Central role for marginal zone B cells in an animal model of Sjogren's syndrome

Abstract

Patients with Sjogren’s syndrome (SS) have been shown to have abnormal B cell function and increased numbers of marginal zone B cells (MZB and MZB precursors. The current studies utilized the Interleukin 14 alpha transgenic mouse model (IL14aTG) for SS to investigate the roles of marginal zone B cells (MZB) of the innate immune system in the pathophysiology of the disease. Eliminating MZB from IL14aTG mice by B cell specific deletion of RBP-J resulted in complete elimination of all disease manifestations of SS. Mice had normal salivary gland secretions, negative autoantibodies and normal histology of the salivary and lacrimal glands compared to IL14aTG mice at the same time points. In contrast, eliminating B1 cells by deleting btk did not ameliorate the disease. Therefore, MZB are critical for the development of SS.

Systemic manifestations of primary Sjögren's syndrome in the NOD.B10Sn-H2/J mouse model

“…Murine anti-ANA ELISAs (Alpha Diagnostics) were also carried out in accordance with manufacturer instructions with the following modifications: horseradish peroxidase conjugated to anti-IgG or IgM respectively was used to detect isotype-specific ANA (Southern Biotech), as previously described [10]. Murine anti-carbonic anhydrase 6 (CA6), anti-parotid secretory protein (PSP), and anti-salivary protein-1 (SP1) ELISAs were developed and performed by Immco Diagnostics, as previously described [12]. …”

What can Sjögren's syndrome-like disease in mice contribute to human Sjögren's syndrome?

“…Fortunately, these types of studies are now feasible with recent advances in – omics technology and the recently developed B6· Baff and B6· IL14a TG mice [85]. The interleukin-IL14α transgenic B6· IL14a mouse not only reproduces the clinical and immunological features of SS, but also a temporal development of lymphomagenesis directly correlating with age [25,86,87]. Importantly, lymphomas of these mice are clinically and genetically similar to lymphomas commonly seen in human SS patients, thereby permitting longitudinal and translational studies capable of addressing the evolution of the autoimmune disease and lymphomagenesis simultaneously from both a genetic and immunological perspective.…”

Multiple Roles for B-Lymphocytes in Sjogren’s Syndrome

“…First, increased numbers of MZB and MZB precursors have been noted [38,39,40]. In both BAFF transgenic mice and IL-14α transgenic mice, deletion of MZB results in elimination of all the features of SS [39,41].…”

“…First, increased numbers of MZB and MZB precursors have been noted [38,39,40]. In both BAFF transgenic mice and IL-14α transgenic mice, deletion of MZB results in elimination of all the features of SS [39,41]. Second, salivary gland hypo-function has been noted before lymphocytes are present in the salivary gland, suggesting that the lymphocytes themselves are not directly inducing cellular cytotoxicity [32,36,42].…”

“…First, eliminating lymphotoxin-alpha (LTα) prevents the development of all the clinical manifestations of SS [43]. MZB spontaneously produces LTα in IL14α transgenic mice, but not in C57BL/6 controls [39]. Eliminating the type 1 interferon receptor has no influence on the early manifestations of SS, submandibular and lacrimal gland injury, but does prevent late manifestations, such as parotid gland and lung injury and lymphoma [37].…”