Shinichi Sato

Signaling thresholds influence the balance between humoral immunity and autoimmunity. Cell surface CD19 regulates intrinsic and Ag receptor-induced B lymphocyte signaling thresholds, and transgenic mice that overexpress CD19 by 3-fold generate spontaneous autoantibodies in a genetic background not associated with autoimmunity. To quantify the extent that genetically determined differences in expression of a single cell surface molecule can influence autoantibody production, we have assessed auto

SSc patients have distinct abnormalities of blood homeostasis and B cell compartments, characterized by expanded naive B cells and activated but diminished memory B cells. Our results suggest that CD19 overexpression in SSc memory B cells is related to their hyperreactivity.

CD19 serves as a cell surface response regulator that establishes signaling thresholds critical for B lymphocyte development and activation. B lymphocytes from CD19-deficient mice are hyporesponsive to transmembrane signals, while B lymphocytes from mice that overexpress CD19 to even a small extent (25% increase) become hyperresponsive. The B-1 subpopulation of B lymphocytes is particularly sensitive to CD19 regulation, since their development is severely decreased in CD19-deficient mice. The ef

Serum CTGF levels were increased in patients with SSc, and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. In addition, it appears that production of CTGF is involved in the development or maintenance of fibrosis rather than in initiation of fibrosis in SSc. These data suggest that CTGF plays a critical role in the development of fibrosis in SSc.

The tight-skin (TSK/+) mouse, a genetic model for human systemic sclerosis (SSc), develops cutaneous fibrosis and autoantibodies against SSc-specific target autoantigens. Although molecular mechanisms explaining the development of fibrosis and autoimmunity in SSc patients or TSK/+ mice remain unknown, we recently demonstrated that SSc patients overexpress CD19, an important regulatory molecule expressed by B lymphocytes. B cells from CD19-deficient mice are hyporesponsive to transmembrane signal

To determine the role of chemokines in the pathogenesis of systemic sclerosis (SSc), we examined serum levels, spontaneous production by peripheral blood mononuclear cells (PBMC), and histological distribution in the affected skin, of MCP-1, MIP-1alpha and MIP-1beta in SSc patients. Serum levels of these chemokines were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels of these chemokines in culture supernatants from PBMC were also measured by ELISA. Serum levels and s

Establishing signal transduction thresholds that regulate B lymphocyte responses to foreign Ags and tolerance to self Ags is critical for humoral immune responses. The effects of altered signaling thresholds in B lymphocytes were examined in CD19-deficient mice and transgenic mice that expressed human CD19 at varying densities. Human CD19 restored normal B cell function and development to CD19-deficient mice when expressed at levels comparable to those of circulating human B cells. While CD19 ex