| Co-Investigator(Kenkyū-buntansha) |
NAGAFUCHI Hiroko St.Maianna University School of Medicine, Institue of Medical Science, Assistant Professor, 難病治療研究センター, 助手 (80278001)
TAKENO Mitsuhiro St.Maianna University School of Medicine, Departments of Immunology and Medicine, Associate Professor, 医学部, 講師 (50236494)
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| Research Abstract |
It remains unclear why women are more susceptible to systemic lupus erythematosus(SLE). Because the process of X chromosome inactivation in female yield two distinct subsets of self-antigens, we have hypothesized that if all thymic antigen presenting cells(APC) expressed the paternal (or maternal)-derived X chromosome, autoreactive T cells which recognize self-antigens encoded by the maternal (or paternal)-derived X chromosome would escape from thymic negative selection. As a result, the maternal(or paternal)-derived X chromosome gene products presented by B cells would stimulate the autoreactive T cells in the periphery, leading to GVHD-like autoimmune responses, as we have previously shown in the female SLE patients.
We first established a non-RI PCR-based quantitative analysis of the androgen receptor gene polymorphisms to determine X chromosome inactivation patterns in a cell population. We found equally random X chromosome inactivation patterns among peripheral blood T cells, B cel
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ls and monocytes of normal subjects. In contrast, there was a significant difference in the proportion of X chromosome inactivation between peripheral blood monocytes and B cells from many SLE patients.
We have next examined the responsiveness of autoreactive SLE T cell clones to monoclonal EBV transformed autologous B cell lines expressing either paternal or maternal-derived X chromosome. The autoreactive T cell clones derived from the same patients proliferated exclusively in response to B cell lines expressing paternal-derived (or maternal-derived) X chromosome, but not those expressing maternal-derived(or paternal-derived) X chromosome, suggesting that paternal-derived or maternal-derived X chromosome encodes the responsible self-antigens for the autoreactive T cell clones in SLE patients.
The mosaicism of X chromosome inactivation among subpopulations of APC may thus contribute to the selection of the particular X chromosome-encoding self-antigens with which autoreactive T cells react in SLE. Moreover, characterization of the self-antigens by the differential display technique showed that amino acid sequences within the X chromosome products are highly homologous with amino acid sequences of several microorganisms. We thus postulate that infection by several microorganisms may trigger the crossreactive T cell response first, and then endogeneous X chromosome products on APC induce shift from the crossreactive response to the autoreactive response. Less
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