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B Cell-activating Factor of the Tumor Necrosis Factor in SS

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B Cell-activating Factor of the Tumor Necrosis Factor in SS
B cell-activating factor (BAFF) has a key role in promoting B-lymphocyte activation and survival in primary Sjögren's syndrome (pSS). The cellular origin of BAFF overexpression in salivary glands of patients with pSS is not fully known. We investigated whether salivary gland epithelial cells (SGECs), the main targets of autoimmunity in pSS, could produce and express BAFF. We used quantitative RT-PCR, ELISA and immunocytochemistry in cultured SGECs from eight patients with pSS and eight controls on treatment with IL-10, tumor necrosis factor α (TNF-α), IFN-α and IFN-γ. At baseline, BAFF expression in SGECs was low in pSS patients and in controls. Treatment with IFN-α, IFN-γ and TNF-α + IFN-γ increased the level of BAFF mRNA in pSS patients (the mean increases were 27-fold, 25-fold and 62-fold, respectively) and in controls (mean increases 19.1-fold, 26.7-fold and 17.7-fold, respectively), with no significant difference between patients and controls. However, in comparison with that at baseline, stimulation with IFN-α significantly increased the level of BAFF mRNA in SGECs of pSS patients (p = 0.03) but not in controls (p = 0.2), which suggests that SGECs of patients with pSS are particularly susceptible to expressing BAFF under IFN-α stimulation. Secretion of BAFF protein, undetectable at baseline, was significantly increased after IFN-α and IFN-γ stimulation both in pSS patients (40.8 ± 12.5 (± SEM) and 47.4 ± 18.7 pg/ml, respectively) and controls (24.9 ± 8.0 and 9.0 ± 3.9 pg/ml, respectively), with no significant difference between pSS and controls. Immunocytochemistry confirmed the induction of cytoplasmic BAFF expression after stimulation with IFN-α and IFN-γ. This study confirms the importance of resident cells of target organs in inducing or perpetuating autoimmunity. Demonstrating the capacity of SGECs to express and secrete BAFF after IFN stimulation adds further information to the pivotal role of these epithelial cells in the pathogenesis of pSS, possibly after stimulation by innate immunity. Our results suggest that an anti-BAFF therapeutic approach could be particularly interesting in pSS.

Primary Sjögren's syndrome (pSS) is a prototypical autoimmune disorder characterized by lymphocytic infiltration of salivary and lachrymal glands leading to xerostomia and keratoconjunctivitis sicca. Polyclonal B cell activation and systemic production of autoantibodies are the main laboratory findings characterizing pSS. Patients with pSS are at increased risk for the development of B cell non-Hodgkin's lymphoma, and some evidence exists that such lymphomas arise from autoreactive B cells.

Recruitment of activated and memory B cells in salivary gland infiltrates, germinal center formation in 20 to 25% of patients, and local secretion of autoantibodies demonstrate the pathogenic role in situ of B cell activation in pSS. Increased expression of a newly described cytokine, termed B cell-activating factor (BAFF) or B-lymphocyte stimulator (BLyS), might explain this pathogenic B cell activation in several systemic autoimmune diseases including pSS.

BAFF has a crucial role in B cell maturation, plasma cell survival, antibody response promotion and immunoglobulin-class switch recombination. Interestingly, for reasons that are not fully understood, autoreactive B cells depend on BAFF for survival more than alloreactive B cells do. The involvement of BAFF in the pathogenesis of autoimmune diseases is well illustrated by BAFF overexpression in mice models, which leads to autoimmune disease mimicking rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and pSS, as well as a twofold increase in occurrence of B cell lymphoma. In humans, an increased serum level of BAFF was reported in patients with RA and SLE, but the more consistent findings concerned pSS, with an increase in BAFF level reported in all four published surveys of patients with pSS. Moreover, we demonstrated in pSS a correlation between the serum level of BAFF and serum level of immunoglobulins and titers of autoantibodies.

Using immunohistochemistry, we and others have shown increased expression of BAFF in salivary glands of patients with pSS. We recently extended these results by demonstrating a threefold increase in BAFF mRNA level in the two main target organs of pSS salivary glands and the ocular surface. However, the cellular origin of BAFF expression in salivary glands of patients with pSS is not well understood. Indeed, monocytes and myeloid dendritic cells, the main cell types involved in the physiological expression of BAFF, are not present in large amounts in salivary glands of patients with pSS. Using immunohistochemistry, we localized BAFF expression in the T cell infiltrate and ductal epithelial cells. However, we could not eliminate the possibility that this finding was due to the passive fixation of BAFF on its receptor.

Glandular epithelial cells are the main target cells of autoimmunity in pSS, currently considered to be an autoimmune epithelitis. These cells, after exogenous aggression, possibly of viral origin, express co-stimulation molecules and lymphoid chemokines and are suitably equipped to present autoantigens, which suggests that salivary gland epithelial cells (SGECs) can act as non-professional antigen-presenting cells. Thus, we proposed that SGECs could also express BAFF in pSS. To avoid the limitation of immunohistochemical studies, potentially showing passive BAFF fixation on one of its receptors rather than the cellular production of BAFF, we investigated BAFF mRNA expression in salivary gland cell lines. We then investigated BAFF mRNA expression in SGECs from patients with pSS and controls, and BAFF protein secretion in supernatants from these cell cultures. We evaluated the contribution of different patterns of cytokine environment on BAFF mRNA and protein expression, using stimulations with various cytokines known to have a pathogenic role in pSS. Our results demonstrate the inducible expression of BAFF mRNA and BAFF protein under stimulation by IFN in SGECs, which might have a key pathogenic role in pSS autoimmune epithelitis.

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