Endosomal TLR Triggering Of B Cells In Sjögren’s Syndrome Induces Increased Plasma Cells Differentiation, Ig Class Switch and Immunoglobulin Production

Marie Wahren-Herlenius¹, Susanna Brauner¹, Marika Kvarnström¹, Lasse Folkersen¹, Sabrina Görgen¹, Christina Trollmo², Vivianne Malmström³ and Gunnel Nordmark⁴, ¹Department of Medicine, Karolinska Institutet, Stockholm, Sweden, ²Department of Medicine, Karolinska Institutet, Stochkolm, Sweden, ³Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden, ⁴Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: plasma cells and toll-like receptors, Sjogren's syndrome

Session Information

Title: Sjögren's Syndrome: Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Patients with primary Sjögren’s syndrome have B cell disturbances resulting in hypergammaglobulinemia and autoantibody production. Most patients are not treated by immunomodulatory drugs, enabling studies of an unmanipulated human autoreactive immune system. In this study we used the novel approach of employing vaccination as a tool to analyze immune responses in vivo.

Methods: Patients with Sjögren’s syndrome receiving no treatment and healthy controls were vaccinated twice against the H1N1 influenza, and monitored by multiple sampling.

Results: Surprisingly, patients developed higher titers of IgG H1N1 antibodies, increased total IgG and increased autoantibody levels in response to vaccination. In addition, an expansion of CD138+ plasmablasts was observed, and up-regulation of several B cell promoting cytokines, including IL-10, IL-6 and IL-7. To dissect the B cell hyperreactivity, immunoglobulin class switch was induced in vitro in CD19+IgD+ B cells from patients and controls. Significantly more plasmablasts and higher titers of IgM and IgG were observed in TLR9 stimulated Sjögren-patient derived cultures in vitro. Similar results were obtained by TLR7 stimulation, but not by a-CD40 or BAFF that induce class switch through other pathways. The importance of the endosomal TLR pathway in plasma cell differentiation and immunoglobulin production was further demonstrated by analyzing B cells from patients treated with the drug chloroquine, which targets the endosome. In these patients, no differences were observed in class switch and plasma cell differentiation compared to healthy individuals. This observation was further confirmed by in vitro treatment of IgD+ B cells with chloroquine which significantly inhibited class switch and plasma cell differentiation.

Conclusion: In conclusion, we demonstrate for the first time that B cell activation via endosomal TLRs leads to enhanced plasma cell differentiation and class-switch in patients with Sjögren’s syndrome, explaining the induction of hypergammaglobulinemia in Sjögren’s syndrome patients.

Disclosure:

M. Wahren-Herlenius,
None;

S. Brauner,
None;

M. Kvarnström,
None;

L. Folkersen,
None;

S. Görgen,
None;

C. Trollmo,
None;

V. Malmström,
None;

G. Nordmark,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/endosomal-tlr-triggering-of-b-cells-in-sjogrens-syndrome-induces-increased-plasma-cells-differentiation-ig-class-switch-and-immunoglobulin-production/