The Soluble CTLA-4 Receptor and its Emerging Role in Autoimmune Diseases

CTLA-4, expressed by activated T and B lymphocytes, is a co-stimulatory receptor transducing a potent inhibitory signal. Increasing evidence showed CTLA-4 gene as an important susceptibility locus for autoimmune endocrinopathies and other autoimmune disorders. A soluble form of cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4) was recently found and shown to possess CD80/CD86 binding activity and in vitro immuno-regulatory functions. sCTLA- 4 is generated by alternatively spliced mRNA. Low levels of sCTLA-4 have been detected in normal human serum, but increased serum levels have been observed in several autoimmune diseases (e.g. Graves' disease, myasthenia gravis, systemic lupus erythematosus, type 1 diabetes, systemic sclerosis, celiac disease and autoimmune pancreatitis disease). The biological significance of increased sCTLA-4 serum level has not been fully clarified. On one hand, we can hypothesize that sCTLA-4 can specifically inhibit the early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could compete with membrane-bound CTLA-4 for CD80/CD86, in later T lymphocytes activation phase, causing a reduction of inhibitory signaling. Thus, this doubleedged nature of CD80/CD86 blocking by sCTLA-4 may result in different outcomes during the clinical course of the disease.