ALTERED T-LYMPHOCYTE SIGNALING IN RHEUMATOID-ARTHRITIS

Synovial and peripheral blood T cells from patients with rheumatoid ar thritis are functionally deficient. This may be secondary to their red uced cytokine (e.g. interleukin-2) synthesis. We have investigated the possibility of an alteration in pathways common to interleukin-2 prod uction and proliferation in peripheral blood T cells from patients wit h active rheumatoid arthritis. Intracellular calcium levels ([Ca2+](i) ) were analyzed by flow cytometric methods in Indo1-loaded T cells. Th ese were purified by negative selection from patients or age/sex-match ed controls, and stimulated with phytohemagglutinin-P or anti-CD3. Rhe umatoid [Ca2+](i) responses to both stimuli were reduced (p < 0.005). Patient cell samples included a larger proportion of non-responding ce lls, but even in the responsive population the magnitude of the respon se in rheumatoid cells was impaired compared with those in normal cell samples (p < 0.0001) for both; stimuli. Proliferation responses were also impaired Ip < 0.005), and there was a positive correlation betwee n the paired [Ca2+](i) elevation and proliferative responses for both stimuli. CD2 and CD3 expression were normal, and the proportions of CD 4, CD8 and CD45RO and CD45RA. subsets were also unaffected by disease. Thus a signaling defect downstream of CD2 or CD3 surface molecules ma y contribute to functional deficiencies in rheumatoid T lymphocytes. T his effect is not due to non-steroidal anti-inflammatory drugs which s ome patients were taking. We have demonstrated similar alterations in [Ca2+](i) responses and proliferation in a smaller study of patients w ith inflammatory bowel disease, indicating that such changes might be present in other chronic inflammatory states.