NU608 Adaptive Immunity PDF

1 In this module we will look at the 3rd line of defense in the immune system…that of adaptive immunity. Adaptive immune responses refer to immunity that is acquired through previous exposures to infectious and other foreign antigens. The components of the adaptive immune system are the T and B cell...

1 In this module we will look at the 3rd line of defense in the immune system…that of adaptive immunity. Adaptive immune responses refer to immunity that is acquired through previous exposures to infectious and other foreign antigens. The components of the adaptive immune system are the T and B cell lymphocytes and their products. 2 Another way to classify immune responses is by the type of cells. Regulatory cells – orchestrate and control immune response. They direct the action of the immune response Effector cells are those cells that are able to attack the antigen and destroy it 3 Primary cells of the specific immune system are white blood cells called lymphocytes. Lymphocytes represent 25-35% of the WBC and 99% of the cells reside in the lymph. Recall that the lymphocytes are derived from the stem cell. These undifferentiated cells congregate in central lymphoid tissues where they mature into distinct types: Some give rise to pre-T cells that migrate to thymus where they divide and are processed into T cells, (which is involved in cell-mediated immunity). The others are processed into B cells, move through blood to lymph tissue to plasma cell producing antibodies. About 60-60% of blood lymphocytes are T cells & 10-20% are B cells. After the lymphocytes are stimulated by their antigen, they (both) acquire a memory response in which they are capable of “remembering” the antigen & responding more rapidly & efficiently if the pathogen invades again. 4 What is an antigen? Antigen can be any substance (foreign to the individual– such as bacteria, dust, pollen, proteins produced by cancer cells) that stimulates a response by the immune system. Antigen-presenting cells are macrophages or special cells known as dendritic cells which are phagocytic cells. These cells have long finger-like projections which gives them their name. These cells function as key cells that initiate “adaptive” immunity – they process and present the foreign antigen to the lymphocytes. 5 The key trigger for activation of B & T cells is the recognition of the antigen by the unique surface receptors of the lymphocytes. It is essential that the immune system recognizes and initiates attack against “nonself” (foreign) or damaged cells. To ensure this appropriate response – potential antigens are presented to the immune system (mainly T-cells) in combination with self-antigens (which are called MHC proteins – major histiocompatibility complex). The T-cells then determine whether the cell presented to them is abnormal or normal – if it determines the antigen/MHC complex is abnormal the immune response is initiated and the cell is “killed”. 6 Each individual possesses cell surface antigens that are unique to each individual – these are the MHC protein complexes – as they are unique to each individual they serve as cellular “fingerprints”. Because these are expressed on such high concentration on leukocytes they are referred to as human leukocyte antigens (HLAs). MHC are involved in “self” recognition and cell-to-cell communication and fall into two categories (MHC I and MHC II). MHC I are found on all cells (except RBCs) – they bind and present antigens ONLY to cytotoxic T-cells (CD8 cells) - these cytotoxic cells are then stimulated to initiate killing of the “abnormal” cell MHC II are found only on the surface of macrophages and B cells – they bind and present antigens to helper T-cells (CD4 cells). The CD4 cells will then initiate an immune response by secreting ytokines that activate B cells to become plasma cells (which are the cells that secrete antibodies). 7 B lymphocytes  Responsible for humoral immunity. Humoral immunity provides for elimination of bacteria, neutralization of bacterial toxins, prevention of viral infection & immediate allergic responses The activated B cell divides & undergoes maturation into a plasma cell…it is the plasma cell that produces thousands of antibody molecules per second. These antibodies are then released into blood & lymph where they bind & remove their unique antigen (with help of other immune cells & molecules). Memory B-cells are generated & distributed into the peripheral tissues in preparation for subsequent antigen exposure An Antibody are also known as gamma globulins or immunoglobulins. 8 An Antibody (also known as gamma globulin, immunoglobulin) Antibodies are glycoproteins produced by the plasma cells in response to a challenge by an antigen. All antibodies are similar in appearance. They are composed of combinations of light and heavy polypeptide chains which consist of: Variable portion  different for each specificity of antibody This is the portion that attaches specifically to a particular type of antigen Constant portion  determines the other properties of the antibody such as, the diffusibility of antibody in tissues This is the portion that activates complement and attachment to complement 9 Mechanisms of action: Antibodies act mainly in three ways to protect the body against invading agents by: Direct attack on the invader Activation of the complement system Stimulation of IR Antibody can inactivate the invading agent in one of several ways: Agglutination  antibody-antigen complexes and become bound together in a clump Precipitation  complex of the antigen/antibody becomes so large that it’s rendered insoluble & precipitates Neutralization  antibodies cover the toxic site on the antigen Lysis  antibody directly attack membranes of the cellular agent causing rupture of the cell There are five specific immunoglobulins produced in response to an antigen: IgG, IgM, IgA, IgE and IgD 10 IgE Involved in inflammation, allergic responses & combating parasitic infections It binds to mast cells and basophils in skin and mucous membranes This then triggers the cells to release histamine & other mediators involved in inflammation & allergies It is also the antibody most stimulated during a parasitic infection IgD Found primarily on cell membranes of B lymphocytes Its role in the immune response is not completely clear Serves as an antigen receptor for initiating the differentiation of B cells 11 IgA Is known as a “secretory” immunoglobulin Found in tears, saliva, colostrums, bronchial, GI, prostatic & vaginal secretions Considered a primary defense against local infections in mucosal tissue IgA acts locally rather than through the systemic circulation Prevents attachment of virus & bacteria to epithelial cells IgA is a major component of breast milk (and is not available in any of the commercial formulas) which provides immunity to the neonate. 12 IgM Macromolecule - first circulating immunoglobulin to appear in response to an antigen Bound to B lymphocytes Activates complement Very effective in gram negative infection Diagnostically useful as presence of IgM suggests a current infection by a specific antigen 13 IgG Most abundant of circulating immunoglobulins (represents approximately 80% of all circulating antibodies) Protects against bacteria, toxins and viruses in body fluids Activates the complement system Only immunoglobulin that can cross the placenta & transfer immunity from the mother to the fetus This is a form of passive immunity 14 Immunity is the state in which one is protected from disease development. Immunity can be either active or passive depending on whether the antibodies or T cells are produced by the individual or administered directly Active immunity It’s the cellular and humoral immune response that is produced by the individual after initial exposure to an antigen or after immunization Typically considered a long-lived immunity Passive immunity Does not involve the host’s immune response Occurs when antibodies or T lymphocytes are transferred from a donor to the recipient Temporary as the donor’s antibodies are eventually destroyed and does not provide a memory response 15 Primary response – – – – Initial exposure Latent period or lag phase B cell differentiation is occurring After 5 to 7 days, an IgM antibody for a specific antigen is detected An IgG response equal or slightly less follows the IgM response Secondary response – – – – More rapid Larger amounts of antibody are produced Rapidity is due to the presence of memory cells that do not have to differentiate IgM is produced in similar quantities to the primary response, but IgG is produced in considerably greater numbers 16 T lymphocytes  Function in the activation of other T & B cells, in control of viral infection, in rejection of foreign tissue grafts & in delayed hypersensitivity responses. These immune responses are called cell-mediated or cellular immunity Two main functions: Direct killing through what is known as effector cells  aid in the final stages of the immune response cytotoxic T lymphocytes help in causing destruction & removal of the antigen T cytotoxic cells  activated CD8+ t Cytotoxic cells destroy target cells by releasing cytotoxic enzymes, toxic cytokines, and can trigger programmed cell death (apoptosis) in the target cell Typically target cell surfaces such as body cells infected by viruses or those transformed by cancer CD8 are especially important in controlling replicating viruses and intracellular bacteria because antibody cannot penetrate living cells. Assistance or activation of other cells through what is known as regulatory cells  assist in orchestrating & controlling the immune response Helper T cells  the CD 4+ helper T cell (TH) serves as the master switch for the immune system Activated helper T cells secrete cytokines that influence the function of nearly all the other cells of the immune system These cytokines activate & regulate B cells, cytotoxic T cells, Natural killer (NK) cells, macrophages Natural killer cells are: Lymphocytes that is functionally & structurally distinct from T cells and B cells. Non-specific effector cell that can kill tumor cells and virus-infected cells Programmed automatically to kill foreign cells Role is that of immune surveillance for cancerous or virally infected cells. 17 Immunity is the normal adaptive response designed to protect the body against potentially foreign substances. An important but undesirable side effect of immunity is the development of immune hypersensitivity. Hypersensitivity is an exaggerated immune reaction to certain antigens or other molecules. Most hypersensitivity diseases are autoimmune disease and allergy. Every hypersensitivity disease (whether an allergy or autoimmune) involves one of four basic immune mechanisms: B-cell reactions Type 1, immediate hypersensitivity Type 2, cytotoxic hypersensitivity Type 3, immune complex hypersensitivity T-cell reactions Type 4, cellular (delayed) hypersensitivity 18 Type 1 hypersensitivity is an immediate (within minutes) reaction that occurs when antigen combines with preformed antibody that is attached to mast cells This preformed antibody was created by a previous exposure (the initial, sensitizing exposure) to the antigen The sensitizing exposure produces no symptoms But sets the stage for rapid reaction on subsequent exposure On subsequent exposure to the antigen, the antigen combines with IgE antibody already present on the surface of the mast cells & triggers an instant reaction: mast cell degranulation, histamine release, influx of eosinophils and other inflammatory cells into the site. Type 1 reactions include, “hay fever’ (allergic rhinitis), hives, and some cases of asthma. Allergies are very common and appear to be increasing in incidence and severity, particularly in young children. Remember that allergic reactions take many forms, including skin rash, hay fever, vomiting and anaphylaxis. A tendency toward allergic conditions is inherited, and the manifestations of such allergy in a family is referred to as an atopic hypersensitivity reaction. 19 In type II hypersensitivity, often called cytotoxic hypersensitivity, is one in which an antibody attaches directly to an antigen in the target tissue, usually a cell membrane. The antigen is present on the cell membrane. The antigen may be a normal component or foreign. It is not clear why cell membranes sometimes lose their “self” identify and become alien and incite a reaction against self. Circulating IgG antibodies react with the antigen, causing destruction of the cell, either by releasing cytolytic enzymes related to complement activation or by phagocytosis. An example of this type of reaction is the response to an incompatible blood transfusion. A person with type A blood has A antigens on his RBC and anti-B antibodies in his blood and a person with Type B blood has anti-A antibodies. If type B blood from donor is added to the recipient’s type A blood, the antigen-antibody reaction will destroy the RBC (hemolysis) in the type A blood Another type of cytotoxic reaction IgG antibodies bind to target-cell membrane receptors and block receptor function…an example of this is myasthenia gravis, an autoimmune antibody attaches to acetylcholine receptors on the muscle side of the neurotransmitter connection, preventing transmission of the nerve signal to muscle. 20 In this type of reaction, the antigen combines with the antibody, forming an immune complex…which is then deposited in tissue, often in blood vessel walls, and activates complement. The antibodies are not directed against those particular tissue sites, but are trapped in the capillary meshwork. This process causes inflammation and tissue destruction. Formation of these complexes is the cause of most autoimmune diseases. A number of diseases are thought to be caused by these immune complexes: Glomerulonephritis – antibody-antigen complexes form in response to infection, often streptococcal bacteria, and deposit in the glomerular capillaries of the kidneys, Rheumatoid arthritis SLE – complexes form against collagen and cellular DNA, and deposit in multiple sites throughout the body Serum sickness refers to the systemic reaction that occurs when these immune complexes deposits occur in many tissues. We use to see serum sickness more often in the past when they used animal serum for passive immunizations, this illness is far less common today. Arthus reaction is a localized inflammatory and tissue necrosis that results when an immune complex lodges in the blood vessel all, causing a vasculitis 21 These reactions are T cell-mediated reactions, in that cytotoxic (CD8) or helper (CD4) T cells are activated by antigen, leading to destruction of the cells involved. These reactions are often against virally-infected cells and can lead to extensive tissue damage. These reactions are delayed, taking 24 to 72 hours to develop. Examples include delayed allergic reactions, such as the reactions to poison ivy or poison oak. The tuberculin skin test indicated the presence of delayed cell-mediated immunity against the tuberculin bacillus. Some autoimmune disease such as thyroiditis (Hashimoto’s disease) in which T cells are produced against thyroid tissue and graft and tumor rejection are examples. 22 Primary or congenital immunodeficiency occurs as a result of a genetic defect. Whereas acquired immunodeficiency is reduced functioning of the immune system that develops after birth. It can arise in response to infection, malnutrition, chronic stress and pregnancy. Systemic illnesses such as diabetes, renal failure and liver failure can also cause immunodeficiency. And, it’s also just part of … normal effects of aging. 23 So, how do you determine if your client may need referral for immunology work-up? The hallmark of immune deficiencies are the development of unusual or recurrent, severe infections. What is considered normal # of infections? In pre-school children, typically 6 to 12 infections a year (of which 3-4 are ear infections) is considered normal. And, with adults 2-4 infections. But in clients with immune deficiencies in addition to increase number the infections are more severe…instead of URI they develop pneumonia, increased abscesses, meningitis, increased bloodstream infections noted. T-cell deficiencies usually present with viral and/or opportunistic type infections. Varicella, herpes, CMV, fungal infections. B-cell deficiencies usually present with bacterial infections with encapsulated organisms (such as strep, GBS, E.coli, pseudomonas) Complement deficiencies present similar to the B-cell deficiencies 24 Most primary immune deficiencies are the result of a single gene defect. Generally, the mutations are sporadic and are not inherited. There is a family history in only about 25% of individuals. 25 Bruton’s agammaglobulinemia is caused by failure of B-cell precursors to become mature B cells. This is an x-linked disease and affects only males. These individuals are susceptible to meningitis, recurrent otitis media and sinus and pulmonary infections Selective IgA deficiency is another common defect in which individuals are unable to produce IgA but are able to produce the other classifications of immunoglobulins, Individuals frequently present with chronic intestinal candidiasis. It occurs in about 1in 400 but 2/3 of the individuals have no overt symptoms (as the other classes of immunoglobulins are okay and they are able to compensate). 26 Di George Syndrome is the complete or partial absence of T-cell immunity. It is characterized by severe congenital structural defects of the heart and low levels of calcium, which may result in seizures, This syndrome exhibits a congenital aplasia or hypoplasia because of deletions on chromosome 22. 27 SCIDS occur when a common stem cell for all white blood cells is absent. Therefore, T-cells, B-cells, and phagocytic cells never develop. Most children with SCID caused by reticular dysgenesis (which is the most severe form) die in utero or very soon after birth. This is rare with only about 40 cases reported each year. It’s a genetic mutation that leads to absence of all immune function. In infants with SCIDs (the course resembles AIDS with many of the infants dying from opportunistic infections). Tx: bone marrow transplantation; stem cell transplantation 28 29