Researchers studying autoimmune diseases have found a molecular mechanism that explains how T-cells in lupus patients avoid apoptosis and are stimulated to produce antibodies against the patients own DNA.
Investigators at Northwestern University (Chicago, IL, USA) used gene microarray profiling, which was validated by functional and biochemical studies, to establish that lupus patients activated T-cells resisted apoptosis by markedly upregulating and sustaining cyclo-oxygenase-2 (COX-2) expression. COX-2 is an enzyme that makes prostaglandins, which cause inflammation, pain, and fever.
Inhibition of COX-2 activity caused apoptosis of lupus T-cells by augmenting Fas signaling and markedly decreasing the survival molecule c-FLIP (cellular homolog of viral FLICE inhibitory protein). Only some COX-2 inhibitors were able to suppress the production of pathogenic autoantibodies to DNA by causing autoimmune T-cell apoptosis, an effect that was independent of prostaglandin E2 (PGE2). These findings were published in the April 2004 issue of Nature Medicine.
Senior author Dr. Syamal Datta, professor of medicine and immunology at Northwestern University said, COX-2 inhibitors also have been used, with limited success, to treat patients with lupus and in laboratory models of lupus, but in doses much lower than the concentration required to achieve cell death and elimination of autoimmune T-cells.