B-cell hyperactivity in primary Sjögren's syndrome

Abstract

Primary Sjögren's syndrome (pSS) is characterized by mononuclear inflammatory infiltrates and IgG plasma cells in salivary and lacrimal glands which lead to irreversible destruction of the glandular tissue and is accompanied by sensation of dryness of mouth and eyes. B cells play a central role in the immunopathogenesis and exhibit signs of hyperactivity. Hyperactivity of B cells is the consequence of the coordinated and integrated action of stimulation of the B-cell receptor, CD40 and toll-like receptors in the presence of appropriate cytokines. As discussed, overexpression of type I IFN and BAFF on one hand and IL-6 and IL-21 on the other hand are critically involved in the enhanced plasma cell formation in pSS patients. Hyperactivity of B cells results in secretion of autoantibodies and production of various cytokines. These insights in the role of B cells in the pathogenetic process of pSS offer ample targets for successful therapeutical intervention in pSS.

Keywords::

• autoantibodies
• autoimmunity
• B cells
• chemokines
• cytokines
• primary Sjögren's syndrome
• pathogenesis
• salivary gland

Financial & competing interests disclosure

Work that has been described in this review has been sponsored in the past by grants from the NIH (USA), Dutch Arthritis Foundation and by an unrestricted investigator driven grant from Hoffman La Roche. H Bootsma was sponsored by unrestricted investigator driven grants from Hoffman La Roche and Bristol Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Periductal lymphoid infiltrates in salivary glands and presence of IgG plasma cells are the major histopathological finding in primary Sjögren's syndrome (pSS). With time, the organization grade of the infiltrates increase, leading to ectopic lymphoid tissue with a dominance of B cells during disease progression and presence of ectopic germinal centers.

• Chemokines are the driving force of the recruitment of lymphocytes. Initially proinflammatory chemokines such as CXCL10 are involved, while at later stages the homeostatic chemokines CXCL12, CXCL13, CCL19 and CCL21 play a critical role in maintaining the inflammatory infiltrate.

• Besides B-cell receptor/CD40/Toll-like receptor engagement, cytokines are critically involved in B-cell activation. Key cytokines involved in B cell activation, proliferation and differentiation are all overexpressed in salivary gland tissue, saliva and serum. Both the type I interferon/B cell-activating factor/a proliferation-inducing ligand axis and the IL-6/IL-21 axis contribute to the hyperactivity of B cells in pSS patients.

• B-cell hyperactivity is further reflected by presence of clonal expansions in salivary gland tissue, which may culminate in neoplastic transformations, leading to non-Hodgkin lymphoma.

• Changes in B cell subset distribution in peripheral blood also reflect increased hyperactivity. Increased expression of CD38 on B cells and reduced numbers and frequencies of CD27⁺ memory B cells may be suggestive of their activated state.

• Aberrant signaling of the B-cell receptor might be involved in breaking tolerance and development of autoimmune disease. Both B cell intrinsic factors and Toll-like receptor engagement may play a role in this process.

• Hyperactivation leads to increased antibody production, resulting in hypergammaglobulinemia, elevated levels of free light chains and β2-microglobulin and production of autoantibodies directed against SSA/Ro and SSB/La autoantigens and rheumatoid factor. In addition to this classical role of B cells, they are an important source of cytokine production.

• Understanding the role of B cells in pSS pathogenesis, availability of biological disease-modifying antirheumatic drugs to a variety of targets involved in B cell activation and development of disease activity indices European League Against Rheumatism Sjögren's syndrome disease activity index and patient reported index are crucial for the development beneficial therapies for treatment of pSS patients.

Notes