Unbalanced B-cell Receptor Signaling Promotes B-cell Survival in SLE

In systemic lupus erythematosus (SLE), an imbalance between the tyrosine kinase Syk and the serine/threonine kinase Akt may contribute to enhanced B-cell survival, according to research published in Arthritis & Rheumatology.

Thomas Dörner, MD, and colleagues from the German Rheumatism Center found that an imbalance between serine and tyrosine phosphatases leads to diminished Syk phosphorylation in SLE. This imbalance creates a disruption in the B-cell receptor signaling pathways, leading to enhanced survival of lupus B cells and differentiated plasma cells.

While previous studies suggest that B-cell receptor (BCR) signaling abnormalities may contribute to the B-cell hyperactivity underlying SLE, a detailed analysis of the nature of the BCR signaling abnormalities and their relationship to B-cell hyperactivity had not been conducted. Therefore, a comprehensive analysis of BCR signaling abnormalities in human SLE and their relationship to B-cell survival was performed in this study.

The researchers analyzed B cells from 46 healthy donors (36 women, 10 men) with a mean age of 35 years (range 25-58) and 63 patients with lupus (57 women, 6 men) with a mean age of 42 years (range 22-76) who had a mean SLE Disease Activity Index (SLEDAI) of 7.7 (range 1-32).

Using flow cytometry, they assessed phosphorylated (p)-CD22, p-Syk, and p-Akt, as well as the basal expression of B-cell co-receptors CD22 and CD19. Using confocal microscopy studies, they determined recruitment of CD22 and the tyrosine phosphatase SHP-1 to the activated B-cell receptor complex. They also measured phosphatase activity in patients with lupus compared with healthy participants.

The researchers found that B cells from patients with SLE exhibited decreased levels of Syk phosphorylation and reduced intracellular calcium release after activation of the BCR as compared to healthy participants. 

In contrast, while Syk phosphorylation was diminished after BCR activation in patients with lupus, Akt phosphorylation was significantly increased.

“Altogether, the current data suggest that an imbalanced regulation of the 2 B-cell receptor associated signaling axes (Syk and Akt pathway) in the context of increased tyrosine phosphatase activity could contribute to the breakdown of tolerance and the development and maintenance of autoimmunity in patients with SLE,” the authors wrote.

“These findings suggest for the first time that an imbalance in phosphatase and kinase activity in human SLE B cells could contribute to some of the known B-cell abnormalities and the development and maintenance of autoreactive B cells described in patients with SLE,” the authors concluded.

Summary and Clinical Applicability

Disruption of B-cell receptor signaling pathways in patients with SLE may lead to improper B-cell negative selection, imparting survival advantages to potentially autoreactive B-cells. This new understanding of altered negative selection and increased B-cell survival may be a topic for investigation in the development of future therapies targeted against autoreactive B cells.

Reference

Fleischer SJ, Daridon C, Fleischer V, Lipsky PE, Dörner T. Enhanced tyrosine phosphatase activity underlies dysregulated B-cell receptor signaling and promotes survival of human lupus B-cells. Arthritis Rheum. 2016; doi:10.1002/art.39559.