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Soluble fibrinogen-like protein 2 (sFGL2) is the soluble form of fibrinogen like protein 2. As a novel immunoregulatory molecule, sFGL2 is secreted mainly by T cells, especially regulatory T cells, and exerts an immunoregulatory property rather than a prothrombinase function in the immune system. sFGL2 changes not only the proliferation and differentiation of T cells but also the maturation of antigen presenting cells. Besides its innate and adaptive immunoregulatory functions, sFGL2 also induces apoptosis in cells including renal tubular epithelial cells through Fcγ receptors (FcγRs). It may affect transplantation via regulation of immunity and induction of apoptosis of different cells in a spatiotemporal manner. Here, we review the research progresses on sFGL2 including its structure, functions, and molecular mechanisms via which sFGL2 might affect organ transplantation, as well as discuss its characteristics and potential of becoming a therapeutic target in patients with rejection.