Expansion of Autoreactive Unresponsive CD21−/low B Cells in Sjögren's Syndrome–Associated Lymphoproliferation

D Saadoun, B Terrier, J Bannock… - Arthritis & …, 2013 - Wiley Online Library
D Saadoun, B Terrier, J Bannock, T Vazquez, C Massad, I Kang, F Joly, M Rosenzwajg
Arthritis & Rheumatism, 2013Wiley Online Library
Abstract Objective Primary Sjögren'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 …
Objective
Primary Sjögren'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.
Wiley Online Library