Page 248 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 15 Immunoglobulin Function 229

KEY CoNCEPtS virions from infected cells. Nonneutralizing antibodies, or
Virus Neutralization neutralizing antibodies at suboptimal concentrations, have been
found in some instances to enhance the infection of host cells
• Antibodies can neutralize (decrease the replication of) viruses by by virus (e.g., HIV-1 or dengue virus). It should be noted, however,
blocking attachment to the host cell, preventing penetration of the that the clinical relevance of this enhancement, at least in the
host cell membrane, or interfering with uncoating of the virus within case of HIV, remains to be determined. Finally, some nonneutral-
the cell. izing antibodies, or those antibodies that fail to directly neutralize
• Neutralizing antibodies typically recognize proteins or glycoproteins virus in an in vitro assay, can mediate protective effects in vivo,
on the virion surface.
• Some antibodies that bind to virion surface proteins or glycoproteins presumably by engaging antigen-nonspecific effector mechanisms
are not neutralizing. In some cases, such antibodies may contribute (i.e., complement or Fc receptor-bearing cells) or perhaps through
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to immunity, whereas in others, they may enhance infection. cellular signal transduction.
• The magnitude of neutralization mediated by a given antibody may
vary with the host cell used for the measurement. Neutralization of Toxins and Enzymes
• Neutralization in vitro is usually related to protection in vivo, but these
two properties are not always perfectly correlated.
KEY CoNCEPtS
Bacterial Immunity

antibody for a given virus is not an intrinsic property of the • By neutralizing exotoxins, antibodies can prevent disease mediated
antibody but is a property of the relationship between the antibody by bacterial pathogens such as Corynebacterium diphtheria and
and the virus, under defined conditions. Consequently, neutraliza- Clostridium tetani.
tion titers in serum do not always correlate perfectly with protec- • Antibodies alone or with complement-derived split products can
opsonize pyogenic pathogens such as Streptococcus pneumoniae.
tion from infection or disease in vivo. • Through activation of the classical pathway of complement leading
There are several mechanisms by which antibodies can to assembly of the membrane attack complex, antibodies can mediate
inactivate viruses (Chapter 25). The process by which a virus destruction of some bacteria, most notably Neisseria meningitidis and
infects a cell involves multiple steps. These include attachment N. gonorrhoeae.
to one or more membrane components, penetration of or fusion • Antibodies can bind to bacterial adhesins thereby interfering with
with the membrane, uncoating, and genome expression. Although pathogen attachment to mucosal epithelial cells.
the most obvious mechanism of neutralization is prevention of • Antibodies can bind to and inhibit bacterial proteins other than toxins
performing critical metabolic or virulence-related functions.
viral attachment to the host cell surface, some antibodies can
block other steps. For example, neutralizing antibodies for
enveloped viruses, such as influenza virus, have been shown to In many bacterial infections, the clinical consequences of infection
prevent fusion between the virion and cell membranes, and result from toxic molecules liberated by the bacterial cells rather
neutralizing antibodies for poliovirus have been shown to interfere than from the presence of the microorganisms themselves.
with viral uncoating in the host cell. Antibodies to such toxins can provide life-saving protection from
Different isotypes of antibodies may employ different neu- disease while not directly eliminating the bacteria producing the
tralization mechanisms to varying degrees, although this statement toxins. A classic example is infection with Corynebacterium
should not be interpreted to mean that there is a one-to-one diphtheriae, which secretes a potentially lethal exotoxin. A more
correspondence between isotypes and neutralization mechanisms. recent example is the emergence of Clostridium difficile, which
For example, IgG or IgM antibodies in blood can mediate protec- secretes both an enterotoxin (toxin A) and cytotoxin (toxin B).
tion against a virus either directly, in some cases, or with the Not only is there a correlation between antibody titers to toxin
assistance of complement components in others. However, IgA, A and B and prevention of relapse, passive immunotherapy with
the dominant isotype in mucosal secretions, operates under antibody also prevented relapse. 17
conditions where complement is less plentiful than in blood. Bacteria can also produce additional virulence factors, such
Thus virus-specific IgA is more likely to utilize virus-inactivating as enzymes that facilitate spreading of the pathogen through
mechanisms that do not require complement, such as prevention tissues. Host antibodies that inactivate such enzymes can have
of attachment. a beneficial influence on the clinical course. Inactivation of toxins
Traditional thinking maintains that antibody mediates any or enzymes is presumed to result from direct competition between
protective effects extracellularly. However, it has been reported antibody and the target molecule or substrate of the toxin or
that IgA antibodies, being transported by the polymeric Ig enzyme or from the stabilization or induction of conformations
receptor, can mediate protection against intracellular influenza incompatible, to some degree, with the normal function(s) of
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virus. Similar phenomena have been reported for rotavirus the toxin or enzyme. However, recent evidence in mice suggests
and HIV. that the protection afforded by exotoxin-neutralizing antibodies
There are several other notable features of antibody–virus can depend on the presence of Fcγ receptors. 18
interactions. Not all antibodies that bind to molecules on the
virion surface will neutralize the virus in all conditions. For a FUNCTIONS MEDIATED BY ANTIBODY AND
given virus-encoded gene product, such as the influenza virus ADDITIONAL MOLECULES OR CELLS
hemagglutinin, binding of antibodies to some sites, but not others,
will effect neutralization. Some gene products on the virion Complement Activation
surface may fail to routinely support viral neutralization (e.g., Regardless of whether binding of antibody to antigen directly
influenza neuraminidase). However, antibody to influenza mediates protective effects, antibody bound in vivo will activate
neuraminidase, while nonneutralizing, is thought to slow the antigen-nonspecific effector mechanisms. The exact mechanisms
spread of infection by interfering with the escape of progeny will depend on the isotype of the antibody as well as on other