Apoptosis of the secretory epithelium as a triggering factor of early dysfunction and autoimmune response has been explored in SS patients and models [32–34] and the potential of certain TNF-α superfamily members, as SS susceptibility biomarkers has emerged from microarray studies in a transgenic mice model of SS [35]. Remarkably, local over-expression of TNF-αR1 in murine glands was shown to reduce saliva secretion [36], while TNF-α has been reported as a potent BVD-523 cell line inducer of acinar apoptosis and TNF-αR1 expression in prediabetic

NOD mice [16]. However, TNF-α/TNF-αR1effects are also commonly associated with cytokine synthesis and cell survival in immune cells, being the final cellular fate determined primarily by a pivotal factor such as NF-κB [28]. NF-κB is dysregulated in autoimmune disorders and, particularly in SS patients but not in other autoimmune disorders, a lack of a proteasome subunit – multi-functional peptidase 2 – in immune cells could result in a lower NF-κB activity

[37]. Finally, macrophage high functional plasticity guarantees ABT-888 in vitro the silent clearance of apoptotic cells that involves the synthesis of anti-inflammatory mediators IL-10, PGE2 and TGF-β to maintain tissue homeostasis [38]. While NOD macrophages expressed an inflammatory profile in resting conditions, a shift to a regulatory phenotype of NOD macrophages was seen when faced to apoptotic acinar cells. Interestingly, NOD macrophages presented lower phagocytosis of acinar apoptotic cells. A lower avidity and efficacy to engulf apoptotic thymocytes has been reported previously for NOD macrophages [39–41]. In contrast to results presented herein, phagocytosis of apoptotic thymocytes elicited an inflammatory profile in NOD macrophages, suggesting that selective suppressor mechanisms PFKL might be involved in the clearance of apoptotic acinar cells. Evidence presented here also suggests that VIP might contribute to the homeostatic surveillance function of macrophages in the glands by stabilizing a regulatory phenotype for

silent phagocytic clearance. This work was funded by the National Agency of Sciences and Technology ANPCyT (PICT 1971 and 2165) and University of Buenos Aires (20020100100505 and X172). The authors declare that they have no competing interests. “
“Granulomatous experimental autoimmune thyroiditis (G-EAT) is induced by mouse thyroglobulin (MTg)-sensitized splenocytes activated with MTg and interleukin (IL)-12. Our previous studies showed that, when used as donors and recipients, interferon (IFN)-γ−/− and wild-type (WT) DBA/1 mice both develop severe G-EAT. Thyroid lesions in IFN-γ−/− mice have many eosinophils and few neutrophils, while those in WT mice have extensive neutrophil infiltration and few eosinophils.