Immune Disorders Flashcards

Question

ANTIGEN PRESENTATION

Answer 1

SPECIFIC FUNCTION OF THE ACQUIRED IMMUNE SYSTEM Antigen-presenting cells (APCs) reside in tissues where one of their major roles is surveillance against microbial invasion. Microbes that gain entry through epithelial surfaces are captured by dendritic cells. Dendritic cells ingest the microbe or proteins from the microbe, then proteolytically digest them such that peptide antigens are produced. These “extracellularly-derived” peptides are then ‘presented’ on the surface of the dendritic cell bound to MHC class II molecules. Dendritic cells will migrate through the lymphatic system to downstream lymph nodes. Once there, the presented antigens are recognized by CD4+ helper T-cells. Since MHC class I molecules are present on all cells, dendritic cells also express MHC class I and can present intracellular antigens (i.e. those derived from intracellular pathogens like viruses) to CD8+ cytotoxic T-cells.

Answer 2

SPECIFIC FUNCTION OF THE ACQUIRED IMMUNE SYSTEM 1. CD4+ helper T-cell response - The main function of CD4+ T-cells is to ‘help’ activate other cell types involved in immunity. - This helper function is mediated through production of cytokines and through the expression of CD40 ligand (CD40L). - Once activated via recognition of specific antigen presented by APCs, CD4+ T-cells secrete the cytokine interleukin-2 (IL-2), and also express a high-affinity receptor for IL-2. IL-2 induces proliferation of T-cells, allowing for expansion of an antigen-specific T-cell population. - Some of these activated T-cells differentiate into specific types of effector T-cells that perform specific functions; these include TH1 cells that secrete IFN-, TH2 cells which secrete IL-4, IL-5, and IL-13, and TH17 cells which secrete IL-17. - IFN-gamma activates phagocytosis and the production of antimicrobial substances in macrophages, as well as antibody production in B-cells. - TH2 cells are mainly involved in activation of mast cells and eosinophils, rather than macrophages. - TH17 cells are involved in activation of neutrophils. - CD40L is expressed on the surface of CD4+ T-cells, and binds to CD40 on B-cells and macrophages to help activate them in conjunction with the secreted cytokines. 2. CD8+ cytotoxic T-cell response - once activated, the CD8+ T-cells differentiate into cytotoxic lymphocytes. These cells function to destroy cells infected by microbes, often viruses or intracellular bacteria, in order to eliminate the infection. - Recognition of infected cells occurs via MHC class I molecules: the infected cell can present peptide antigen derived from the infectious organism bound to MHC I. - CD8+ cells specific for that antigen will bind antigen and MHC class I, then destroy the cell. - CD8+ cytotoxic cells produce the proteins perforin and granzyme-B which are stored in cytoplasmic granules. These proteins are released into target cells (perforin allows entry of granzyme-B across plasma membrane) whereby granzyme-B triggers apoptosis via proteolytic cleavage and activation of caspases (family of proteases which activate apoptotic death).

Answer 3

SPECIFIC FUNCTION OF THE ACQUIRED IMMUNE SYSTEM Once activated, B-cells differentiate into plasma cells or memory B-cells. Activation can occur in a T-cell-independent or –dependent manner. - T-cell-independent activation occurs with polysaccharide or lipid antigens, which may have multiple identical epitopes that can bind to several B-cell antigen receptors. - T-cell-dependent activation occurs with protein antigens which cannot bind to many antigen receptors, therefore full activation requires T-cell mediated cytokine stimulation coupled with CD40 ligand expression (co-activation). Plasma cells are antibody-secreting cells. - When a specific B-cell becomes activated, it then undergoes proliferation/clonal expansion. Some of these clonal cells differentiate into plasma cells which secrete antibodies with identical antigen-specificity to the B-cell receptor that first recognized the antigen. - Secreted antibodies have several functions including binding to an antigen on microbes in order to neutralize them, activation of the complement system, and opsonization (coating) pathogens to target them for phagocytosis. There are 5 classes of antibodies: - IgG – opsonize microbes, activates complement, crosses the placenta (passive immunity) - IgM – activates complement - IgA – secreted in mucosal tissues (protection of mucosal epithelia) - IgE - coats certain parasites, activates mast cells and eosinophils - IgD – specific functions uncertain Some cells of the immune system such as neutrophils, macrophages and natural killer cells have cell surface receptors to the Fc portion (non-variable) of antibodies, allowing them to recognize and destroy (in a nonspecific manner) opsonized cells/microbes. This is known as antibody-dependent cell-mediated cytotoxicity (ADCC). Memory B-cells and T-cells are long-lived effector lymphocytes whose purpose is to allow fast activation upon exposure to the specific antigen they recognize.

Answer 4

Disorders of the immune system may be broadly divided into: i. Hyperfunction -Hyperfunction, usually termed HYPERSENSITIVITY, results in damage of normal tissue ii. Hypofunction- In general, hypofunction or immunodeficiency results in two main forms of disease, as you would expect if you recall the two basic functions of the immune system: 1. Defense - Disorders of defense, the most common manifestation of immune hypofunction, results in increased susceptibility to infections. The type of infection seen depends on whether cell-mediated, humoral or both forms of immunity are affected. 2. Surveillance- Disorders of surveillance lead to increased frequency of malignant disease. Patients with immunodeficiency syndromes and those on immunosuppressive medications have a much higher incidence of cancer.

Answer 5

Hypersensitivity reactions are those reactions causing tissue injury. These often represent an “excessive” immune response to an antigen. Hypersensitivity reactions may result from immune response to self-antigens (autoimmunity), reactions to microbes, or reaction to environmental antigens. The disease states that result from hypersensitivity reactions are often chronic due to persistence of the antigens and amplification of the immune response. There are 4 types of immune reactions which may lead to tissue damage or disease: 1. Anaphylactic 2. Antibody-mediated 3. Immune complexes 4. Cell-mediated immunity

Answer 6

HYPERSENSITIVITY REACTIONS Examples: Asthma, hayfever, bee sting, peanuts - IgE/mast cell interaction. - Release of vasoactive amines. (e.g. histamine) In type I, reactions result from TH2 helper T-cells, which help in the activation of IgE-producing B-cells/plasma cells. IgE molecules are attached to mast cells, which become activated and degranulate (release histamine, leukotrienes, prostaglandins and other mediators) when IgE binds antigen in a previously sensitized individual. This are termed allergic (or atopic) reactions. - The effects of the reaction include vascular permeability and smooth muscle contraction. - The reaction can be localized or systemic. - Depending on the severity, the reaction may be life-threatening (i.e. anaphylactic reaction).

Answer 7

HYPERSENSITIVITY REACTIONS Example: Transfusion reactions due to mismatched blood, thrombocytopenic purpura (ITP), Goodpasture syndrome. - IgG or IgM/complement interaction - Lysis of cells In type II reactions, antibodies are produced which bind to antigens on surfaces of cells or tissue components. These antibodies can then activate complement, or bind to Fc receptors on phagocytes. Thus, circulating cells which are opsonized by the antibody may then be targeted for destruction by phagocytes (e.g. ITP), while other cells and tissues targeted by the antibodies are damaged secondary to complement activation and subsequent inflammation.

Answer 8

HYPERSENSITIVITY REACTIONS Example: Systemic lupus erythematosus, post-streptococcal glomerulonephritis - Antigen-antibody complexes in the circulation are trapped in various organs (e.g. kidney) where they produce injury by complement activation and neutrophil activation In type III reactions, antibodies are directed against circulating antigens. These antigens may be endogenous (e.g. nucleoproteins) or exogenous (e.g. proteins from microbes). The antibodies and antigens bind together to form circulating immune complexes. Immune complexes form in the course of normal immune responses; it is only when formed in large amounts that they cause problems. These are eventually deposited in tissues where they activate complement and neutrophil-mediated inflammation. The complexes may be deposited in blood vessels, including blood vessels of specific organs, or several tissues/organs (systemic). The tissue damage is manifested by necrotizing vasculitis (acute inflammation within the blood vessel wall with necrosis), associated ischemic necrosis and acute inflammation in the affected surrounding tissue.

Answer 9

HYPERSENSITIVITY REACTIONS 1. delayed-type hypersensitivity mediated by CD4+ T-cells - Examples: contact dermatitis due to poison ivy, tuberculin reaction, granulomatous inflammation - In delayed-type hypersensitivity, CD4+ T-cells differentiate into different classes of helper T-cells upon exposure to antigen via antigen-presenting cells. - Depending on the particular cytokine(s) secreted by the APC, the T-cell differentiates into either TH1 or TH17 cells. - Upon subsequent exposure, the differentiated Tcells migrate to the site of the antigen and are activated in conjunction with APCs. - The TH1 cells secrete IFN- , a cytokine which activates macrophages, promoting phagocytosis and production of microbicidal substances. - TH17 secrete IL-17, a cytokine which is chemotactic for neutrophils, recruiting them to the site of exposure and inciting acute inflammation. - In cases of delayed-type hypersensitivity, tissue damage results. - Formation of granulomas (def: aggregate of epithelioid macrophages surrounded by a rim of lymphocytes) occurs in some types of delayed-type hypersensitivity where there is persistence of an organism or other antigen (e.g. tuberculosis). - The initial CD4+ T-cell infiltrate is replaced by activated macrophages which fuse to form multinucleated giant cells. 2. T-cell-mediated cytotoxicity, mediated by CD8+ T-cells - Examples: viral hepatitis, type I diabetes, solid-organ transplant rejection - In T-cell mediated cytotoxicity, CD8+ cells destroy cells expressing a particular antigen (eg. self antigen expressed on islet cells of the pancreas in type I diabetes).

Answer 10

See table for summary

Answer 11

Autoimmune diseases occur due to a breakdown of the normal processes which maintain a state of immunological tolerance to self-antigens. The current concepts of immunological tolerance involve two main factors: - Discrimination of self and non-self antigens by antigen reaction T cells (recognition). - Suppression of immune responses to self antigens by suppressor T cells. It is thought that autoimmunity results from two main factors: 1. Genetic susceptibility to autoimmunity runs in families - many patients have more than one autoimmune disease - particular HLA alleles are linked to autoimmune diseases - genetic polymorphisms are linked to autoimmune diseases 2. Environmental factors - microbes including viruses and bacteria may trigger autoimmune diseases - UV radiation - ?smoking - tissue damage - ?hormones The clinical picture in the different autoimmune diseases depends on: a) the target (antigen). b) type of immune reaction (cell-mediated, humoral or both). c) changes secondary to the destruction of the target organ or type of immune reaction

Answer 12

1. Systemic lupus erythematosus: a) Target: DNA b) Immune reaction: Type III - circulating DNA-antiDNA complexes c) Dermatitis, nephritis, arthritis: Due to trapping of complexes in skin, kidneys and joint synovium. 2. Hashimoto's thyroiditis: a) Target: thyroid follicular cells b) Immune reaction: Type II - cytotoxic antibody - complement activation Type IV - cell-mediated c) Hypothyroidism due to the destruction of thyroid cells.

Answer 13

Primary (congenital); Secondary (acquired) Clinical Features Associated With Immunodeficiency 1. Chronic infection. 2. Recurrent infection (greater frequency than expected). 3. Unusual infecting agents (low pathogenic potential). 4. Poor resolution or poor response to antibiotic treatment.

Answer 14

Certain generalizations may be made regarding immunodeficiency syndromes: 1. Cell-mediated immune deficiencies (T-cell dysfunction) may present very early (such as during the neonatal period) (e.g. DiGeorge syndrome - congenital absence of thymus). It usually affects the humoral system as well because of a lack of helper/suppressor effect on B cells. Thus, pure T cell dysfunction is unlikely 2. Pure B cell dysfunction (with normal T cell function) is possible (e.g. Bruton's syndrome). 3. Pure B cell dysfunction is not detected until the infant is 5-6 months old, because of protection by maternal IgG antibodies. 4. Both T and B cell deficiency can occur in the same patient (e.g. severe combined immunodeficiency disease). - Specific primary (congenital) immunodeficiency disorders

Answer 15

- X-linked agammaglobulinemia - Common variable immunodeficiency - Isolated IgA deficiency - Hyper-IgM syndrome - DiGeorge syndrome - Severe combined immunodeficiency Recurrent infections may also occur in the presence of intact T and B cell function. These are due to defects in the amplification systems, e.g. deficiency of specific complement components, disorders of the mononuclear phagocytic system and of the granulocyte series. Chronic granulomatous disease results from phagocytic dysfunction (absence of lysosomal enzymes in monocytes and granulocytes).

Answer 16

Deficiency of complement proteins Chronic granulomatous disease (defect in NADPH oxidase) Rare mutations in Toll-like receptors

Answer 17

These may occur due to: 1. Infections: - Rubella----->Temporary - Measles -----> Immuno - Mycoplasma ----->deficiency - Human Immunodeficiency Virus (HIV) ----> Acquired Immunodeficiency Syndrome (AIDS). 2. Immunosuppressive therapy: i.Cytotoxic drugs, cortisone (e.g. chemotherapy for cancer) ii.Irradiation iii.Anti-lymphocyte serum globulin (ALG) 3. Malignancy (especially lymphoma) 4. Chronic illness 5. Malnutrition 6. Aging