Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production.

TLDR

The study examined how CD40/CD40L costimulation contributes to systemic lupus erythematosus and suggested that further research into CD40L hyperexpression may reveal regulatory defects in pathogenic T and B cells. Active lupus patients exhibited markedly increased CD40L expression on CD4+, CD8+, and B cells—21-, 22-, and 20.5‑fold increases respectively—yet CD40L upregulation could still be down‑regulated by autologous B‑cell CD40, and blocking CD40L with an antibody significantly reduced pathogenic autoantibody production, supporting anti‑CD40L therapy.

Abstract

We investigated the role of the costimulatory molecules, CD40 and its ligand CD40L, in the pathogenesis of human SLE. In comparison to normal subjects or patients in remission, PBMC from active lupus patients had a 21-fold increase in the frequency of CD40L-expressing, CD4+T cells. However, the expression of CD40L induced in either lupus or normal T cells by mitogenic stimulation could be down-regulated equally well by CD40 molecules on autologous B cells. Active lupus patients also had a 22-fold increase in percentage of CD8+ T cells expressing CD40L, consistent with their unusual helper activity in SLE. Surprisingly, patients with active lupus had a 20.5-fold increase in B cells that spontaneously expressed high levels of CD40L, as strongly as their T cells. Although lupus patients in remission had low levels of CD40L+ cells in the range of normal subjects, mitogen-induced upregulation of CD40L expression in the T and B cells was markedly greater than normal, suggesting an intrinsic defect. A mAb to CD40L blocked significantly the ability of lymphocytes from lupus patients with active and established disease to produce the pathogenic variety of antinuclear autoantibodies in vitro, bolstering the possibility of anti-CD40L immunotherapy for lupus. Future studies on the hyperexpression of CD40L could elucidate a regulatory defect in the pathogenic T and B cells of lupus.