Altered B cell receptor signaling in human systemic lupus erythematosus

Abstract

Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized by a loss of B cell tolerance and the production of anti-self antibodies. Accompanying this break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have been shown to be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhibitory immunoglobulin receptor FcγRIIB is also reduced in Lupus IgM-CD27+ memory cells. Because the relative contribution of different memory and transitional B cell subsets can be abnormal in SLE patients, we believe studies targeted to well defined B cell subsets will be necessary to further our understanding of signaling abnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal. • The lipid raft localization of signaling molecules is altered in some SLE patients.Lyn is decreased in lipid rafts and CD45 increased.• Expression and function of the inhibitory immunoglobulin receptor FcγRIIB is reduced in memory B cells in SLE patients.• The composition of memory B cell subsets is altered in SLE patients and they have a higher prevalence of activated cells. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. • B cell signaling in well defined memory subsets can be studied using intracellular flow cytometric analysis. NIH Public Access

Activation of TLR7 increases CCND3 expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus

“…CCND3 is a key gene in B-cell development and differentiation, and there are many important activated signaling pathways that contribute to the abnormality of B cells in SLE patients, including IFNa, the BCR signaling pathway and the TLR7 pathway. 18,34,35 In this study, we found that other than the two other signaling pathways, only the activation of TLR7 increased the expression of CCND3. Thus, it is necessary for us to uncover the molecular mechanism of the TLR7 pathway in elevating CCND3 in active SLE.…”

“…18,34,35 To determine whether activation of those pathways could affect CCND3 expression in B cells, we stimulated mouse B cells with IFN-a (1000 U/mL), anti-IgM (5 mg/mL) or TLR7 agonist R848 (1 mg/mL) for 6 h or 24 h. Compared with the control, B cells treated with R848 showed a significant increase in the expression of CCND3 in a time course experiment, while treatment with IFN-a or anti-IgM did not show any significant difference (Figure 4a). The protein expression results were consistent with the transcriptional results (Figure 4b).…”

Rituximab inhibits B-cell receptor signaling

“…In this disease, BCR-constitutive activation was proven and potentially related to defective Fc␥RIIB signaling or/and circulating B-cell stimulator. 37 Our study raises the possibility that, in LE, RTX also acts through BCR inhibition.…”

Balance between inflammatory and regulatory cytokines in systemic lupus erythematosus

“…Neurologic and psychiatric manifestations are common in SLE and occur in up to 75% of patients (Ballok, 2007). Pathophysiologically SLE is characterized by the dysfunction of T, B, and dendritic cells (DC), skewed cytokine production, breakdown of immunological tolerance, and the production of antinuclear autoantibodies (Jenks and Sanz, 2009;Crispín et al, 2010;Perl, 2010;Tsokos, 2011). The disturbance of the cytokine balance is implicated in the pathogenesis of SLE; therefore, cytokine balance might be a candidate target for treating SLE.…”