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.

The darker side of follicular helper T cells: from autoimmunity to immunodeficiency

“…6,32 Earlier studies have provided indirect evidence to indicate the role of T FH cells in promoting human autoimmunity, e.g., production of pathogenic autoantibodies in SLE patients caused by dysregulated GC reactions, 31,48 presence of the aggregates of T and B cells containing plasmablasts in the kidneys of patients with lupus nephritis 49 and reduced GC reactions upon blocking CD40L-CD40 interactions in patients with active SLE. 50 Recent studies have further provided clearer evidence on the role of T FH cells in promotion of both systemic and organ-specific autoimmune diseases in humans. [51][52][53][54][55] Simpson et al 51 performed an elegant study investigating the role of T FH cells in patients with SLE and Sjogren's syndrome.…”

B cells biology in systemic lupus erythematosus—from bench to bedside

“…CD40 in lipid raft is decreased on activated B cells from SLE [49], but functionally active CD154 (CD40L) expression on SLE B cells is increased [50,51]. CD154 transgenic mice have increased number and enhanced survival of B cells [52].…”

“…CD154 transgenic mice have increased number and enhanced survival of B cells [52]. Spontaneous proliferation and Ig secretion of peripheral B cells from active lupus patients could be inhibited by blockade of CD154-CD40 interaction [50]. Ligation of CD40 with CD154 provides an important co-stimulation signal and plays an essential role in GC reaction.…”

“…Ligation of CD40 with CD154 provides an important co-stimulation signal and plays an essential role in GC reaction. Studies show that CD40-CD154 interaction could not only induce T cell priming, promote Th2 type cytokines production and enhance T cell medicated immune effects, but also reciprocally function to promote B cell proliferation, isotypeswitching, activation and antibody production [50,[53][54][55].…”

B lymphocyte signaling pathways in systemic autoimmunity: Implications for pathogenesis and treatment

“…One possibility is to interfere with the induction and maintenance of GC reactions that produce autoantigen-specific memory and Ig-secreting plasma cells by blocking CD40-CD154 interactions. Results from a recent uncontrolled open-label study showed that treatment of SLE with a humanized monoclonal antibody (mAb) to CD154 (BG9588, 5c8) significantly reduced serum autoantibodies and proteinuria, and also reduced the disease activity score on the SLE Disease Activity Index (52). Whereas the antibody used in these studies elicited an increase in the frequency of thrombotic events, and thus conferred unacceptable side effects, the use of another mAb to CD154 (24-31, IDEC-131) in SLE is apparently not associated with an increased frequency of thrombosis, although minimal efficacy of this latter mAb has been noted (53).…”