Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions

Abstract

To determine the role of CD154-CD40 interactions in the B cell overactivity exhibited by patients with active systemic lupus erythematosus (SLE), CD19+ peripheral B cells were examined before and after treatment with humanized anti-CD154 mAb (BG9588, 5c8). Before treatment, SLE patients manifested activated B cells that expressed CD154, CD69, CD38, CD5, and CD27. Cells expressing CD38, CD5, or CD27 disappeared from the periphery during treatment with anti-CD154 mAb, and cells expressing CD69 and CD154 disappeared from the periphery during the post-treatment period. Before treatment, active-SLE patients had circulating CD38 (bright) Ig-secreting cells that were not found in normal individuals. Disappearance of this plasma cell subset during treatment was associated with decreases in anti-double-stranded DNA (anti-dsDNA) Ab levels, proteinuria, and SLE disease activity index. Consistent with this finding, peripheral B cells cultured in vitro spontaneously proliferated and secreted Ig in a manner that was inhibited by anti-CD154 mAb. Finally, the CD38(+/++)IgD(+), CD38(+++), and CD38(+)IgD(-) B cell subsets present in the peripheral blood also disappeared following treatment with humanized anti-CD154. Together, these results indicate that patients with active lupus nephritis exhibit abnormalities in the peripheral B cell compartment that are consistent with intensive germinal center activity, are driven via CD154-CD40 interactions, and may reflect or contribute to the propensity of these patients to produce autoantibodies.

Differential effects of epratuzumab on peripheral blood B cells of patients with systemic lupus erythematosus versus normal controls

“…Several B cell extrinsic but also some intrinsic factors enhancing B cell survival, activation and proliferation have been identified in mouse models of lupus and in human SLE 26 – 37. In particular, a role of CD40/CD154 interactions has been suggested repeatedly in autoimmune mouse models and in patients with SLE 27 36 37. In addition, cell damage and impaired clearance can result in an increased load of chromatin-containing immune complexes, which were shown to stimulate autoreactive B cells in a TLR-dependent manner 30.…”

The CD40/CD40L costimulatory pathway in inflammatory bowel disease

“…A very recent report describes the outcome of administration of another humanised CD40L monoclonal antibody (BG9588, 5c8) to patients with systemic lupus erythematosus. 52 Blockade of the CD40 pathway significantly reduced serum autoantibodies, proteinuria, and clinical activity of the disease in a small group of patients. Although the use of this antibody was also associated with side effects, these results are notable because they provide in vivo proof of principle, and demonstrate the considerable potential of anti-CD40L therapy in immune mediated disorders.…”

Regulation of Humoral Immunity by Complement

“…Moreover, ectopic germinal centers, i.e. form in non-lymphoid tissues, are a hallmark of chronic autoimmunity such as in arthritis (Grammer et al, 2003). Therefore, it seems plausible that differentiating autoreactive B cells may have a similar requirement for co-receptor engagement of C3d along with B cell receptor binding of self-antigen.…”