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Baron S, editor. Medical Microbiology. Fourth edition. Galveston (TX): college of Texas clinical Branch in ~ Galveston; 1996.


Viral Activation that Immunity

Immunity come viral infection is resulted in by a variety of specific and nonspecificmechanisms. The activation of different immune functions and also the term andmagnitude the the immune an answer depend on exactly how the virus interacts through hostcells (on whether it is a cytolytic, steady-state, latent, and/or integratedinfection) and on how the virus diffusion (by local, primary hematogenous,secondary hematogenous, and/or nervous device spread). Therefore, famous antigensmay be current in different parts that the body depending upon the route of spreadand step of infection. Local infections at surface such together the mucosa canelicit regional cell-mediated and also humoral (IgA) immune responses, but notnecessarily systemic immunity. The host has multiple immune defense functionsthat can remove virus and/or viral disease.

Humoral Immunity: Virus and/or virus-infected cells have the right to stimulate Blymphocytes to create antibody (specific for viral antigens) Antibodyneutralization is most efficient when virus is current in large fluid spaces(e.g., serum) or on moist surfaces (e.g., the gastrointestinal and respiratorytracts). IgG, IgM, and also IgA have actually all been shown to exert antiviral activity.Antibody have the right to neutralize virus by: 1) prevent virus-host cabinet interactions or 2)recognizing viral antigens on virus-infected cells which deserve to lead toantibody-dependent cytotoxic cells (ADCC) or complement-mediated lysis. IgGantibodies space responsible for most antiviral task in serum, if IgA isthe most vital antibody once viruses epidemic mucosal surfaces.

Cell-Mediated Immunity: The ax cell-mediated immunity refers to(1) the recognition and/or death of virus and virus-infected cells byleukocytes and (2) the manufacturing of different soluble determinants (cytokines) bythese cell when stimulated by virus or virus-infected cells. Cytotoxic Tlymphocytes, organic killer (NK) cells and also antiviral macrophages can recognizeand death virus-infected cells. Helper T cells have the right to recognize virus-infected cellsand produce a number of important cytokines. Cytokines produced by monocytes(monokines), T cells, and NK cells (lymphokines) play crucial roles inregulating immune functions and developing antiviral immune functions.

Virus-Induced Immunopathology

Immune-mediated an illness may develop in certain virus epidemic in which viralantigens and also uncontrolled immune hypersensitivity come them persist for a longperiod. Immune-mediated condition can be mediated by both humoral andcell-mediated immune functions. Immune-complex syndrome can be mediated byvirus/virus antigen antibody complexes. T cell (cytotoxic and helper) deserve to alsomediate immunopathologic injuries via a variety of mechanisms. Immunopathologycan result from tissue/organ damages via cytotoxic T cells, inflammation inducedvia cytokines, antibody to add complement, antibody-antigen complexes and/orADCC.

Roles that Immune Functions during Viral Infections

The early, nonspecific responses (nonspecific inhibition, herbal killer cellactivity, and interferon) border virus multiplication during the acute step ofvirus infections. The later specific immune (humoral and also cell-mediated)responses role to aid eliminate virus at the end of the acute phase, andsubsequently to maintain certain resistance to reinfection.


The general principles of immunology room presented in thing 1. The present chapter discusses viral activation ofimmunity, humoral and cell-mediated immunity, virus-induced immunopathology, androles the immune functions during viral infections.

Viral Activation the Immunity

The term immunity as supplied in this thing covers the mechanisms whereby a organize mayspecifically recognize and also react come viruses. The nonspecific defenses space consideredin chapter 49. The hold immuneresponse might be beneficial, detrimental, or both. One immune an answer to a virusappears very first during the main infection that a susceptible, nonimmune organize (Table 50-1) and increases throughout reinfectionof an immune host. The specific immune responses that space effective versus virusesare (1) cell-mediated immunity involving T lymphocytes and also cytotoxic effector Tlymphocytes, (2) antibody, with and also without its communication with enhance andantibody-dependent cell-mediated cytotoxicity (ADCC), (3) natural killer (NK) cellsand macrophages, and (4) lymphokines and monokines (Fig. 50-1). Some of these immune functions may interact, oftensynergistically, with nonimmune defense mechanisms (see Ch. 49).



Figure 50-1

The immune system solution to a virus. (1) Virus bearing an antigenic epitope. (2) processing of antigen tofragments. (3) Presentation that antigen (Ag) to T cells (on the infectedcell surface) and also B cells (free antigenic pieces or viruses). (4 and 5)Regulator (more...)

Viral Antigens

The degree to which famous antigens room exposed to the host immune defenses isgoverned by the intracellular replication that viruses and by the numerous possibletypes the virus-host cell communication (Fig.50-2; see likewise Ch.1).


Figure 50-2

Virus-host cell interactions. The level to which viral antigens are exposed to the organize immunedefenses is administer by the obligate intracellular replication ofviruses. This exposure different according to the virus-host cellinteractions presented here; i.e., (more...)

Acute Cytolytic Infection

Acute cytolytic infection, the most common kind of virus-host cabinet interaction(Fig. 50-2a-c), results in damage of the infected cell. Thereare three methods in which the immune system have the right to encounter the virus orvirus-specific antigens the cytolytic viruses. In part cases, the immune systemencounters famous antigen only as soon as cell lysis release the virions (Fig. 50-2a). Many viruses (e.g.,reoviruses and also coxsackieviruses), however, likewise induce virus-specific antigenson the cabinet surface before cell death occurs and also sometimes prior to viralmultiplication is complete (Fig. 50-2b).In the third kind of cytolytic epidemic (Fig.50-2c), common amongst enveloped viruses (e.g., herpesviruses,poxviruses, paramyxoviruses), virus-specific antigens are existing on the cellsurface and also the cells release the transmittable virions by budding for a shortperiod prior to cell death. This viruses (e.g., herpesviruses, poxviruses, andparamyxoviruses) occasionally are disseminated by contiguous spread out from cabinet tocell without exposure come extracellular antibody. Cell-mediated immune responsesare believed to be important in managing the local spread the this kind ofinfection.

Persistent Infections

Some viruses produce a chronic (steady-state) infection rather than an acuteinfection that the organize cell: progeny virions are released continuously, withlittle adverse result on cellular metabolism. This cells to express virus-specificantigens on your surface and produce abundant virus progeny, yet are no killedby the transmittable process. In some steady-state infections the progeny virus isreleased through budding v the cabinet membrane, and virus deserve to spread from cell tocell without gift exposed to the extracellular environment. DNA viruses execute notproduce steady-state infections, however some RNA viruses (paramyxoviruses andretroviruses) do.

Latent Infections

Latent infections result when an infecting virus (e.g., a herpesvirus) ismaintained within a cell because that a long time (sometimes years) without giving riseto progeny virus or damaging the cell. Cells infected in this means may expressvirus-specific antigens on their cell surface. Months to years after infection,the virus in this cells can be reactivated, replicate, and cause disease. Themechanisms whereby viruses are maintained intracellularly for long periods andthen reactivated are only incompletely understood. Many latent epidemic occurin sequestered locations of the body (such together the concerned system), where recognitionof infected cells by the immune device is believed to be difficult. In addition,any cell that harbors a virus but does not express viral antigens is notrecognized through the immune system.

Integrated Virus Infection

There is another form of persistent virus-host cell interaction, integrated virusinfection, in which every or part of the famous nucleic mountain becomes integratedinto the genome that the hold cell. Progeny virions may never it is in assembled orreleased indigenous the hold cell. New virus-specific antigens, however, can bedetected in ~ the cell or ~ above the cabinet surface. Infection v retroviruses isa standard example of this mechanism.

In most cases, the immune system is activated since the virus and also its antigensappear in the extracellular liquid or on the cell membrane.

Virus Spread

Another important consideration in how viral infections trigger an immuneresponse is the method in i m sorry a certain virus spreads in the host. In animalhosts, four varieties of famous spread space recognized: (1) neighborhood spread, in i beg your pardon theinfection is confined mainly to a mucosal surface or body organ (as in infection ofthe respiratory tract epithelium through rhinoviruses or the the cradle epitheliumby rotaviruses); (2) main hematogenous spread, in i beg your pardon the virus isinoculated straight into the bloodstream (e.g., insect-transmitted viruses) andthen disseminates to target organs; (3) secondary hematogenous spread, in whichthe initial virus infection and replication (often fairly asymptomatic)occur on a mucosal surface ar with subsequent dissemination to target organs viathe bloodstream (e.g., usual viral exanthems, poliomyelitis, and mumps); and(4) nervous system spread, in which viruses (such together herpesviruses andrabiesviruses) pecking via the concerned system. Therefore, viral antigens maybe existing in various parts of the body relying on the course of spread andphase the infection. Various immune mechanisms might operate in ~ the various sitesof virus spread and infection .

Virus Location

The location of the virus in the host is necessary not only for knowledge theimmune response, but additionally for developing and administering a vaccine. Forexample, local infections on surfaces such together the mucosa of the respiratory tract orgastrointestinal tract may elicit neighborhood cell-mediated and humoral (IgA) immuneresponses, yet not necessarily systemic immunity. The reverse is additionally true:systemic immune does not constantly lead to local mucosal immunity. For example,the Salk polio vaccine, which consists of eliminated virus administeredsystemically, elicits serum IgG together the significant antibody and also induces little or nosecretory response. As a result, the immunized separation, personal, instance resists systemicinfection, yet may end up being a short-lived carrier, with virus persisting at theintestinal portal the entry because of the lack of secretory antibody. The orallyadministered, live Sabin polio vaccine, top top the other hand, induces secretoryantibody in the intestine and also is effective in staying clear of replication andsubsequent mucosal penetration by the virus.

Multiplicity of Immune Defenses

Recent studies have revealed a good complexity of hold immune defenses againstviral infections. This complexity arises from the many contents of the hostimmune defenses and also their interactions v one another. The presence of avariety of defenses is not surprising in see of the diversity of viruses,hosts, routes of infection, human body compartments, cells, and mechanisms of virusmultiplication and also spread. The instance is further complicated by the varyingeffectiveness the the different host defenses throughout the different phases the theprimary viral epidemic (implantation, infect target organs, and also subsequentrecovery of each of the infected tissues), as well as during resistance toreinfection. Furthermore, the activated host defenses have the right to actually cause diseasemanifestations. The visibility of many defenses against each infection helpsexplain why impairment of one or a few defenses go not completely abrogate hostresistance to viral infections. Numerous immune and nonimmune hold defenses mayoperate to manage viral epidemic or, at times, include to the diseaseprocess.

Many the the immune defenses against viral intrusion are reasonably well understood,but the relative effectiveness of each requires added research. Inparticular, together this thing attempts to do clear, humoral and cell-mediatedimmunity room not independent, yet interact intimately to influence the durationand magnitude of each form of immune response.

Humoral Immunity: B Lymphocytes

As described in thing 1, specificB lymphocytes answer to viral antigen presented by immunization or infection.Binding the antigen come the cell surface ar immunoglobulin receptors, adhered to byinteraction the the B cell with macrophages and also helper T lymphocytes, reasons theB cell to identify into clones the antibody-secreting plasma cells, eachcapable that secreting antigen-specific immunoglobulin of one of five majorclasses: IgG, IgM, IgA, IgD, and also IgE (Fig.50-1). Antitoxin act versus viruses generally by binding come andneutralizing virions and by directing the lysis that infected cells by complementor killer leukocytes.

Neutralization that virion infectivity

At the very least three immunoglobulin classes have been demonstrated to exertantiviral activity: IgG, IgM, and IgA. These antibodies have the right to neutralize theinfectivity of virtually all well-known viruses. Antibody binds to the virusextracellularly, one of two people neutralizing it immediately or prevent itsinteraction with host cells. Antibody that has bound to virus have the right to block theinfection that a cell at among three steps: (1) attachments of virus to thecell surface, (2) penetration of virus right into the cell, and (3) uncoating ofvirus inside the cabinet (Fig. 50-3).The device of famous neutralization requires the binding of antibody tovirus cloak proteins; this usually changes the viral receptor for the targetcell. Much more rarely, tied antibody may also interfere v penetration oruncoating.


Figure 50-3

Mechanisms of virus neutralization through antibody in ~ thecellular level. In ~ the to move level, antibody have the right to block the complying with stepsassociated through a virus infection: (1) virus attachments andadsorption to the cabinet surface, (2) penetration of the virusinto (more...)

The precise mechanism the neutralization is unclear, but it more than likely involveschanges in the steric configuration of the virus surface. Theseantibody-virus interactions have the right to take place separately of complement.

Antibody additionally can neutralize virus by resulting in aggregation (Fig. 50-4), thus preventing adsorptionof virus to cells and decreasing the variety of infectious particles.Antibody and complement exhilaration together can inactivate specific viruses (inmost cases, enveloped viruses). Antibody is most effective versus virus inlarge liquid spaces (e.g., serum) and on moist body surfaces (e.g., therespiratory and also gastrointestinal tracts), where the virus is exposed toantibody because that a reasonably long duration before escaping into cells.Consequently, viruses that spread out by viremia are successfully eliminated bylow level of circulating antibody. Much higher levels that antibody areneeded to prevent the spread of viruses that perform not take trip in the bloodplasma (such together herpesviruses and rabiesviruses), because these virusesspend only a brief duration traversing the little extracellular spaces betweencells in solid tissue.

Figure 50-4

Extracellular neutralization that virus through antibody. Antibody have the right to reduce the number of infectious corpuscle by linkingvirions and thereby bring about aggregation. Antibody alone or withcomplement can likewise inactivate viruses.

Besides binding directly to virus, antitoxin may boost phagocytosis. Threetypes of antibody interactions with phagocytic cells are seen: directbinding that antibody to the surface of the phagocytic cell (cytophilicantibody), uptake of antigen antibody complexes through the Fc receptor, anduptake of antigen-antibody-complement complexes v the C3b receptor(see Ch. 1). This phagocytosisof virions may an outcome in inactivation the virus (see Ch. 49), and also in the activationof the phagocytic cabinet which can lead to cytokine production.

Antibody impacts on virus-infected cells

Antibody additionally can action on virus-infected cell by recognizing virus-specificantigens on the surface ar of infected cells (Fig. 50-3). Complement can then cause lysis of this cells. Thiscomplement-mediated lysis wake up both by the classic and also the alternativecomplement pathways. Antibody-coated infected cells likewise can be damaged byvarious effector cell via ADCC. Alternatively, however, part antibodies canmask viral antigens on the surface of infected cells, thereby removing orcovering antigens top top the surfaces of these infected cells.

Physical barriers to antibody

Before antibody can integrate with and neutralize the virus, it need to reach thesite that virus replication. Barriers to the circulation of antibody includethe cabinet membrane, i beg your pardon excludes antibody, and anatomic organization barriers,which border the distribution of macromolecules into certain organs such asthe main nervous system.

IgG Antibodies

IgG is the most thoroughly studied antibody class and also is responsible because that mostantiviral activity in serum. IgG antibodies with infected (inflamed) sitesby transduction (leakage) indigenous capillaries. IgG is specifically protectivein generalized viral infections that have actually a viremic step (e.g., measles,polio, and also hepatitis), perhaps since virions in serum space exposed toantibody. IgG antibodies are transferred passively from mother to offspringthrough the placenta and also usually carry out temporary security againstgeneralized viral infections during the very first 6 to 9 month of life.Antibody is most protective when present before infection or during thespread that virus to target organs.

Production and also the roles of antibody classes

After immunization or infection v viruses, miscellaneous classes that antibodyappear sequentially. For example, during primary epidemic or immunization,most antigens an initial elicit IgM (early antibody) responses; IgA and also IgGresponses follow within a few days. Reinfection, in contrast, stimulatesproduction largely of IgG, although part IgM and also IgA are generated. Once theprimary antigenic stimulation is in the respiratory tract or gastrointestinaltract, IgA antibody is predominant, add by some IgM. Theseantibodies are secreted locally at mucosal surfaces and also are crucial inprotecting the host versus localized surface viral epidemic such as thecommon cold, influenza, and enteric famous infections. As soon as viral replicationis confined come a mucosal surface, resistance to epidemic is determinedprimarily by secretory IgA; serum IgG antibody offers less protection.Viral epidemic that begin on a mucosal surface and also then spreadhematogenously (e.g., measles, rubella, and also polio) can be prevented at themucosal phase by local secretory antibody and also at the viremic phase by IgGantibodies. If serum IgG just is induced in a host, hematogenous spread out canbe prevented, yet viral replication quiet may happen on the mucosalsurface.

IgE antibodies and immediate hypersensitivity

Recent information argues that viruses that tie to IgE antibodies maytrigger instant hypersensitivity responses through the release ofvasoactive mediators (see Ch.1). This observations might explain numerous of the noticeable allergicmanifestations, such as wheezing and also urticaria, that accompany some viralinfections.


Complement enhances the phagocytosis of countless viruses. This enhancedphagocytosis is due to coating (opsonization) the virions by match or bycomplement bound come antibody. Complement likewise can neutralize virus byenhancing one of two people antibody-mediated steric alters on the virus oraggregation of the virus via antibody. In addition, match can directlyinactivate antibody-coated, sheathe virions.


A tiny minority of patients through impaired B-lymphocyte function(hypogammaglobulinemia limited to special needs of humoral immunity) have asignificantly increased frequency of major poliovirus and enterovirusinfections of the nervous system (in enhancement to an ext frequent and severeinfections through pyogenic bacteria). The hazard of central nervous systeminvasion is concerned the duration of viremia, as has actually been presented inimmunosuppressed animals. The food of most viral epidemic is typicallybenign in many of these hypogammaglobulinemic patients, describe thattheir weak antibody response and other defense mechanisms might be effective.The advancement of normal specific resistance to reinfection inhypogammaglobulinemic patients might result, in part, from their abilityeventually to develop low level of serum antibody to virus, as well as fromthe action of their intact cell-mediated immune system.

Cell-Mediated Immunity

Cell-mediated immunity (CMI) was once thought to it is in mediated solely by Tlymphocytes; however, the is currently clear the it is mediated by a selection of celltypes, cell factors, or both. Virus-infected or virally changed cellsactivate strong cell-mediated immune responses (Fig. 50-1). For part viral infections, cell-mediated immunereactions might be an ext important 보다 antibody in beforehand termination of viralinfection and also prevention of dissemination within the host. Recent proof showsthat cell mediated immunity features at the body surfaces, as well asinternally. Cell-mediated immune responses to viral infections indicate Tlymphocytes, ADCC, macrophages, natural killer (NK) cells, lymphokines, andmonokines (Figs. 50-5 and also 50-6).

Figure 50-5

Lysis of virus-infected cell by cytotoxic effector cells. Cytotoxic effector cells the can damage virus-infected cellsinclude cytotoxic T cells, natural killer cells, and also activatedmacrophages. Cytotoxic T lymphocytes have the right to recognize and destroyvirus-infected (more...)

Figure 50-6

Cell-mediated events in viral infections. Soluble mediators encompass immune interferon, chemotactic factors,macrophage migrate inhibitory factor, and lymphotoxin; otherlymphokines and also monokines are not depicted. Cytotoxic effectorlymphocytes, macrophages, (more...)

T Lymphocytes

Much evidence indicates the T lymphocytes are important in restore from viralinfections. That the plenty of functional subsets the T cells, those the expressspecific cytotoxic task against virus-infected or revolutionized cells havearoused the most interest.

Cytotoxic T lymphocytes

The generation of virus-specific cytotoxic T lymphocytes (CTLs) is believedto be crucial in staying clear of viral multiplication (Fig. 50-5). Presumably, the T lymphocytes preventvirus multiplication by ruining infected cells before mature, infectiousvirus particles have the right to be assembled. This hypothesis assumes the viralantigens appear on the plasma membrane prior to the relax of virus progeny,a check out that is substantiated by researches of many, however not all,infections.

Exposure to a virus-infected cabinet can reason the antigen-specific Tlymphocytes to identify into cytotoxic effector T cells, which can lysevirus infected or virally transformed cells. This cytotoxic T cell arespecific not only for the viral antigen but also for me majorhistocompatibility antigens and will lyse virus-infected cells just if thesecells likewise express the correct significant histocompatibility facility (MHC) geneproducts.

Activation of cytotoxic and other T lymphocytes may be one of the earliestmanifestations of one immune response. T-cell effector attributes occur asearly together 3 to 4 work after initiation the a viral infection. However, T-cellresponses frequently decrease rapidly, in ~ 5 come 10 work of removed of thevirus (although virus-specific storage T cells persist for lengthy periods). Incontrast, antibodies usually come to be measurable later on in the famous infection(after 7 days) and also persist in ~ high levels for much much longer (often foryears).

Helper T cells may be as crucial as cytotoxic T cell in the immuneresponse to a virus infection. Helper T cells are compelled for thegeneration that cytotoxic T cells and for optimal antibody production. Inaddition, helper T cells, and cytotoxic T cells produce a number ofimportant soluble determinants (lymphokines) that have the right to recruit and also influence othercellular materials of the immune and also inflammatory responses.

Animal studies indicate that impairing the T-cell defenses enhancesinfections by herpes simplex virus, poxviruses, and Sindbis virus andenhances the advancement of tumors induced by polyomavirus. Since the hostretains some resistance come infections, T lymphocytes more than likely are not thesole defense against these viruses. Disability of T lymphocytes additionally hindersT cell-dependent antibody production. In humans, T-cell special needs isassociated largely with more frequent and severe poxvirus and also herpesvirusinfections. Nevertheless, these infections still carry out not construct in mostindividuals through T-cell deficiencies, also though the pervasiveness ofherpesviruses (and many other viruses) is great.

Antibody-Dependent Cell-Mediated Cytotoxicity

Effector leukocytes because that ADCC have surface receptors the recognize and bind tothe Fc part of IgG molecules. Once IgG binds to virus-specified antigens onthe surface of an infected cell, the Fc part becomes a target because that effectorcells capable of mediating ADCC . Binding of this effector cell to the Fcportion of IgG bound to the infected-cell surface antigens outcomes in lysis ofthe infected cell. ADCC is a an extremely efficient method of lysing virus-infected cellsbecause the requires significantly less antibody 보다 does antibody-complementlysis.

Lymphocytes, macrophages, and neutrophils space all capable of mediating ADCCagainst virus infected cells. The lymphocytes through this capability appear to beheterogeneous. Herbal killer cells, and null lymphocytes through Fcreceptors for IgG, appear to have the ability to mediate ADCC activity.


Macrophages are vital in both particular and nonspecific responses to viralinfections (e.g., herpesvirus infections). Components that change macrophageactivity have the right to influence the outcome of one infection. Moreover, due to the fact that macrophagesare main to the induction of T and B lymphocyte responses, any effect onmacrophages will affect B and T cells.

Macrophages confer protection versus viruses v either an intrinsic or anextrinsic process. In the former, virions room disposed of in ~ macrophagesacting either as phagocytes or together nonpermissive host cells. In the latter case,macrophages retard or ablate virus multiplication in bordering cells bydestroying virus-infected cell or by developing soluble components (interferons)that action on this cells. Phagocytosis of some viruses through macrophages decreasesvirus levels in body fluids (as during viremia) and thereby impedes virusspread. These impacts are created only if the virus is destroyed or containedby macrophages. If a virus replicates in macrophages, the infected macrophagesmay assist in transmission of the virus to various other body cells. The permissiveness ofmacrophages for virus replication may depend on the age and genetic constitutionof the host and on the specific condition that the macrophages.

Macrophage activation mediated one of two people by assets of epidemic (viral andcellular) or by soluble factors developed by T cells (e.g., gamma interferon)often boost phagocytosis and the elimination of complimentary virus particles. Anotherimportant effector device of triggered macrophages is their capacity torecognize and destroy virus-infected and also virus-transformed cells (Fig. 50-5). In addition, activatedmacrophages get involved in virus inhibition by creating cytokines (interferon,etc.) and also mediating ADCC.

Natural Killer Cells

Natural killer (NK) cells exhibit cytotoxic activity against a number of tumorcell lines, specifically against virus-infected or virus-transformed cells(Fig. 50-5). Organic killer ornatural killer-like cells, which have been uncovered in almost every mammalianspecies examined and even in some invertebrates, are determined as largegranular lymphocytes that possess Fc receptors. They deserve to mediate ADCC activity;their nonspecific cytotoxic task is increased by interferon andinterleukin-2 (IL-2); and they can create a variety of different cytokinesincluding interferon when stimulated with virus or virus-infected cells.

Although organic killer cells screen cytotoxic activity against virus-infectedor transformed cells, lock show small or no cytotoxic activity against normalcells. Unlike that of cytotoxic T lymphocytes, herbal killer cabinet killing isnot human being leukocyte antigen (HLA) restricted, and also natural killer cells do notexhibit standard immunologic specificity. Over there is evidence that naturalkiller cells play critical defensive role in virus epidemic in people andanimals. Their importance is believed to be as result of their ability to producecytokines and to kill virus-infected cells.

Lymphokines and Monokines

Soluble factors from T lymphocytes (lymphokines) and also macrophages (monokines)regulate the degree and duration of the immune responses produced by Tlymphocytes, B lymphocytes, and macrophages (see Ch. 1). Interleukin-2 and also gamma interferon room two suchimportant factors created by triggered T cells. Interleukin-l is a solublefactor developed by macrophages. All 3 of these components are important for thefull differentiation and proliferation of cytotoxic T cells. The twointerleukins are additionally important for antibody manufacturing by B lymphocytes.

Macrophages and also T lymphocytes likewise produce several various other important determinants thatact in both the immune and also the inflammation responses. Gamma interferon canactivate macrophages to end up being cytotoxic toward virus-infected cells and also canincrease the level the phagocytosis and degradation. Lymphotoxins created by Tcells additionally may take part in the destruction of virus-infected cells. Virus canstimulate alpha interferon production from macrophages; this improves naturalkiller cell role and inhibits virus multiplication in neighboring cells.

Virus-Induced Immunopathology

A host plainly has plenty of mechanisms come recognize and eliminate the viruses that itencounters. However, part viruses persist in spite of these mechanisms, and also then theimmune responses may end up being detrimental come the host and also cause immune-mediateddisease. As soon as an antigen (virus) persists, pathologic changes and also diseases resultfrom different species of immunologic interactions, consisting of immediatehypersensitivity, antibody-mediated immune complex syndrome, and tissue damagecaused through cell-mediated effector cells and also antibody plus complement. The thesemechanisms, the immune facility syndrome throughout viral infections has been studiedmost intensively. Two significant complications of deposition that immune complexes arevascular damage and also nephritis. Part viral diseases in i m sorry immune complexes havebeen demonstrated space hepatitis B, transmittable mononucleosis, dengue hemorrhagicfever, and also subacute sclerosing panencephalitis.

Cytotoxic T cells also mediate immunopathologic injury in murine models the humaninfections (i.e., infections v lymphocytic choriomeningitis virus andpoxviruses). Both cytotoxic T cells and T cell responsible because that delayed-typehypersensitivity have likewise been implicated in the pathology associated withinfluenza pneumonia and also coxsackievirus myocarditis that mice. A delicate balancebetween the removed of infected cell that space the source of viral progeny andinjury to critical cells more than likely exists for T cells as well as for the other hostimmune components.

Viruses might sometimes circumvent organize defenses. An important factor that might impairthe function of sensitized T lymphocytes is obvious from the monitoring that Tcells set off by reaction through antigen or mitogen shed their typical resistance tomany viruses. Therefore, these caused T lymphocytes build the capacity tosupport the replication the viruses, top to impairment of T lymphocytefunction.

Roles the Immune functions during Viral Infections

On the basis of the mechanisms defined here and also in thing 49, a hypothetical model deserve to be constructed thatshows just how the immune materials defend against viruses (Fig. 50-1; Table50-1).

Nonspecific Defenses

A major infection in a nonimmune, susceptible host is countered first by thenonspecific defense mechanisms (see Ch.49 ). The beforehand nonspecific responses take place within hours and also consistof interferon production, inflammation, fever, phagocytosis, and natural killercell activity. This defenses may prevent or abort infection; if they carry out not,the virus is disseminated by local spread, viremia, or nerve spread. It then mayseed come a number of target organs and also thereby develop a generalizedinfection.

Specific Defenses Antibody

The occasions that lead to a particular immune an answer begin virtually immediately afterexposure and result in the production of antiviral antibody and cell-mediatedimmunity in 3 to 10 days. The disseminated antibody solution in serum ispredominantly IgG (preceded by IgM); the local antibody an answer in secretionsis mostly secretory IgA (with some IgM). The persistence of IgAantibodies in secretions is much shorter (months) than the persistence that IgGantibody in serum (years). The duty of IgE in secretions is unknown, however it maymediate prompt hypersensitivity and amplify the immune response duringinfection. Antibodies might neutralize virus directly or ruin virus-infectedcells via ADCC or complement. Clearly, serum antibody confers security againstgeneralized epidemic (e.g., measles, polio, and form A hepatitis), in whichvirus should spread through the antibody-containing bloodstream; inoculation ofsmall quantities of antibody right into susceptible individuals stays clear of viral diseasebut might not stop subclinical infection at mucosal surfaces.

In localized epidemic of mucosal surfaces, security does no correlate withthe existence of serum antibody, however it does correlate v the presence of localIgA antibody, as has been presented in person studies the viruses limited to therespiratory street (e.g., respiratory tract syncytial virus and influenza virus) or tothe gastrointestinal street (e.g., enteroviruses). Under some problems in whichserum antibody is present yet local IgA is absent, hypersensitivity rather ofprotective immunity may take place (e.g., respiratory tract syncytial virus infection).Also, serum antibody might not protect versus recurrence of implicit infections,such as herpes zoster (shingles) and herpes simplex, both because the virus perhaps shielded by its intracellular location and also because cell-mediated immunity probably the an ext important defense. Antibody may additionally cause undesirable effects incertain chronic infections. Examples in which little amounts of serum antibodycomplex with virus and also deposit in the kidneys, in order to inducing immune complexdisease, are provided in Table 50-1.

Therefore, serum IgM and also IgG antibody seem come be reliable in preventinginfections the a generalised nature; however, in localized surface infections thepresence the secretory IgA antibody shows up to correlate much far better withprotection than the presence of turn around IgG antibody. In persistentinfections, serum antibody may be responsible for specific long-termsequelae.

Cell-Mediated Immunity

Cell-mediated immunity is important in recovery from and control that viralinfections, especially infections including oncogenic viruses or viruses thatspread straight from cabinet to contiguous cell. In these instances antibodycannot with the virus however virally induced antigens on the surface ar of theinfected cell have the right to be well-known by various effector cells (e.g., cytotoxic Tcells) (Fig. 50-6).

If the virus get target organs, that is more challenging to control. The hostdefenses that might play important roles in target organs are initiallyinflammation, fever, and also interferon and also subsequently cell-mediated immunity.

In part situations, cell-mediated immunity might develop prior to antibody productionbegins. Because that example, cytotoxic effector T cells have actually been uncovered in bronchialwashings 3 come 4 job after initiation of intranasal epidemic in mice; in ~ thistime, antibody cannot yet be detected.

Cell-mediated immune responses can cause tissue damage; the lung lesions producedin influenza might be examples. The lethal results of lymphocytic choriomeningitisvirus in mice room mediated through cytotoxic effector T cells. The rashes in manyexanthems (such together measles) is thought to stand for a cell-mediated assault onvirus localized within cell of the dermis and also its vasculature.

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Baron S, Grossberg SE, Klimpel GR, Brunell PA:Mechanisms of action and pharmacology: the immune and also interferon systems. InGalasso G (ed): Antiviral Agents and also Viral diseases of Man. Crow Press, NewYork, 1984 .