibody against environmental antigens and binding of IgE to mast cells. Develops as a response to Th2 activation - Mechanism of tissue injury/disease: mast cell-derived mediators; cytokine-mediated inflammation - Causes vascular leakage and mucosal secretions, followed by inflammation (late-phase reaction) - Disorders: allergy (aka atopy) – hay fever, food, asthma, anaphylaxis, etc. - Sequence of events:  1. Activation of Th2 and IL-4-secreting follicular helper T (Tf) cells  Secrete cytokine IL-4 and IL-13 that promote neutrophil and eosinophil-rich inflammation (IL-4) and mucus (IL-13)  2. Stimulation of IgE antibodies in response to antigen  3. Binding of IgE to Fc receptors (specific for  heavy chain) of mast cells and antigen  Sensitization: coating of mast cells with IgE to make that mast cell sensitive to activation by a subsequent encounter to that antigen  4. Cross-linking of bound IgE by antigen to trigger biochemical signals from signal-transducing chains of FcRI  5. Release of mast cell mediators o Antibody-mediated (Type 2): antibodies other than IgE (IgM or IgG) that are directed against cell or tissue antigens - Mechanisms: complement and Fc receptor mediated recruitment/activation of leukocytes; opsonization and phagocytosis of cells; abnormalities in cellular function o Immune complex-mediated (Type 3): antigens against soluble antigens (IgM or IgG) that form complexes with the antigens, and the complexes deposit in blood vessels and tissues  inflammation and tissue injury - Mechanisms: complement and Fc receptor mediated recruitment/activation of leukocytes, and tissue damage secondary to impaired blood flow o T-cell mediated (Type 4): result from the reactions of T lymphocytes (against self-antigens in tissues) - Mechanisms: macrophage activation, cytokine-mediated inflammation, direct target cell lysis, cytokine-mediated inflammation o Mast cells (of Type 1 hypersensitivity): present in all connective tissues and usually adjacent to blood vessels. Which mast cells are activated depends on route of entry of the allergen - Activation results from binding of the allergen to two or more IgE antibodies on the cell  crosslink - Activation leads to three types of responses:  1. Rapid release of granule contents (degranulation)  2. Synthesis and secretion of lipid mediators  3. Synthesis and secretion of cytokines - Mediators: responsible for acute vascular and smooth muscle reactions and inflammation  Histamine: causes dilation of small blood vessels, increases vascular permeability, and stimulates transient contraction of smooth muscles   Proteases: damage to local tissues  Arachidonic acid metabolites: vascular dilation, leukotrienes (stimulates smooth muscle contraction)  Cytokines: induces inflammation (late-phase reaction) and stimulates recruitment of leukocytes (eosinophils [component of allergies], neutrophils, and Th2 cells) o FcRI: high-affinity receptor for IgE that binds to Fc portion of the  heavy chain and also signals proteins o TNF: mast cell-derived necrosis factor; reduces inflammation (beneficial to arthritis and IBD) o Cytokine IL-5: produced by Th2 cells, innate lymphoid cells, and mast cells, and activates tissue injury o Hay fever: allergic rhinitis and sinusitis that are reactions to inhaled allergens o Food allergies: ingested allergens that trigger mast cell degranulation  vomiting and diarrhea o Bronchial asthma: form of respiratory allergy in which inhaled allergens stimulate bronchial mast cells to release mediators  bronchial constriction and airway obstruction o Anaphylaxis: most severe form of immediate hypersensitivity; systemic reaction characterized by edema in many tissues and caused by widespread mast cell degranulation in response to the systemic distribution of the antigen; bee stings, penicillin, nuts, shellfish, o Immediate hypersensitivity therapy: inhibiting mast cell degranulation, antagonizing the effects of mast cell mediators, and reducing inflammation (antihistamines for various allergies, agents that relax bronchial muscles for asthma, and epinephrine for anaphylaxis) - Corticosteroids: used to inhibit inflammation in diseases where inflammation is an important pathologic component (example: bronchial asthma) o Desensitization: aka allergen specific immunotherapy; repeated administration of small doses of allergens; changes T cell response away from Th2 dominance or antibody response away from IgE by inducing tolerance in allergen-specific T cells or by stimulating regulatory T cells o How diseases are caused by antibodies and antigen-antibody complexes: antibodies other than IgE may bind to their target antigen in cells and tissues or by forming immune complexes that deposit in blood vessels (including vessels through which plasma is filtered at high pressure - tend to be systemic and manifest as widespread vasculitis, arthritis, and nephritis - often autoantibodies against self-antigens (failure of self-tolerance) - Streptococcal infections:  antibodies of these cross-react with an antigen in heart tissues which trigger an inflammatory disease called rheumatic fever  antistreptococcal antibodies deposit in kidney causing inflammatory process leading to renal failure o Mechanisms of Tissue Injury and Disease (Type 2 Hypersensitivity): - Inflammation: IgG and IgM antibodies against tissue antigens and immune complexes deposited in vessels induce inflammation by attracting/activating leukocytes - Opsonization and Phagocytosis: if antibodies bind to cells, cells are opsonized and may be ingested/destroyed by host phagocytes - Abnormal cellular responses: may cause disease without directly inducing tissue injury, may inhibit receptor function  example: antibodies against acetylcholine receptor inhibit neuromuscular transmission causing paralysis  example: Graves disease – antibodies against receptor for thyroid-stimulating hormone stimulate thyroid cells o Chronic hypersensitivity disorders: - Serum sickness: induced by systemic administration of a protein antigen that elicits an antibody response and leads to the formation of circulating immune complexes - Arthus reaction: induced by subcutaneous administration of a protein antigen to a previously immunized animal; results in the formation of immune complexes at the site of antigen injection and vasculitis - Therapy:  limit inflammation  intravenous IgG (IVIG) from healthy donors  treatment of patients with an antibody specific for CD20 results in depletion of B cells  blocking CD40 to inhibit helper T cell-dependence B cell activation and antibodies to block cytokines that promote the survival of B cells and plasma cells o Causes of T cell-mediated hypersensitivity (Type 4): autoimmunity and exaggerated/persistent responses to environmental antigens - Autoimmunity: directed against cellular antigens with restricted tissue distribution (limited to a few organs)  - Exaggerated/persistent responses to environmental antigens:  sensitivity to chemicals (poison ivy)  tuberculosis  excessive polyclonal T cell activation leads to large amounts of inflammatory cytokines (superantigens) that bind to invariant parts of T cell receptors and T cell clones and activates them o Mechanisms of Tissue Injury: In T cell-mediated diseases, inflammation is induced by cytokines that are produced by CD4+ T cells or by killing of host cells by CD8+ CTLs; caused mainly by macrophages and neutrophils - Activation of Th1 (source of interferon-/IFN-, the macrophage activating cytokine) and Th17 (recruitment of leukocytes, specifically neutrophils) o Delayed-type hypersensitivity (Type 4) (DTH): reaction mediated by T cell cytokines; occurs 24-48 hours after exposure to a protein antigen is challenged by the antigen - Occurs because it takes several hours for circulating T lymphocytes to home to the site of antigen challenge, respond to the antigen, and secrete cytokines - Manifested by infiltrates of T cells and blood monocytes in the tissues, edema and fibrin deposits, and tissue damage o Many organ specific autoimmune diseases in humans are believed to be caused by T cells o Epitope spreading: indicates that the initial immune response against one or a few self-antigen epitopes may expand to include responses against many more self-antigens o Chronic inflammatory diseases: aka immune-mediated inflammatory diseases Chapter 12: Congenital and Acquired Immunodeficiencies (disease caused by defective immunity) o Immunodeficiency diseases: disorders caused by defective immunity - Congenital/primary immunodeficiencies: genetic abnormalities in one or more components of the immune system - Acquired/secondary immunodeficiencies: defects in the immune system as a result of infections, nutritional abnormalities, or medical treatments that cause loss or in adequate function of various components of the immune system o Congenital (Primary) Immunodeficiencies: caused by genetic defects that lead to blocks in the maturation of B lymphocytes and/or T lymphocytes - Susceptible to infections that may manifest after birth or mild infections in adult life - Severe combined immunodeficiency (SCID): defects in both B and T lymphocytes; caused by:  X-SCID: about half of SCID cases are X-linked and more than 99% are caused by mutations in the c chain that signal receptors for cytokines (IL-2, 4, 7, 9, 15, and 21). When c isn’t functional, immature T lymphocytes cannot mature and proliferate in response to IL-7 (humans). This leads to deficient cell- mediated immunity, defective humoral immunity, and deficient NK cells (IL-15)  Adenosine deaminase (ADA) and purine nucleotide phosphorylate (PNP): deficiency of ADA/PNP leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA. These metabolites block T lymphocytes (some B) maturation  JAK3 encoding mutation: autosomal recessive form of SCID involved in c chain signaling  RAG1 or RAG2 mutations: autosomal recessive form of SCID involved in VDJ recombination and required for Ig and T cell receptor maturation/gene recombination o Defects in Maturation of B or T Lymphocytes - X-linked agammaglobulinemia: (most common B cell maturation block) pre-B cells in the bone marrow fail to expand, resulted in the decrease of B lymphocytes and serum Ig.  Caused by mutations in gene encoding Bruton Tyrosine Kinase (BTK), located on the X chromosome, making women carriers and men affected. (BTK functions to deliver signals to promote survival, proliferation, and maturation of B cells) - DiGeorge syndrome: (most common T cell maturation block) results from incomplete development of the thymus, causing a failure to develop mature T cells (improves w/ age) o Defect in B Cell Responses - X-linked Hyper-IgM Syndrome: defective B cell heavy-chain isotype (class) switching. Caused by mutations on X chromosome gene encoding CD40L (helper T cell protein that binds to CD40 on B cells, dendritic cells, and macrophages). Failure to express CD40L leads to defective T cell-dependent B cell responses and T cell-dependent macrophage activation   Susceptible to Pneumocystis jiroveci, a fungus that survives within phagocytes in the absence of helper T cells - Common variable immunodeficiency (CVID): (primary immunodeficiency) poor antibody response to infections and reduced IgG, IgA, and IgM. Defect in genes involved with B cell maturation/activation o Defective Activation of T Lymphocytes - Bare Lymphocyte syndrome: failure to express class II MHC molecules, causing a decrease in CD4+ T cells (can’t recognize peptide antigens to be able to mature) - Th1 and Th17 deficiency: Th1 = nontuberculous mycobacterial infection; Th17 = fungal and bacterial infection o Defects in Innate Immunity - Chronic granulomatous disease: mutations in genes encoding phagocyte oxidase, which catalyzes the production of microbicidal reactive oxygen species in lysosomes. Result = neutrophils and macrophages unable to kill microbes they phagocytose and tries to compensate by sending more macrophages and activating more T cells, which stimulate more phagocytes - Leukocyte adhesion deficiency: mutations in genes encoding integrins and molecules that activate integrins. Result = blood leukocytes do not adhere to vascular endothelium and not recruited to site of infection - C3 deficiency: results in severe infections; fatal - C2 and C4 deficiency: results in increased bacterial/viral infection or lupus - Chediak-Higashi syndrome: disease in which the lysosomal granules of leukocytes to not function normally (affects phagocytes and NK cells) - Mutations affecting MyD88: associated with bacterial pneumonia - Mutations affecting TLR3: associated with herpesvirus encephalitis o Lymphocyte Abnormalities Associated with other Diseases - Wiskott-Aldrich syndrome: characterized by eczema, reduced blood platelets, and immunodeficiency. X linked. Platelets and leukocytes do not develop normally - Ataxia-telangiectasia: gait abnormalities, vascular malformations, and immunodeficiency. Result = abnormal DNA repair and defective lymphocyte maturation o Therapy of Congenital Immunodeficiencies - Hematopoietic stem cell transplantation (most widely used) - Intravenous injections of pooled Ig (IVIG): provides passive immunity and helps with X-linked agammaglobulinemia - Gene therapy: normal c was introduced into patient’s bone marrow stem cells o Acquired (Secondary) Immunodeficiencies: not genetic and are acquired during life - HIV (most serious), cancers involving bone marrow (chemo damages proliferating cells resulting in immunodeficiency), protein-calorie malnutrition o Acquired Immunodeficiency Syndrome (AIDS) - Human immunodeficiency virus (HIV): retrovirus that infects cells of the immune system, mainly CD4+ T lymphocytes, and causes progressive destruction of these cells  Consists of two RNA strands (containing proteins that regulate transcription of viral genes) within a protein core, surrounded by a lipid envelope derived from infected host cells but containing viral proteins  Life cycle  1) Infection of cells  2) Production of a DNA copy of a viral RNA and its integration into the host genome (integrated viral DNA = provirus)  3) Expression of viral genes  4) Production of viral particles  Infects through glycoprotein envelope called gp120 which binds to CD4 and chemokine receptors on human cells  Major cell types infected: CD4+ T lymphocytes, macrophages, and dendritic cells which get activated along with the provirus, leading to the production of viral RNAs/proteins - Pathogenesis of AIDS: develops over years as HIV becomes activated and destroys cells. As virus enters body, it infects CD4+ T cells, dendritic cells, and macrophages at entry site, at lymphoid organs, and in circulation. There is largest destruction of T cells in mucosal tissues.  CCR5: mutation that does not permit HIV entry into CD4+ T cells; remain disease free for years after HIV infection   Depletion of CD4+ T cells after HIV infection is caused by cytopathic effect of the virus, resulting from production of viral particles in infected cells and death of uninfected cells. Viral gene expression/replication kills T cells o Clinical Features of HIV Infection and AIDS - Acute HIV syndrome: patients may experience acute illness after early HIV infection before disease enters latency - Latency: progressive loss of CD4+ T cells in lymphoid tissues and destruction of these tissues. Eventually, CD4+ T cell count declines and when it falls below 200 cells per mm3, AIDS occurs - Clinical AIDS: full-blown AIDS causes patients to be infected by opportunistic intracellular microbes because lack of T cell-mediated immunity. Patients with AIDS show defective cytotoxic T lymphocyte (CTL) responses to viruses and are at risk for infections by extracellular bacteria. - Susceptible to cancers B cell lymphomas (caused by Epstein Barr virus) and Kaposi’s sarcoma (caused by herpesvirus) - Advanced AIDS patients often have wasting syndrome (significant loss of body mass) and dementia caused by infection of macrophages in brain - The immune response to HIV is ineffective in controlling spread of the virus and its effects – virus mutates gp120 region that is target of antibodies; CTLs can’t kill them because virus inhibits class I MHC molecules; antibody- coated viral particles bind to Fc receptors on macrophages and follicular dendritic cells in lymphoid organs and increase virus entry into cells; dead cells cleared by macrophages, which migrate and spread infection - Elite controllers or long-term nonprogressors: patients who can control HIV infection without therapy (have HLA alleles such as HLA-B57 and HLA-B27) o Therapy and Vaccination Strategies - HAART (highly active antiretroviral therapy and ART (antiretroviral therapy): current treatment of AIDS that controls replication of HIV and its complications by blocking viral reverse transcriptase activity. Helps strop opportunistic infections and cancerous tumors