Abstract
Auto-reactive B lymphocytes and its abnormal CD40 signaling play important roles in the pathogenesis of systemic lupus erythematosus (SLE). In this study, we analyzed CD40 expression and CD40/CD154 induced activation of NF-κB signaling pathway in B cells from SLE patients. B cells from healthy volunteers and tonsilar B cells from chronic tonsillitis were used as negative and positive controls. Results showed CD40-induced NF-κB signaling was constitutively activated in B cells from active lupus patients, including decreased CD40 in raft portion, increased phosphorylation and degradation of IκBα, phosphorylation of P65, as well as increased nuclear translocation of P65, P50, c-Rel, which could be blocked by anti-CD154. CD154 stimulation could induce further phosphorylation and degradation of IκBα, as well as phosphorylation of P65 and nuclear translocation of P65. In addition, CD40-induced kinase activities in B cells from lupus patients mimicked that of tonsil B cells, in that IKKα/β were more activated compared to normal B cells. CD40-induced NF-κB activity was blocked by both IκB phosphorylation and proteosome degradation inhibitors in both lupus and normal B cells. All together, our findings revealed that canonical NF-κB signaling is constitutively activated in active lupus and is mediated by CD154/CD40. CD40 induced NF-κB activation is different in human lupus B lymphocytes compared with normal B cells.
Highlights
Systemic lupus erythematosus (SLE) is a complex autoimmune disease which is characterized by abnormal B cell activation and differentiation into short and long lived plasma cells that produce pathogenic autoantibodies [1]
As previous studies revealed that B cells from active lupus could express CD154 both in human and mice model [16], we set out to investigate whether CD154 expressed on B cells is involved in constitutive NF-kB activation by treating B cells from lupus patients with antagonistic anti-CD154, and we found that blocking CD154 expression on B cells from active lupus patients could antagonize constitutive activation of canonical NF-kB signaling, including nuclear translocation of P65 and c-Rel, which was similar to that observed in tonsil B cells but not in B cells from non-active SLE patients (Fig. 4A)
Our results showed that the total cell protein levels of IKKa, b, e and TBK1 were not affected by CD154 stimulation in B cells from both normal controls and lupus patients (Fig. 5A), whereas CD154-induced kinase activities were different in normal controls and lupus patients (Fig. 5B), with the later mimicked that of tonsil B cells, in that IKKa and IKKb were more activated in SLE B cells compared to normal B cells (Fig. 5C)
Summary
Systemic lupus erythematosus (SLE) is a complex autoimmune disease which is characterized by abnormal B cell activation and differentiation into short and long lived plasma cells that produce pathogenic autoantibodies [1]. CD40 is a TNF superfamily transmembrane glycoprotein expressed mainly on B cells, and it plays a pivotal role in B cell differentiation and activation [3]. Interaction between CD40 and its ligand, CD154, provides a costimulatory signal that induces T cell-dependent B cell proliferation and differentiation with subsequent antibody production, which plays an important role in the pathogenesis of SLE [7,8,9]. In 1999, Vakkalanka RK et al demonstrated high level of serum CD154 in most lupus patients, and CD154 had the capacity to mediate B cell apoptosis by inducing CD95 expression [11]. Serum CD154 level correlated with the titer of antidouble-stranded DNA antibody and with disease activity [12]
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