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Immunity to Microbes

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.

General Features of lmmune Responses to Microbes

Defense against microbes is mediated by the efector mechanisms of innate and adaptive immunity. The innate immune system provides early defense, and the

adaptive immune system provides a more sustained and

stronger response. Adaptive immune responses to microbes induce effector

cells that eliminate the microbes and memory cells that

protect the individual from subsequent infections..

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.

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.

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.

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.

Immunity to Extracellular Bacteria

Extracellular bacteria are capable of replicating outside host cells, for example, in the circulation, in connective tissues, and in tissue spaces such as the airways and intestinal lumens. Many different species of extracellular bacteria are pathogenic, and disease is caused by two principal mechanisms;

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.

Innate Immunity to Extracellular Bacteria

The principal mechanisms of innate immunity to extracellular bacteria are complement activation, phagocytosis, and the inflammatory response. Gram positive bacteria contain a peptidoglycan and gram negative bacteria contain LPS in their cell walls that activates the alternative complement pathway.

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.

Adaptive lmmune Responses to Extracellular Bacteria

Humoral immunity is the principal protective immune response against extracellular bacteria, and it functions to eliminate the microbes and neutralize their toxins. The effector mechanisms used by antibodies to combat these infections include neutralization, opsonization and phagocytosis, and activation of classical complement pathway.

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.

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.

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.

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.

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.

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.

Evasion of lmmune Mechanisms by Extracellular Bacteria

The virulence of extracellular bacteria has been linked to a number of mechanisms that resist host immunity like antiphagocytic mechanisms and inhibition of complement . Bacteria with polysaccharide-rich capsules resist phagocytosis. The major mechanism used by bacteria to evade humoral immunity is genetic variation of surface antigens.

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.

Immunity to lntracellular Bacteria

A characteristic of facultative intracellular bacteria is their ability to survive and even replicate with in phagocytes. Because these microbes are inaccessible to circulating antibodies, their elimination requires the mechanisms of cell-mediated immunity.

Innate Immunity to lntracellular Bacteria

The innate immune response to intracellular bacteria consists mainly of phagocytes and NK (natural killer) cells. Phagocytes, initially neutrophils and later macrophages, ingest and attempt to destroy these microbes. But pathogenic intracellular bacteria are resistant to degradation with in phagocytes.

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.

Adaptive Immune Responses to lntracellular Bacteria

The major protective immune response against intracellular bacteria is cell-mediated immunity. Individuals with deficient cell-mediated Immunity are extremely susceptible to infections with intracellular bacteria (and viruses).

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.

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).

The histologic hallmark of infection with some intracellular bacteria is granulomatous inflammation due to T cell and macrophage activation, and resistance to intracellular killing.

Evasion of Immune Mechanisms by Intracellular Bacteria

The outcome of infection by these organisms often depends on whether the T cellstimulated microbicidal mechanisms of macrophages.

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.

Innate and Adaptive lmmunity to Fungi

The principal mediators of innate immunity against fungi are neutrophils and macrophages. Patients with neutropenia are extremely susceptible to opportunistic fungal infections. Neutrophils liberate fungicidal substances, such as reactive oxygen intermediates and lysosomal enzymes.

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.

Innate lmmunity to Viruses

The principal mechanisms of innate immunity against viruses are inhibition of infection by IFNs and NK cell-mediated killing of infected cells. IFNs function to inhibit viral replication in both infected and uninfected cells by inducing an "antiviral state. NK cells kill cells infected with a variety of viruses and are an important mechanism of immunity against viruses early in the course of infection.

Adaptive lmmune Responses to Viruses

Adaptive immunity against viral infections is mediated by antibodies, which block virus binding and entry into host cells, and by CTLs, which eliminate the infection by killing infected cells. Antibodies are produced and are effective against viruses only during the extracellular stage of the Viruses.

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.

Evasion of lmmune Mechanisms by Viruses

Viruses can alter their antigens by point mutations or by reassortment of RNA genomes in RNA viruses. Some viruses inhibit class I MHC-associated presentation of cytosolic protein antigens. Some viruses Produce molecules that inhibit innate and adaptive immunity. Poxviruses produces competitive antagonists to IFN-y, TNF, ILl, IL18, and chemokines.

Innate lmmunity to Parasites The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to








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

Adaptive lmmune Responsest o Parasites Different parasites elicit quite distinct adaptive immune responses.

Pathogenic protozoa have evolved to survive within

host cells, so protective immunity against these organisms is mediated by mechanisms similar to those that eliminate intracellular bacteria and viruses.

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

1 cell -derived cytokines.

Defense against many helminthic infections is mediated by the activation of TH 2 cells, which antibodies and

results in production of IgE activation of eosinophils.

IgE antibodies bind to the surface of the helminth, eosinophilsthen attach via FC receptors, and the eosinophils are activated to secret granule

enzymes that destroy the parasites.

Immune Evasion by Parasites


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,

autoimmune disease develops.


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.

Central tolerance occurs because during maturation in

the generative lymphoid organ lymphocytes pass through

a stage in which lymphocytes encounter self antigens leads to tolerance .

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

self antigens in peripheral tissues.

The principal mechanisms of lymphocyte tolerance are

- Apoptotic cell death, called clonal deletion;

- Functional inactivation without cell death,

called clonal anergy;

- Suppression of lymphocyte activation and

effector functions by regulatory lymphocytes

Central tolerance is mainly due to clonal deletion,

whereas all the three mechanisms contribute to peripheral tolerance. On recognition of self antigens, some immature lymphocytes undergo a second round of antigen receptor gene rearrangements, producing receptors

with a different (i.e., nonself) specificity.

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

nonself occurs in the fetal thymus , Clonal deletion

It involves the killing of T cells (negative selection) that react against antigens (primarily self MHC proteins) present in

the fetus at that time.

The self-reactive cells die by a process of programmed cell death called apoptosis. Tolerance to self acquired within the thymus is called central tolerance,

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

some are inhibited

Others suppressed by regulatory T cells producing

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.

Clonal ignorance
clonal ignorance refers to self-reactive T cells that are

ignorant by physical separation from the target antigens,

eg, the blood-brain barrier, T cells reactive to self-antigen not represented in the thymus will mature and migrate to the periphery but they may never encounter the appropriate antigen because it is sequestered in

inaccessible tissues.
Such cells may die out for lack of stimulus.

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.

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 response that successfully eliminates them, there is

loss of a stimulus for continued proliferation and

differentiation of lymphocytes, so immune responses decline.

Antibody levels: Free IgG antibody at high concentrations can

suppress immune responses

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

deliver an inhibitory signal to B cells.


Helper T-cell subset cytokine regulation

Helper T-cell subset cytokine regulation is one of the most important regulatory mechanisms. Antigen-stimulated helper T cells exist in two distinct subsets, Th 1 and Th2.

Each helper subset stimulates one arm of the immune system,

and inhibits the other, mainly through secretion of different cytokines. The interferon-y secreted by the Th1 cell inhibits Th2 cytokine production.

Helper T-cell subset cytokine regulation

Th2 cells, on the other hand, stimulate antibody production from B cells extracellular pathogens or soluble foreign antigens (e.g., exotoxins) through the production of IL-4, IL-5, IL-6, and IL1O. IL-4 is a potent inhibitor of macrophage function IL-1O inhibits Th1-cell function.

and direct it against