Background/Purpose: Upon B cell receptor stimulation, B cells increase protein expression levels of the key downstream signaling molecule Bruton’s tyrosine kinase (BTK). BTK-transgenic mice that overexpress BTK exclusively in B cells, spontaneously develop antinuclear autoantibodies and SLE/Sjögren-like autoimmunity. These mice exhibit increased levels of T follicular helper (Tfh) cells and T regulatory (Treg) cells in lymphoid tissues and develop lymphoid infiltrates in salivary glands and lungs, which contain ectopic germinal centers. Therefore, we aimed to investigate whether BTK expression is also dysregulated in B cells from patients with primary Sjögren’s syndrome (pSS).

Methods: Twenty-six treatment-naïve pSS patients, which fulfilled the revised AECG criteria, and 26 sex- and age-matched healthy controls were included in this study. Fifteen pSS patients were treated with abatacept (i.v.) for 24 weeks. Peripheral blood mononuclear cells (PBMCs) and serum were collected from 26 patients at baseline, and from 15 treated patients at 4, 12, 24, 36 and 48 weeks after the first dose of abatacept. B and T cells were analyzed by 12-color flow cytometry. (auto-)Antibodies were measured by ELISA. Histopathological analysis was performed on parotid gland biopsies from 15 pSS patients before and after abatacept treatment.

Results: Flow cytometry analysis of PBMCs from pSS patients and healthy controls revealed that in 16 of 26 of the patients, BTK expression levels were increased in B cells, compared to levels in healthy controls (p=0.032). Excitingly, these levels were consistently higher in all B cell subsets, including naïve B cells. In pSS patients with high BTK expression levels, serum RF levels were also increased (p=0.035) and a trend towards increased levels of Ro52 and Ro60 (SSA) was found. There was no correlation between BTK levels in B cells from pSS patients and total serum immunoglobulins (IgG, IgA, IgM). Treatment of pSS patients with abatacept, which targets co-stimulation of T cells, resulted in a decrease of the elevated BTK expression levels in circulating B cells to levels in healthy controls (p=0.003). We further observed that abatacept treatment reduced absolute numbers of circulating Tfh and Treg cells, while numbers of Th1, Th2 and Th17 were not affected. Although abatacept did not influence the amount of infiltrate in parotid gland tissue, the number of germinal centers declined, illustrating the Tfh cell dependency of these structures.

Conclusion: We show that BTK levels in circulating B cells are increased in a large proportion of pSS patients. High BTK levels may reduce thresholds for B cell activation, and thereby contribute to B cell autoreactivity. In pSS patients, this is reflected by the positive association of elevated BTK levels in B cells with serum RF levels. The observation that abatacept treatment reduced BTK levels in pSS patients implies that high BTK levels are -at least partly- dependent on T cell co-stimulation. Our data may further suggest that Tfh cells play a pivotal role in T cell dependent BTK expression. Together, this study underlines the importance of interfering with B-T cell interaction in the treatment of pSS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/brutons-tyrosine-kinase-levels-are-increased-in-b-cells-from-patients-with-primary-sjogrens-syndrome/