B Cell Receptor Signaling in Human Systemic Lupus Erythematosus

Aimee E. Pugh-Bernard; John C. Cambier


Curr Opin Rheumatol. 2006;18(5):451-455. 

In This Article

B Cell Signaling in Systemic Lupus Erythematosus

Although the cause of SLE remains unsolved, the research accumulated thus far points to numerous aberrations in antigen-receptor mediated signaling events exhibited by SLE B cells and highlights signaling defects that presumably play a central role in the pathogenesis of the disease. Abnormal B cell signalling certainly plays a significant role in the breakdown of B cell tolerance and subsequently the pathogenesis of SLE.

Increased Calcium Flux and Phosphorylation of Cytosolic Proteins

Calcium is an important intracellular messenger that is involved in modulating a vast array of cellular events. Signaling events through the BCR in SLE B cells are abnormal, as indicated by increased intracellular calcium flux and phosphorylation of multiple proteins. Stimulation of freshly isolated peripheral blood B cells from patients with SLE with BCR ligand led to unusually high calcium responses and increased tyrosine phosphorylation of proteins relative to peripheral blood B cells from healthy individuals and disease controls.[26] The signaling alterations found in this study did not correlate with disease activity or treatment, and clearly demonstrate the existence of SLE-specific signaling alterations in B cells.

Defective FcγRIIB Signaling Related to Enhanced Calcium Flux

Co-aggregation of FcγRIIB with BCR leads to the generation of signals that block antigen-induced B cell activation events, including phosphoinositide hydrolysis, p21 ras activation and calcium mobilization.[27] Inhibition through FcγRIIB is mediated primarily by the activation of the SH2-containing inositol 5´-phosphatase (SHIP) which hydrolyzes PI(3,4,5)P3, an essential element of BCR signaling. In some situations this receptor mediates inhibition by dephosphorylation of CD19, which is required for PI-3K activation and generation of PI(3,4,5)P3.[27,28,29] As discussed above, BCR stimulation in SLE B cells results in increased calcium flux compared to B cells from healthy individuals and disease controls. Because ligation of FcγRIIB attenuates intracellular calcium mobilization, Enyedy et al.[30] measured changes in intracellular calcium levels following BCR crosslinking by F(ab')2 fragments of anti-µ or whole anti-µ antibodies in the B cells of patients with SLE and other rheumatic diseases and healthy controls. They found that in SLE B cells, FcγRIIB signaling is defective, regardless of disease activity.

Further, the reduced function of FcγRIIB in SLE B cells was not due to decreased expression of FcγRIIB, IgM or CD19 on the surface of B cells from SLE patients, as all were expressed at comparable levels in patients with SLE, disease controls and healthy donors. Additionally, SHIP protein levels were significantly lower in SLE B cells, suggesting that SHIP is less available to connect with FcγRIIB and inhibit BCR signaling in SLE B cells.[30] These findings suggest that deficient FcγRIIB-mediated inhibition contributes to the increased calcium response and hyperactivity of human SLE B cells.

Analysis of FcγRIIB-deficient mice revealed spontaneous autoantibodies and glomerulonephritis on specific genetic backgrounds suggesting that FcγRIIB plays a role in peripheral tolerance[31] and is a susceptibility factor under the control of epistatic modifiers for the pathogenesis of disease.[32]

A separate group discovered an FcγRIIB Ile232Thr transmembrane domain polymorphism associated with SLE susceptibility in Asians. This receptor was less effectively distributed to detergent-insoluble lipid rafts under resting conditions and after coligation with BCR.[33*] Floto et al. [34*] further analyzed this FcγRIIB polymorphism by generating stable transfectants of either wild-type FcγRIIB1 or FcγRIIB1T232 into the human monocytic cell line, U937. Membrane fractionation revealed that while FcγRIIB1 readily separated into the lipid raft-enriched fractions, the FcγRIIB1T232 was excluded. Although the mechanism by which this transmembrane domain polymorphism prevents partitioning into the lipid raft fraction is unclear, this study suggests that defective signaling through FcγRIIB1T232 enhances the inflammatory response thought to promote SLE. Further, the expression of this defective FcγRIIB1 may reduce the B cell's threshold for antigen presentation and potentially result in compromised peripheral tolerance.[34*]

Decreased Expression of the B Cell Protein Tyrosine Kinase Lyn

The protein tyrosine kinase Lyn plays a unique role in BCR signaling by exerting positive and negative effects. While the positive role of Lyn appears to be redundant, its role as a negative regulator of BCR signaling is indispensable. The negative signaling role of Lyn was identified in Lyn-deficient mice, in which peripheral B cells exhibited enhanced activation of downstream effectors, intracellular calcium elevation and B cell hyperactivity resulting in autoantibody production.[35,36] The inhibitory function of Lyn is mediated in part by its ability to phosphorylate CD22, FcγRIIB, and other immunoreceptor tyrosine-based inhibitory motif containing inhibitory coreceptors.[37] Expression of Lyn is significantly decreased in both resting and BCR stimulated peripheral blood B cells from two-thirds of SLE patients analyzed. This reduction was unrelated to disease activity and was disease-specific.[38] Further, statistically significant alterations at the transcriptional level were confirmed by a 2.5-fold decrease in Lyn mRNA in SLE patients compared to healthy individuals. Comparison of clinical manifestations to Lyn levels revealed that central nervous system disease and renal involvement were exhibited only in patients with decreased levels of Lyn. Additionally, anti-dsDNA autoantibodies were detected in five of eight patients with decreased levels of Lyn, potentially linking Lyn deficiency with autoantibody production and renal disease. This study found no difference in the B cell surface expression of CD22, regardless of disease activity, when comparing SLE B cells to B cells from healthy controls and patients with other systemic autoimmune diseases.[38]

Another group analyzed the level and subcellular distribution of Lyn in SLE B cells and found that slightly more than half of the SLE patients analyzed had reduced levels of Lyn protein, which was subsequently determined to be due to increased ubiquitination of the protein.[39*] Translocation of Lyn to lipid rafts was found to be significantly decreased in SLE B cells compared with healthy donors. Similarly, the level of Lyn protein in the nonlipid raft fractions was reduced, regardless of disease activity and medication. Altered Lyn expression was also found to be associated with increased spontaneous proliferation, the production of anti-dsDNA autoantibodies and the increased production of interleukin-10.[39*] The combination of these findings suggest that decreased expression of Lyn in SLE B cells alters BCR signaling and may explain the B cell hyperactivity characteristic of the disease.

Mice targeted with a gain-of-function mutation resulting in constitutively activated Lyn B cells (Lynup/up mice) displayed heightened calcium flux in response to BCR stimulation, the development of circulating autoreactive antibodies and lethal autoimmune glomerulonephritis.[40] Lyn-deficient mice exhibited impaired BCR-mediated signaling, the production of autoantibodies, and glomerulonephritis.[35,36] Combined, these findings suggest that the expression of signaling molecules such as Lyn are tightly regulated and optimal within narrow ranges of expression. Both over expression and underexpression of Lyn results in autoimmunity.

Increased Expression of B Lymphocyte Stimulator in Systemic Lupus Erythematosus and Chronic Occupation of B Cell Activating Factor Receptors on Systemic Lupus Erythematosus B Cells

B lymphocyte stimulator (BLys), also known as BAFF, is a member of the tumor necrosis family that is important for B cell survival and maturation.[41] Serum levels of BLys were found to be significantly higher in SLE patients than healthy controls and appeared to be associated with the production of anti-dsDNA antibodies of all immunoglobulin classes (IgM, IgG, and IgA).[42] This finding suggests that BAFF may directly promote derailment of B cell tolerance to dsDNA by selectively driving the production of anti-dsDNA antibodies. The same group later determined that although the cell surface expression levels of BAFF receptors were not significantly different between SLE patients and healthy controls, the level of BAFF receptor occupancy was greatly increased in SLE patients regardless of disease activity.[43*] The increased occupancy of BAFF receptors on SLE blood B cells may contribute to the pathogenesis of SLE as it has been shown previously that excess BAFF can rescue self-reactive B cells from peripheral deletion.[44]


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