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The development of an infectious disease in an individual involves complex interactions between the microbe and the host. The key events during infection include entry of the microbe, invasion and colonization of host tissues, evasion from host immunity, and tissue injury or functional impairment.
The immune system responds in distinct and specialized ways to different types of microbes to most effectively combat these infectious agents. Because microbes differ greatly in patterns of host invasion and colonization, their elimination requires diverse effector systems.
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The specialization of adaptive immunity allows the host to respond optimally to each type of microbe. The survival and pathogenicity of microbes in a host are critically influenced by the ability of the microbes to evade or resist the effector mechanisms of immunity.
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microorganisms have developed a variety of mechanisms for surviving in the face of powerful immunologic defenses. A common strategy used by many microbes is antigenic variation. In many infections, tissue injury and disease may be caused by the host response to the microbe and its products rather than by the microbe itself.
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five types of pathogenic microorganisms that illustrate the main features of immunity to microbes: extracellular bacteria, intracellular bacteria, fungi, viruses, and protozoan and multicellular parasites.
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First, these bacteria induce inflammation, which results in tissue destruction at the site of infection. Second, many of these bacteria produce toxins, which have diverse pathologic effects. Many exotoxins are cytotoxic, and they kill host cells. Other exotoxins stimulate the production of cytokines that cause disease.
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One result of complement activation is opsonization and enhanced phagocytosis of the bacteria and the membrane attack complex lyses the bacteria. Complement by-products participate in inflammatory responses by recruiting and activating leukocytes. Phagocytes bind extracellular bacteria by various surface receptors, including mannose receptors and scavenger receptors, Toll-like receptors and bind opsonized bacteria by complement receptors.
activated phagocytes secrete cytokines, which induce leukocyte infiltration into sites of infection (inflammation). Injury to normal tissue is a pathologic side effect of inflammation. Cytokines also induce the systemic manifestations of infection, including fever and the synthesis of acutephase proteins.
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Neutralization is mediated by high-affinity IgG and IgA isotypes, opsonization by some subclasses of IgG, and complement activation by IgM and subclasses of IgG. Cytokines that are produced by CD4+T helper cells stimulate antibody production, induce local inflammation, and enhance the Phagocytic and microbicidal activities of macrophages.
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Interferon-y (IFN-y) is the T cell cytokine responsible for macrophage activation, and tumor necrosis factor (TNF) and lymphotoxin trigger inflammation. The principal injurious consequences of host responses to exlracellular bacteria are inflammation and septic shock, which are caused by cytokines produced mainly by activated macrophages.
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Septic shock is the most severe cytokineinduced pathologic consequence of infection by gram-negative and some gram positive bacteria. It is a syndrome characterized by circulatory collapse and disseminated intravascular coagulation. TNF is the principal mediator of septic shock.
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Some bacterial toxins like superantigens stimulate all the T cells in an individual that express a particular family of V beta T cell receptor genes with the subsequent production of large amounts of cytokines causing septic shock. A late complication of the humoral immune response to bacterial infection may be the generation of disease-producing antibodies.
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The two rare sequelae of streptococcal infections of the throat or skin that are manifested weeks or even months after the infections are controlled. Rheumatic fever is a sequelae to pharyngeal infection with some serologic types of betahemolytic streptococci. Some of these antibodies that are produced to the M protein of the Strep. pyogenes cross-react with myocardial sarcolemmal proteins and myosin causing carditis.
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Poststreptococcal glomerulonephritis is a sequelae to infection of the skin or throat with beta-hemolytic streptococci. Antibodies produced against these bacteria form complexes with bacterial antigen and cause nephritis.
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Some surface antigens of bacteria such as gonococci and Escherichia coli are contained in their pili which are responsible for bacterial adhesion to host cells. The pilin genes of gonococci undergo extensive gene conversion. Haemophilus influenzae, changes in the production of glycosidases lead to chemical alterations in surface LPS and other polysaccharides.
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Intracellular bacteria activate NK cells by stimulating macrophage to produce IL12, a powerful NK cell-activating cytokine. The NK cells produce IFNy, which in turn activates macrophages and promotes killing of the phagocytosed bacteria.
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cell-mediated immunity consists of two types of reactions Macrophage activation by the T cell-derived signals CD40 ligand and IFN-y, which results in killing of phagocytosed microbes. lysis of infected cells by cytolytic T lymphocytes (CTLs). CD4+ T cells differentiate into TH1 effectors under the influence of IL.12, which is produced by macrophages and dendritic cells.
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The effectors of cell-mediated Immunity are CD4+ T cells and CD8+ CTLs. The macrophage activation that occurs in response to intracellular microbes is also capable of causing tissue injury. This injury may be manifested as delayed type hypersensitivity (DTH) reactions to microbial protein antigens (like PPD).
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The histologic hallmark of infection with some intracellular bacteria is granulomatous inflammation due to T cell and macrophage activation, and resistance to intracellular killing.
lmmunity to Fungi
Fungal infections, also called mycoses, are important causes of morbidity and mortality in humans. The immune responses to these microbes are often combinations humoral and cell mediated immunity.
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C.neoformans inhibit the production of cytokines such as TNF and IL12 by macrophages and stimulate production of IL10, thus inhibiting macrophage activation. Cell-mediated immunity is the major mechanism of adaptive immunity against fungal infections like H.capsulatum and Candida.
lmmunity to Viruses
Viruses are obligatory intracellular microorganisms that replicate within cells. Innate and adaptive immune responses to viruses are aimed at blocking infection and eliminating infected cells. The innate immune response to viral infection is primarily through the induction of interferons (IFN-y and IFN-B) and the activation of NK cells.
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Antiviral antibodies function mainly as neutralizing antibodies to prevent virus attachment and entry into host cells. Complement activation may also participate in antibody-mediated viral immunity, mainly by promoting phagocytosis and direct lysis of viruses with lipid envelopes. Elimination of viruses that reside within cells is mediated by CTLs, which kill the infected cells.
Innate lmmunity to Parasites The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to
phagocytic
killing
and
may
even
replicate
within
macrophages. Phagocytes also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed.
Many helminths have thick teguments that make them resistant to the cytocidal mechanisms of neutrophils and
macrophages.
Adaptive lmmune Responsest o Parasites Different parasites elicit quite distinct adaptive immune responses.
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In contrast, metazoa such as helminths survive in extracellular tissues, and their elimination is often dependent on special types of antibody responses. The principal defense mechanism against protozoa that survive within macrophages is cell-mediated macrophage activation by TH immunity, particularly
Defense against many helminthic infections is mediated by the activation of TH 2 cells, which antibodies and
IgE antibodies bind to the surface of the helminth, eosinophilsthen attach via FC receptors, and the eosinophils are activated to secret granule
Tolerance
Tolerance is a specific immunologic unresponsiveness to antigens that are present
during embryonic life are considered self and do not stimulate an immunologic response. When the immune system recognizes a self antigen and mounts a strong response against it,
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CONT
the immune system has to recognize self-MHC to mount a response against a foreign antigen. the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.
When specific lymphocytes encounter antigen - Lymphocytes activated, leading to immune responses. - Lymphocytes are inactivated or eliminated leading to tolerance. - The antigen is ignored.
Normal individuals are tolerant of their own antigens (self antigens). - Failure of self tolerance results in immune reactions against self or autologous antigensAutoimmunity.
the most sensitive Tolerance of lymphocyte is during maturation are the thymus for T cells and the bone marrow for B lymphocytes. Therefore, in the generative lymphoid organs, immature lymphocytes normally encounter only self antigens at high concentrations, and clones of lymphocytes whose receptors recognize these self antigens with affinity are killed (deleted). This process is called negative selection.
Peripheral tolerance is induced by -recognition of antigens without adequate levels of the costimulators that are required for lymphocyte activation, or by persistent and repeated stimulation by
Repeated stimulation of T lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis
T-Cell Tolerance
T lymphocytes acquire the ability to distinguish self from
T-Cell Tolerance
tolerance acquired outside the thymus is called peripheral tolerance. Peripheral tolerance is necessary because some self reactive T cells are not killed in the thymus, there are several mechanisms involved:
some self-reactive T cells are killed
inhibitory cytokines.
Clonal anergy
Clonal anergy is the terms used to describe self-reactive T cells that are not activated because proper co stimulation does not occur . Both T-cell and B-cell clonal deletion fail to eliminate all autoreactive cells. The mechanism of clonal anergy involves the inappropriate presentation of antigen, leading to a failure of interleukin2(IL-2) production. Inappropriate presentation is due to a failure of Costimulatory signal, eg. Sufficient amounts of IL-1 might not be made, or cell surface proteins, such as CD28 on the T cell and B7 on the B cell, might not interact properly.
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Clonal ignorance
clonal ignorance refers to self-reactive T cells that are
inaccessible tissues.
Such cells may die out for lack of stimulus.
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B cell Tolerance
B cells also become tolerant to self by two mechanisms. Clonal deletion, probably while the B-cell precursors are in the bone marrow. clonal anergy of B cells in the periphery. Tolerance in B cells is less complete than in T cells, an observation supported by the finding that most autoimmune disease are mediated by antibodies.
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Immune Regulation
Regulation of immune responses, which prevents
overproduction of antibody or excessive proliferation of T cells and/or B cells, occurs at several levels. Antigen concentration: As antigen levels decrease during an
Immune Regulation
Antigen-antibody complexes: -When antigen is free, it can bind to B cells and act as a stimulatory signal. -when most of the antigen is bound in complexes with IgG, it
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