Re: low dose naltrexone

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here goes

Curr Top Microbiol Immunol. 2001;253:219-45. Related Articles, Links


The role of T-cell-mediated mechanisms in virus infections of the
nervous system.

Dorries R.

Department of Virology, Institute of Medical Microbiology and Hygiene,
University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim,
Germany. Ruediger.Doerries@xxxxxxxxxxxxxxxxxxxxxxxx

T lymphocytes play a decisive role in the course and clinical outcome
of viral CNS infection. Summarizing the information presented in this
review, the following sequence of events might occur during acute virus
infection: After invasion of the host and a few initial rounds of
replication, the virus reaches the CNS in most cases by hematogeneous
spread. After passage through the BBB, CNS cells are infected and
replication of virus in brain cells causes activation of the
surrounding microglia population. Moreover, local production of
IFN-alpha/beta induces expression of MHC antigens on CNS cells, and
microglial cells start to phagocytose cellular debris, which
accumulates as a result of virus-induced cytopathogenic effects. Upon
phagocytosis, microglia becomes more activated; they up-regulate MHC
molecules, acquire antigen presentation capabilities and secrete
chemokines. This will initiate up-regulation of adhesion molecules on
adjacent endothelial cells of the BBB. Transmigration of activated T
lymphocytes through the BBB is followed by interaction with APC,
presenting the appropriate peptides in the context of MHC antigens. It
appears that CD8+ T lymphocytes are amongst the first mononuclear cells
to arrive at the infected tissue. Without a doubt, their induction and
attraction is deeply influenced by natural killer cells, which, after
virus infection, secrete IFN-gamma, a cytokine that stimulates CD8+ T
cells and diverts the immune response to a TH1-type CD4+ T
cell-dominated response. Following the CD8+ T lymphocytes,
tissue-penetrating, TH1 CD4+ T cells contact local APC. This results in
a tremendous up-regulation of MHC molecules and secretion of more
chemotactic and toxic substances. Consequently an increasing number of
inflammatory cells, including macrophages/microglia and finally
antibody-secreting plasma cells, are attracted to the site of virus
infection. All trapped cells are mainly terminally differentiated cells
that are going to enter apoptosis during or shortly after exerting
their effector functions. The clinical consequences and the influence
of the effector phase on the further course of the infection depends on
the balance and fine-tuning of the contributing lymphoid cell
populations. Generally, any delay in the recruitment of effector
lymphocytes to the tissue or an unbalanced combination of lymphocyte
subsets allows the virus to spread in the CNS, which in turn will cause
severe immune-mediated tissue effects as well as disease. If either too
late or partially deficient, the immune system response may contribute
to a lethal outcome or cause autosensitization to brain-specific
antigens by epitope spreading to the antigen-presenting system in
peripheral lymphoid tissue. This could form the basis for subsequent
booster reactions of autosensitized CD4+ T cells--a process that
finally will end in an inflammatory autoimmune reaction, which in
humans we call multiple sclerosis. In contrast, a rapid and specific
local response in the brain tissue will result in efficient limitation
of viral spread and thereby a subclinical immune system-mediated
termination of the infection. After clearance of virus-infected cells,
downsizing of the local response probably occurs via self-elimination
of the contributing T cell populations and/or by so far unidentified
signal pathways. However, much of this is highly speculative, and more
data have to be collected to make decisive conclusions regarding this
matter. Several strategies have been developed by viruses to escape T
cell-mediated eradication, including interference with the MHC class I
presentation pathway of the host cell or "hiding" in cells which lack
MHC class I expression. This may result in life-long persistence of the
virus in the brain, a state which probably is actively controlled by T
lymphocytes. Under severe immunosuppression, however, reactivation of
viral replication can occur, which is a lethal threat to the host.

.

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