PERTURBATION OF THE T-CELL REPERTOIRE IN RHEUMATOID-ARTHRITIS

Aberrations in the T cell repertoire with the emergence of oligoclonal populations have been described in patients with rheumatoid arthritis (RA). However, the extent of the repertoire perturbations as well as the underlying mechanisms are not known. We now have examined the dive rsity of the peripheral CD4 T cell repertoire by determining the frequ encies of arbitrarily selected T cell receptor (TCR) beta-chain sequen ces. Healthy individuals displayed a highly diverse repertoire, with a median frequency of individual TCR beta-chain sequences of 1 in 2.4 x 10(7) CD4 T cells. In RA patients, the median TCR beta-chain frequenc y was increased 10-fold, indicating marked contraction of the repertoi re (P < 0.001), The loss in TCR diversity was not limited to CD4 memor y T cells but also involved the compartment of naive T cells, suggesti ng that it reflected an abnormality in T cell repertoire formation and not a consequence of antigen recognition in the synovium, Also, contr ol patients with chronic inflammatory disease such as hepatitis C expr essed a diverse repertoire indistinguishable from that of normals. Tel omere length studies indicated an increased replicative history of per ipheral CD4 T cells in RA patients, suggesting an enhanced turnover wi thin the CD4 compartment. Compared with age-matched controls, terminal restriction fragment sizes were 1.7 kilobases shorter (P < 0.001), Th ese data demonstrate an altered CD4 T cell homeostasis in RA that may contribute to the autoimmune response as well as to the immunodeficien cy in these patients.