PERIPHERAL DELETION OF RHEUMATOID-FACTOR B-CELLS AFTER ABORTIVE ACTIVATION BY IGG

Rheumatoid factor (RF) B cells proliferate during secondary immune res ponses to immune complexed antigen and antigen specific T cells, but h igher affinity RFs are not detected except in patients with rheumatoid arthritis and other autoimmune diseases. Consequently, there must exi st highly efficient mechanisms for inactivation of these higher-affini ty RF B cell clones under normal circumstances. Exposure of transgenic mice expressing a human IgM RF to soluble human IgG in the absence of T cell help causes antigen specific B cell deletion in 2-3 days. The deletion is independent of the Fas/Fas ligand (FasL) pathway of apopto sis and is preceded by a phase of partial activation involving increas e in cell size and expression of B7 and ICAM-1, and transient release of low levels of immunoglobulin. Complete B cell activation involving the formation of germinal centers and sustained high level RF secretio n only occurs if T cell help is provided simultaneously. RF B cells ex posed to tolerogen remain competent to secrete RF in vitro if provided with an appropriate antigenic stimulus and T cell help. Consequently, death of these cells is not preceded by anergy. Abortive activation/d eletion of B cells by antigen in-the absence of T cell-derived surviva l signals may represent the major mechanism for maintaining peripheral tolerance in B cells expressing higher affinity RF. The lack of anerg y, and the potential for reactivation before death, provide a means fo r maintaining RF production under pathologic circumstances, such as ma y occur in the inflamed rheumatoid synovium.