Die Spezifität der systemischen und intrathekalen Immunantwort bei der Infektion mit dem humanen T-lymphotropen Virus 1 (HTLV-1)

Abstract

The retrovirus HTLV-1 induces a myelitis called HTLV-1 associated myelopathy/ tropical spastic paraparesis (HAM/TSP). In this chronic inflammatory CNS disease, HTLV-1 infected CD4+ T-lymphocytes infiltrate into the spinal cord and express retroviral proteins.In HTLV-1 infected patients the specificity of the systemic and intrathecal immune response against non-denaturated HTLV-1 proteins was analyzed first. It was shown by using a cell-EIA combined with a RIPA that there is an intrathecal IgG synthesis against several HTLV-1 proteins in HAM/TSP. Second, in HTLV-1 infected humans with and without HAM/TSP the fine specificity of IgG antibodies was screened. Humans with HAM/TSP showed more antibody specificities compared to humans without disease. However, no single specificity was exclusively linked to the disease. Furthermore, immune reactivity to immunodominant tax and rex antibody epitopes was also diverse in HAM/TSP patients. The serum quantity and intrathecal synthesis of specific IgG antibodies did not correlate for 14 env and gag epitopes, however there was a strong correlation for 2 immunodominant env gp21 epitopes. HAM/TSP patients with disease-associated haplotypes showed a larger variety of antibody specificities than patients without.HTLV-1 gp21 specific HLA DR1 restricted CD4+ T-cell lines were isolated and characterized for the first time. Immunodominant helper T-cells recognized highly conserved sequences of the transmembrane protein gp21 in nanomolar concentrations.These data confirmed that the B-cell as well as the T-cell response in HTLV-1 infection is polyclonal. The intrathecal oligoclonal B-cell response however is associated with the disease HAM/TSP. B-cells and T-cells target sequences of HTLV-1 gp21 which are overlapping or close to each other. Following, a model of T-cell / B-cell cooperation is suggested to explain the immune activation at very low levels of antigen and the persistence of the immune response in the CNS in HAM/TSP.