Module 4 - Immunity & Immune Disorders Flashcards

Question

T-lymphocytes What are CD4+ T cells called Why? What re CD8+ T cells? why?

Answer 1

CD4+ T cells are called helper T cells because they secrete soluble molecules (cytokines) that help B cells to produce antibodies and also help macrophages to destroy phagocytosed microbes. CD8+ T cells also can secrete cytokines, but their most important role is to directly kill virus-infected cells and tumor cells; hence, they are called cytotoxic T lymphocytes (CTLs).

Answer 2

Constitute 10-20% of peripheral lymphocytes. Arise from yolk sac in embryos, and bone marrow after birth - They mature in the Bone marrow.

Answer 3

Immature B-cells (pre-B) contain cytoplasmic heavy-chain immunoglobulins (Ig). - Later, they develop surface immunoglobulins (Igs).

Answer 4

Mature B-cells are primarily in a resting state, awaiting activation by foreign antigen. On antigenic stimulation, they form plasma cells which secrete 5 classes of immunoglobulins (M, G, A, D, E). Like the T lymphocytes, B- cells recognize antigen via the B-cell antigen receptor complex. - The major one is IgM antigen receptor complex. - Other receptors are complement receptors, IgA and IgE, CD40 and Fc receptors. IgG, IgM, and IgA constitute more than 95% of circulating antibodies. - IgA is the major isotype in mucosal secretions - IgE is present in the circulation at very low concentrations and also is found attached to the surfaces of tissue mast cells - IgD is expressed on the surfaces of B cells but is secreted at very low levels.

Answer 5

T-cells and other non specific factors (e.g. bacterial products and certain factors) are required for maturation and differentiation of B-lymphocytes.

Answer 6

Make up 10-15% of peripheral blood cells; do not bear T-cell receptors or cell surface immunoglobulins They have innate ability to lyse a variety of tumor cells, viral-infected cells and some normal cells without previous sensitization and thus make up part of the innate immune system. Are able to lyse IgG-coated target cells (antibody dependent cell-mediated cytotoxicity [ADCC]) They have CD16 and CD56 surface molecules Interferon promotes their killing activity and prostaglandin E2 is highly suppressive of NK cells.

Answer 7

``` Inhibitory - Inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells ``` Activating - Activating receptors recognize molecules that are expressed or up-regulated on stressed or infected cells

Answer 8

Infections (especially viral infections) and stress are associated with reduced expression of class I MHC molecules and increased expression of proteins that engage activating receptors. The net result is that the NK cells are activated and the infected or stressed cells are killed and eliminated.

Answer 9

They are phagocytic cells, present virtually in all body organs. - They ingest microbes and other particulate antigens and display peptides for recognition by T lymphocytes. - These T cells in turn activate the macrophages to kill the microbes, the central reaction of cell-mediated immunity.

Answer 10

* Process and present antigen to immunocompetent T-cells. * Important in certain cell-mediated immunity such as delayed hypersensitivity reaction * Important in the effector phase of humoral immunity (phagocytose opsonized microbes). * They secrete macrophage-derived cytokines which amplify T-cell responses.

Answer 11

Antigen presenting cells, i.e. they process or degrade antigen intracellulary into peptides and then express or 'present' the Ag peptide on their cell surface to be recognized by the T-cell. Examples: • Interdigitating dendritic cells, expresses high levels of major histocompatibility complex (MHC) antigens • Follicular dendritic cells, bear Fc receptors for IgG

Answer 12

The normal function of MHC molecules is to display peptides for recognition by CD4+ and CD8+ T lymphocytes. The MHC is an intricate system of membrane proteins or antigens, referred to as human leukocyte antigens (HLA). MHC genes are located on chromosome 6 and code for three major classes of molecules (designated as I, II & III). Class III is complement antigen and NOT a histocompatibility antigen.

Answer 13

- Class I molecules are present on all nucleated cells and recognized by cytotoxic T-cells (e.g. during graft rejection or in a virally infected cell). - The extracellular portion of the MHC molecule contains a cleft where foreign peptides bind to MHC molecules for presentation to T cells, and a conserved region that binds CD8, ensuring that only CD8+ T cells can respond to peptides displayed by class I molecules.

Answer 14

Class II is limited to: • Antigen presenting cells (macrophages and dendritic cells) • B-cells • Subsets of activated T cells Thus, Class II molecules are important for interactions between immune cells. The extracellular portion of class II MHC molecules contains a cleft for the binding of peptides generated from exogenous proteins (antigens) and the resulting peptide-MHC complex is recognized by CD4 helper T cells.

Answer 15

Adaptive immune responses develop in steps, consisting of: - antigen recognition; activation - proliferation and differentiation of specific lymphocytes into effector and memory cells - elimination of the antigen - decline of the response, with memory cells being the long-lived survivors. *We will give only a very broad overview of the major events in the immune response (see the text for more details and figures). These general principles apply to protective responses against microbes as well as pathologic responses that injure the host. Categories: 1) Capture and display of antigens - antigen presentation 2) Cell-mediated immunity 3) Humoral Activity

Answer 16

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, 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. The reactions and functions of T lymphocytes and B lymphocytes differ in important ways. - There are two types of responses - cell mediated and humoral (antibody mediated). - Usually both cell-mediated and humoral responses occur in immune reactions but one may predominate, e.g. in fungal or viral infections, cell-mediated immunity predominates and confers protection; while in bacterial infections, humoral immunity predominates.

Answer 17

Mediated by T lymphocytes and natural killer (NK) cells. 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 expression of CD40 ligand (CD40L). - Once activated via recognition of a 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 that further activate macrophages, neutrophils, mast cells or eosinophils. 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.

Answer 18

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 19

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).

Answer 20

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 antigen on microbes in order to neutralize them, activation of the complement system, and opsonization (coating) of pathogens to target them for phagocytosis.

Answer 21

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

Answer 22

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 non- specific manner) opsonized cells/microbes. - This is known as antibody dependent cell-mediated cytotoxicity (ADCC).

Answer 23

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 24

1) Hyperfunction | 2) Hypofunction

Answer 25

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 2) Surveillance

Answer 26

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. 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 27

Hyperfunction, usually termed HYPERSENSITIVITY, results in damage of normal tissue.

Answer 28

1) Anaphylaxis 2) Antibody-mediated / Cytotoxic antibody 3) Immune complexes 4) Cell-mediated immunity

Answer 29

Hypersensitivity reactions are those reactions causing tissue injury. - These often represent “excessive” immune response to an antigen. - Hypersensitivity reactions may result from immune response to self antigens (autoimmunity – see below), 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.

Answer 30

Manifested by a localized or a generalized reaction that occurs immediately after exposure to an antigen (to which the person has been previously sensitized). • IgE/mast cell interaction. • Release of vasoactive amines. (e.g. histamine) • Examples: Asthma, hayfever, bee sting, peanut allergy. 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. - These 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 31

Caused by IgG and IgM cytotoxic antibodies directed against fixed antigens on cell surfaces or in connective tissues (these antibodies can activate the complement system). • IgG or IgM/complement interaction. • Lysis of cells (mediated directly by complement via the membrane attack complex (MAC) or indirectly by opsonization enhancing phagocytosis (C3b or C5b fractions)). • May also include complement-independent reactions, such as antibody-dependent cell-mediated cytotoxicity (ADCC). • Example: Transfusion reactions due to mismatched blood; thrombocytopenic purpura (ITP); Goodpasture syndrome (Ab to type IV collagen leads to damage of lung and kidney basement membrane); also examples of autoimmune diseases myasthenia gravis (formation of Ab to block muscle ACh receptors) and Graves disease (Ab to TSH receptor that stimulates thyroid function).

Answer 32

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 33

Tissue injury mediated by circulating immune complexes. • Antigen-antibody complexes in the circulation are trapped in various organs (e.g. kidney, skin, lung) where they produce injury by complement activation and neutrophil activation. • Example: Systemic lupus erythematosus (SLE), serum sickness caused by injection of foreign protein, characterized by fever, arthralgias, vasculitis and acute glomerulonephritis; rheumatoid arthritis; post- streptococcal glomerulonephritis, see this week's case of post-streptococcal glomerulonephritis.

Answer 34

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 35

- NOT an antibody-mediated response; antigens are processed by macrophages and presented to antigen- specific T lymphocytes. - Activated lymphocytes release a variety of mediators (lymphokines) and recruit and activate lymphocytes, macrophages and fibroblasts. - The resulting injury is caused by T lymphocytes, macrophages or both.

Answer 36

Two types: 1) Delayed-type hypersensitivity mediated by CD4+ T-cells; peaks in 24 to 48 hours, lymphocytes and macrophages are involved (follows presentation of processed Ag with MHC Class II to helper T cells which recruit and activate lymphocytes, macrophages and inflammatory cells causing tissue damage). - Examples: poison ivy, chronic active hepatitis, tuberculin reaction, some autoimmune diseases, organ rejection. 2) T-cell-mediated cytotoxicity, mediated by CD8+ T-cells; CD8+ cells are activated by foreign Ag/MHC Class I complex in virus-infected or tumor cells. - Examples: viral hepatitis, type I diabetes, solid-organ transplant rejection

Answer 37

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 T- cells migrate to the site of the antigen and are activated in conjunction with APCs. - The TH1 cells secrete IFN-y, a cytokine which activates macrophages, promoting phagocytosis and production of microbiocidal 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 (an 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 In T-cell mediated cytotoxicity CD8+ cells destroy cells expressing a particular antigen (e.g. self antigen expressed on islet cells of the pancreas in type I diabetes).

Answer 38

Autoimmune diseases occur due to a breakdown of the normal processes which maintain a state of immunological tolerance to self-antigens.

Answer 39

1) Discrimination of self and non-self antigens by antigen reaction T cells (recognition). 2) Suppression of immune responses to self antigens by suppressor T cells.

Answer 40

1) Genetic susceptibility - 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 o UV radiation - ?smoking - tissue damage - ?hormones

Answer 41

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 42

1. Systemic lupus erythematosus: a) Target: DNA b) Immune reaction: Type III - circulating DNA-anti-DNA complexes c) Female predominance (90% of cases in women between 12 and 40 years old). d) 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 destruction of thyroid cells.

Answer 43

* Primary (genetic or congenital) | * Secondary (acquired)

Answer 44

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 45

Certain generalizations may be made regarding immunodeficiency syndromes: * 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 * Pure B cell dysfunction (with normal T cell function) is possible (e.g. Bruton's syndrome). • Pure B cell dysfunction is not detected until the infant is 5-6 months old, because of protection by maternal IgG antibodies. • Both T and B cell deficiency can occur in the same patient (e.g. severe combined immunodeficiency disease).

Answer 46

``` 1) Disorders affecting lymphocyte function • 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). 2) Disorders affecting innate immunity • Deficiency of complement proteins • Chronic granulomatous disease (defect in NADPH oxidase) • Rare mutations in Toll-like receptors

Answer 47

1. Infections: - Rubella (Temporary) - Measles (Immunodeficiency) - Mycoplasma Human Immunodeficiency Virus (HIV) → Acquired Immunodeficiency Syndrome (AIDS) 2. Immunosuppressive therapy: • Cytotoxic drugs, cortisone (e.g. chemotherapy forcancer) • Irradiation • Anti-lymphocyte serum globulin (ALG) 3. Malignancy (especially lymphoma) 4. Chronic illness 5. Malnutrition 6. Aging