Journal
ARTHRITIS AND RHEUMATISM
Volume 65, Issue 4, Pages 1085-1096Publisher
WILEY-BLACKWELL
DOI: 10.1002/art.37828
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Funding
- Agence Nationale pour la Recherche sur le Sida et les Hepatites
- NIH (National Institute of Allergy and Infectious Diseases) [AI-061093, AI-071087, AI-082713, AI-095848]
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Objective Primary Sjogren's syndrome (SS) is an autoimmune disease associated with a high risk of developing non-Hodgkin's lymphoma. This study was undertaken to determine the nature of B cells driving lymphoproliferation in primary SS. Methods B cell subsets and function were analyzed in peripheral blood from 66 adult patients with primary SS (including 14 patients with B cell lymphoproliferative disease [LPD]) and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. The reactivity of recombinant antibodies isolated from single B cells from patients with primary SS and LPD was tested using an enzyme-linked immunosorbent assay. Results We observed an expansion of an unusual CD21/low B cell population that correlated with lymphoproliferation in patients with primary SS. A majority of CD21/low B cells from patients with primary SS expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment, since their Ig genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21/low B cells from patients with primary SS remained responsive to Toll-like receptor (TLR) stimulation. Molecules specifically expressed in CD21/low B cells that are likely to induce their unresponsive stage were detected in gene array analyses. Conclusion Patients with primary SS who display high frequencies of autoreactive and unresponsive CD21/low B cells are susceptible to developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.
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