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
(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.
Immune response of host to
virus infections, emphasizing cellular responses
Francis A. Ennis, M.D. Director, Center for
Infectious Disease and Vaccine Research
A. T cell triggered and
cytokine mediated immunopathology.
We
hypothesize that certain virus infections e.g. Dengue Hemorrhagic
Fever (DHF: Immunopathogenesis, click icon), or the Hantavirus
Pulmonary Syndrome (HPS) may be due to "over"responses
of dengue or hantavirus specific T cells in certain high-responders,
due to immune responses genes. These T cell responses are
needed for clearance of virus-infected cells but marked inflammatory
responses probably mediated by cytokines, cause endothelial
cell leakness and shock (DHF) or pulmonary edema (HPS). We
are defining CD4+ and CD8+ T cell epitopes, determining the
Th1 and Th2 cytokine responses at the protein and m-RNA levels
and by immunocytochemistry. TCR usage is determined, and correlations
with disease phenotypes are studied.
B. Failure to Eliminate Virus in HCV Infection
Failure of immune response to eliminate HCV infection is very
common and chronic progression liver disease frequently results.
Is this due to a poor CD8+ T cell response in those individuals?
We are also developing CD8+ T cell clones from the liver tissues
and blood cells of patients with HCV infections. We will determine
whether interferon therapy which is the only known treatment,
alters the HCV+ CD8+ CTL responses in the patients who respond
to therapy or those that do not. We are also defining Th1,
Th2 cytokine patterns in liver tissues by immunocytochemistry.
