Viruses are strongly immunogenic and induces 2 types of immune
responses; humoral and cellular. The repertoire of specificities
of T and B cells are formed by rearrangements and somatic
mutations. T and B cells do not generally recognize the same
epitopes present on the same virus. B cells see the free
unaltered proteins in their native 3-D conformation whereas T
cells usually see the Ag in a denatured form in conjunction with
MHC molecules. The characteristics of the immune reaction to the
same virus may differ in different individuals depending on their
genetic constitutions.
Humoral response is responsible for blocking the infectivity
of the virus (neutralization). Those of the IgM and IgG class are
especially relevant for defense against viral infections
accompanied by viraemia, whereas those of the IgA class are
important in infections acquired through a mucosa. (the nose, the
intestine) In contrast, the cellular response kills the
virus-infected cells expressing viral proteins on their surfaces,
such as the glycoproteins of enveloped viruses and sometimes core
proteins of these viruses.
Humoral Response
Abs are elicited by the surface components of intact virions
as well by the internal components of disrupted virions. Also
they are elicited by viral products built into the surface of
infected cells or released by the cells. Antibodies provide the
key to protection against many viral infections. Sometimes, they
are also pathogenic e.g. immune complexes are thought to be
responsible for causing the rash in rubella. Interactions of
virions with Abs to different components of their coats have
different consequences.
Neutralization
virus neutralization consists of a decrease in the infectious
titre of a viral preparation following its exposure to Abs. The
loss of infectivity is bought about by interference by the bound
Ab with any one o the steps leading to the release of the viral
genome into the host cells. the consequences of the virion-Ab
interaction therefore depends on many factors;-
- The structure of the virions
- The target of the Ab e.g. Abs against the HA but not the NA of influenza virus are neutralizing.
- Mutations affecting surface molecules that may alter the susceptibility to certain Abs
- The type of Ab, especially its affinity for the components of the virions
- The number of Ab molecules attached to the virions
Reversible neutralization - The neutralization process
can be reversed by diluting the Ab-Ag mixture within a short time
of the formation of the Ag-Ab complexes (30 mins). It is thought
that reversible neutralization is due to the interference with
attachment of virions to the cellular receptors. The process
requires the saturation of the surface of the virus with Abs.
Stable neutralization - with time, Ag-Ab complexes
usually become more stable (several hours) and the process cannot
be reversed by dilution. Neither the virions nor the Abs are
permanently changed in stable neutralization, for the unchanged
components can be recovered. The neutralized virus can be
reactivated by proteolytic cleavage. Intact Abs can be recovered
by dissociating the Ab- Ag complexes at acid or alkaline pH.
Stable neutralization has a different mechanism to that of
reversible neutralization. It had been shown that neutralized
virus can attach and that already attached virions can be
neutralized. The number of Ab molecules required for stable
neutralization is considerably smaller than that of reversible
neutralization, Kinetic evidence shows that even a single Ab
molecule can neutralize a virion. Such neutralization is
generally produced by Ab molecules that establish contact with 2
antigenic sites on different monomers of a virion, greatly
increasing the stability of the complexes.
Virion sites for neutralization - only epitopes on
molecules involved in the release of the viral genome into the
cells are targets of neutralization. In influenza viruses, only
the HA and not the NA are targets for neutralization. In
polioviruses, all antigenic sites recognizable on the capsid are
targets for neutralization, because the capsid is a unit for
releasing the nucleic acid. For adenoviruses, the main targets
are the hexons rather than the pentons, as the hexons are
strongly interconnected and work together for the release of the
viral DNA. Occasionally, Abs bound to non-neutralizing epitopes
can be detected by neutralization in the presence of complement,
whereby the viral enveloped is attacked by the complement
cascade.
Protective role of neutralizing antibodies - the
neutralizing power of a serum usually reflects the degree of
protection in an infected animal. The correlation, however, is
not always perfect. Discrepancies may be generated by differences
in the neutralizability of a virus in the cells used for assay in
vitro compared to those that the virus infects in vivo. e.g. the
sera of mice protected from yellow fever did not neutralize the
virus in vero cells but did so in a mouse neuroblastoma cell
line. Another possible reason for discrepancy is that an Ab that
does not neutralize in cultures may act in vivo by activating
host responses against the virus or virus-infected cells. e.g.
complement or macrophages. In addition, neutralizing Abs may fail
to protect because rapid viral multiplication overcomes the
neutralizing power. In the early period of immunization, low
affinity Abs act predominantly by activating complement and have
low neutralizing power in cultures. The degree of neutralization
in cultures is probably best estimated by carrying out
neutralization in the presence of complement.
Evolution of viral antigens
Viral evolution must tend to select for mutations that change
the antigenic determinants involved in neutralization. In
contrast, other antigenic sites would tend to remain unchanged
because mutations affecting them would not be selected for and
could even be detrimental. A virus would thus evolve from an
original type to a variety of types, different in neutralization
(and sometimes in HI) tests, but retaining some of the original
mosaic of antigenic determinants recognizable by CFTs.
These evolutionary arguments are consistent with the
observation that the clearest differentiation of types within a
family is present in viruses of rather complex architecture, in
which the Ags involved in the interaction with the cell vary more
than other proteins. Thus enveloped viruses have a
strain-specific envelope but a cross-reactive internal capsid;
adenoviruses have type-specific fibers and family-specific (and
also type-specific) capsomers. Moreover, the C Ag of
polioviruses, which appears only after heating, reveals antigenic
sites that are normally hidden and hence are not affected by
selective pressure. The extent of antigenic variation differs
widely among viruses and is most extensive with lentiviruses and
influenza viruses.
Types of virus-specific antibodies
Different types of viral preparations elicit the formation of
different Abs;-
- Killed virus preparations elicit Abs predominantly directed against the surface of the virions. These Abs have neutralizing and HI activities against the virions as well as CF and precipitating activities against the Ags of the viral coat.
- Live virus preparations elicit antibodies against all the viral antigens, including both external and internal antigens.
- Immunization with internal components of the virions produces CF and precipitating Abs active only toward the Ags of these components.
- Immunization with peptides reproducing segments of virion proteins elicit Abs, the properties of which depend both on the protein and the specific sequences reproduced.
Specificity of test methods
The Abs that react in the different tests may overlap though
they may not be altogether identical. Neutralization is primarily
caused by Ab molecules specific for the sites of the virion that
are involved in the release of viral nucleic acid into the cell.
CF usually involves additional surface or internal Ags.
Neutralization probably requires molecules with a higher affinity
for virions than do HI and CF. After viral infection, the titres
of Abs to different components rise and fall with quite different
time courses.
Because of their high specificity, immunological methods can
differentiate not only between viruses of different families but
also between closely related viruses of the same family or
subfamily. By these means, family Ags may be identified. Usually,
antibodies detected by neutralization tend to be less
cross-reactive and thus are useful in defining the immunological
type. Whereas those detected by CF tend to be more cross-reactive
and the useful in defining the family. By proper procedures,
however, such as immunization with purified Ags, highly specific
CF Abs can be prepared.
The resolving power of Abs is maximized by the use of
monoclonal Abs. Whereas all the methods for measuring viral
antigens are needed for classifying a new isolate, the method of
choice for diagnostic purposes is ELISA, for its high sensitivity
and low cost.
Cell-Mediated Immunity
Cytotoxic T lymphocytes
CMI is very important in localizing viral infections, in
recovery, and in the pathogenesis of viral diseases. In
experimental animals, primary CTLs reach maximal abundance about
6 days after a viral infection and then disappears as infection
subsides. However, memory T cells persists and can be recognized
by culturing spleen cells with virus-infected cells where within
a few days, secondary CTLs appear in culture with much greater
activity than in the initial response.
Formation of CTLs is elicited by cell-associated Ags present
at the cell surface, not only for enveloped viruses, but also for
other viruses whose core or nonvirion proteins reach the cell
surface. As in humoral immunity, type specific and group specific
responses can be seen. Even noninfectious or inactivated viruses
can elicit a cellular response because their envelopes fuse with
the cell plasma membrane in the initial stage of viral
penetration. Moreover, the virions themselves may also be able to
elicit the response after absorbing to the macrophages. Both
internal virion proteins and nonvirion proteins are often
recognized by CTLs. An example is the nucleocapsid proteins of
enveloped viruses, fragments of which reach the cell surface by
an unknown route and are recognized very efficiently, giving rise
mainly to cross-reactive CTLs. Often, Abs to viral surface
proteins do not block their interaction with CTLs, because the
humoral and cellular responses recognize different epitopes.
Antibody-dependent cell-mediated cytotoxicity
The K cells are the effector cells in ADCC. In vitro, these
cells kill virus-infected cells sensitized by IgG from immune
donors but not unsensitized targets. ADCC is very efficient in
vitro against HSV or VZV infected cells, preventing the usual
spread of the virus from infected to neighboring uninfected
cells. Therefore, it may play a role in the defense against human
infection with these viruses. K cells had been shown to mediate
immunity to vaccinia infection rather than Tc cells.
Natural Killer (NK) cells
In man, the principal NK cell is the large granular lymphocyte
(LGL) which comprise 2-5% of peripheral blood lymphocytes.
However, not all lytic cells are LGLs and not all LGLs are NK
cells. There is overlap of the NK population with K cells. The Fc
receptor of the NK cell is however, not involved in the lytic
process. There are also mechanistic differences and K cell
activity is less consistently augmented by interferon and other
immune modulators. NK activity is subject to both positive and
negative regulation in vivo and in vitro. Interferon gamma and
IL-2 are potent inducers. Besides producing lysis, NK cells can
produce alpha-interferon.
The target molecules recognized but NK cells have not been
defined but it appears that some determinants are ubiquitous
whilst others have a more restricted distribution. An alternative
suggestion is that NK cell susceptibility depends on the absence
of normal cell surface antigens such as MHC molecules. The
importance of NK cells in viral infection is partially
understood. It had been shown that mice depleted of NK cells by
treatment with Ab against asialo GM1 show an increased
susceptibility to CMV.
adapted from: http://virology-online.com/general/Immunology.htm
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