Pathogenesis of chronic progressive myelopathy associated with human T-cell lymphotropic virus type I.
Human T-cell lymphotropic virus type I (HTLV-I) induces a chronic demyelinating disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). While only 0.25% of HTLV-I-infected individuals develop HAM/TSP, the mechanisms responsible for the progression of an HTLV-I carrier state to clinical disease are not clear. In particular, no specific sequence differences have been found between HTLV-I recovered from HAM patients and HTLV-I-infected carriers. Since CD4 T cells are the major reservoir of the virus, at least three hypotheses implicating CD4 T cells directly or indirectly have been proposed: 1) The cytotoxic hypothesis predicts that activated and HTLV-I-infected CD4 T cells migrate to the CNS and infect resident cells. Cytotoxic CD8 T cells may then recognize viral antigens on HTLV-I-infected CNS cells causing a cellularly mediated cytotoxic demyelination. 2) The autoimmune hypothesis predicts that either (a) virally reactive T cells crossreact with a CNS antigen, or (b) random infection of CD4 T cells eventually results in the infection of CNS-autoreactive CD4 T cells that, by virtue of the productive HTLV-I infection, become activated, expand and migrate to the CNS, where they encounter their antigen. This results in a specific immune response and demyelination, as is known to occur in experimental autoimmune encephalomyelitis. 3) The bystander damage hypothesis does not implicate a specific response against CNS cells. Instead this hypothesis suggests that the presence of IFN-gamma-secreting HTLV-I-infected CD4 T cells and their recognition by virally specific CD8 T cells in the CNS induce microglia to secrete cytokines, such as TNF-alpha, which may be toxic for the myelin.
Höllsberg
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Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, USA.
D001323:Autoantibodies / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002353:Carrier State / Q000276:immunology / Q000821:virology; D016207:Cytokines / Q000097:blood; D015490:HTLV-I Infections / Q000276:immunology / Q000821:virology*; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology / Q000821:virology*; D009185:Myelin Proteins / Q000276:immunology; D015493:Paraparesis, Tropical Spastic / Q000276:immunology / Q000821:virology*
D001323:Autoantibodies; D016207:Cytokines; D009185:Myelin Proteins