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 FcgammaRIIB 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.

Figure 1

PBL from SLE patients (red) or from healthy control subjects (blue) were stimulated for five minutes with 25 μg/ml anti-IgD (A) or 10 μg/ml anti-IgM (B) (shaded histogram) or control antibody (open histogram). After stimulation cells were fixed immediately with paraformahldehyde and permeabilized with methanol. Cells were then stained with antibodies against CD20, IgM (A) or IgD (B), CD27, and antibodies specific for phosphorylated forms of ERK (pY204/pT202) (A) or BLNK (pY84) (B). Phosporylation for the IgM/IgD+ CD27- naïve populations is shown.