Potential roles for soluble MD-1 in disease progression of autoimmune prone MRLlpr/lpr mice (171.2)

Abstract

Abstract MD-1 is a secreted protein that forms a complex with radioprotective 105 (RP105) on B cells, macrophages and dendritic cells. This complex plays a crucial role in lipopolysaccharide (LPS) recognition by B cells. Disease progression is known to improve in RP105-deficient lupus-prone MRLlpr/lpr mice. Furthermore, a soluble form of the homologous MD-2 protein is present in the plasma of septic patients and can opsonize gram-negative bacteria in cooperation with Toll-like receptor 4. We have now established a flow cytometry-based assay to detect endogenous soluble form of murine MD-1 (sMD-1) and explored potential roles in autoimmunity. The assay was quantitative and validated with sera from MD-1-deficient mice. Interestingly, heat-inactivated murine serum diminished the ability of sMD-1 to bind RP105. The sMD-1 was secreted by bone marrow-derived macrophages from C57BL/6 mice. Autoimmune prone MRLlpr/lpr mice had higher levels of serum sMD-1 than control MRL+/+ mice, and levels markedly increased with disease progression. Expression of MD-1 but not MD-2 mRNA increased with age in the liver and kidney of MRLlpr/lpr mice. Finally, immunohistochemical analyses revealed that MD-1 was present in infiltrated macrophages within perivascular lesions of the MRLlpr/lpr kidney. This correlation suggests that sMD-1 may contribute to pathogenesis in this autoimmune disease model mouse. Also, sMD-1 may be feasible to monitor autoimmune disease severity.