Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disorder characterized by specific pathological features. A hallmark of pSS is B-cell hyperactivity as manifested by the production of autoantibodies, hypergammaglobulinemia, formation of ectopic lymphoid structures within the inflamed tissues, and enhanced risk of B-cell lymphoma. Changes in the distribution of peripheral B-cell subsets and differences in post-recombination processes of immunoglobulin variable region (IgV) gene usage are also characteristic features of pSS. Comparison of B cells from the peripheral blood and salivary glands of patients with pSS with regard to their expression of the chemokine receptors CXCR4 and CXCR5, and their migratory capacity towards the corresponding ligands, CXCL12 and CXCL13, provide a mechanism for the prominent accumulation of CXCR4+CXCR5+ memory B cells in the inflamed glands. Glandular B cells expressing distinct features of IgV light and heavy chain rearrangements, (re)circulating B cells with increased mutations of cμ transcripts in both CD27- and CD27+ memory B-cell subsets, and enhanced frequencies of individual peripheral B cells containing IgV heavy chain transcripts of multiple isotypes indicate disordered selection and incomplete differentiation processes of B cells in the inflamed tissues in pSS. This may possibly be related to a lack of appropriate censoring mechanisms or different B-cell activation pathways within the ectopic lymphoid structures of the inflamed tissues. These findings add to our understanding of the pathogenesis of this autoimmune inflammatory disorder and may result in new therapeutic approaches.
Highlights
Primary Sjögren’s syndrome is a chronic inflammatory autoimmune disease with both organ-specific and systemic manifestations [1,2,3,4]. pSS affects the salivary and lacrimal glands preferentially but may frequently involve other exocrine glands, for example those of the respiratory tract, gastrointestinal tract and skin [1,2,3,4]. pSS has been termed ‘autoimmune exocrinopathy’ [1] or ‘autoimmune epithelitis’ [4]
Disturbed clearance from salivary gland epithelial cells (SGECs) [5,16] may lead to glandular persistence of viruses and to repeated lymphocytic sialadenitis with chronic immune system stimulation [17]. It remains to be determined whether viral infection of the affected glands is primary or secondary to the development of autoimmunity in pSS or whether different viruses may act as endemic triggers in distinct human populations
Taking current data as a basis, this review focuses on the possible role of ectopically formed lymphoid tissue, including germinal center (GC)-like structures, in B-cell disturbances and autoimmune response in patients with pSS
Summary
Primary Sjögren’s syndrome (pSS) is a chronic inflammatory autoimmune disease with both organ-specific and systemic manifestations [1,2,3,4]. pSS affects the salivary and lacrimal glands preferentially but may frequently involve other exocrine glands, for example those of the respiratory tract, gastrointestinal tract and skin [1,2,3,4]. pSS has been termed ‘autoimmune exocrinopathy’ [1] or ‘autoimmune epithelitis’ [4]. The local production of IgG immune complexes, for example of anti-Ro/SSA-nucleoprotein complexes, may contribute to chronic activation and proliferation of MZ-like B cells and, to enhanced risk for lymphoma development In this regard, BAFF and APRIL, two important factors that can promote B-cell survival, have been strongly suggested to be involved in both local and systemic autoimmunity in pSS, including T-cell-independent immune responses [103,104]. B cells may represent recirculating cells from secondary or ectopically formed ‘tertiary’ lymphoid tissues with low-level, transiently expressed or shed CD27 surface molecules In this regard, recent studies of patients with pSS have suggested abnormal B-cell differentiation and activation characterized by depressed percentages of circulating CD27+ memory B cells [22,23,24], enhanced serum IgG levels and elevated levels of soluble CD27 [23]. It remains to be determined whether a molecular defect in metabolizing Ig mRNA or enhanced B-cell turnover in pSS contributes to the alterations in Ig mRNA level
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