Characterization of the B cells in lupus-prone and resistant mouse models.

摘要

The general hypothesis is that in the models of lupus-prone and resistant mice, B cells function differently and contribute to the phenotypes and pathogenesis. Thus, the studies of B-lymphocytes in these models may help to understand the role of B-cells and to identify involved genes. Defect splenic marginal zone (MZ) has been found in the lupus-prone NZM2410 and B6.Sle1/2/3 (TC), but not in the lupus resistant NZM.TAN (TAN) mice. I hypothesize that this defect is due to the abnormal functions of marginal zone B cells and contributes to the pathogenesis. Immuno-fluorescence study revealed that lupus MZ B cells were trans-located inside the follicle. MZ macrophages (MZM) were also found defect only in the lupus mice. Reciprocal bone marrow transfer indicated that the lack of MZM was not the reason of MZB translocation, and MZB miss-location was determined by both bone marrow and stroma-derived factors. Functional studies revealed that MZ B cells in TC and TAN mice were abnormal.;The second goal of the research was to study the phenotypes and functions of the peritoneal cavity (PerC) B cells in these strains. Both lupus-prone and resistant mouse models have increased PerC B cells, especially B1 cells. Studies showed TAN PerC B1 cells had lower activation and higher resistance to activation induced cell death, while B1 cells from NZM2410 and TC had higher proliferation. Finally TAN B1 cells produce little IL-6 and IL-10, while TC B1 cells make more IL-6 and a normal levels of IL-10, suggesting a regulatory role of TC B1 cells in immune response.;The third goal was to study the properties of splenic B cells. Both strains have increased Transitional 1 and Transitional 2 populations and less mature follicular B cells. In vitro stimulations revealed the B cells from lupus mice had a lower activation threshold and higher proliferation/differentiation abilities, while TAN B cells showed the opposite directions. Lupus B cells also had abnormal BAFF-R/TACI expressions, indicating the mechanism behind the phenotypes. Overall these results suggest that B-cell populations in lupus-prone and resistant mice are quite different and may play an important role in the pathogenesis.