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The correct sentence for this section is: \"Our findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland function in the absence of inflammation while systemic deletion can induce a primary Sjögren’s syndrome like phenotype with autoimmunity and loss of gland function.\" (2014) Matriptase Deletion Initiates a Sjögren’s Syndrome-Like Disease in Mice.

Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P sub(1)) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P sub(1) signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P sub(1) phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P sub(1)(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (T sub(H)17 cells) in the peripheral immune and nervous system. S1P sub(1) directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P sub(1) phosphorylation enhances T sub(H)17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.

Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds β2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that β2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.

Forkhead box P3 (FOXP3)-expressing regulatory T (T sub(Reg)) cells have a pivotal role in the regulation of immune responses and in the maintenance of immunological self-tolerance. These cells have emerged as attractive targets for strategies that allow the steering of immune responses in desired directions - arming the immune system to destroy infected cells and cancer cells or downregulating it to limit tissue destruction in autoimmunity. Efforts to understand the generation, activation and function of T sub(Reg) cells should permit the development of therapeutics for reprogramming the immune system. In this Review, we discuss insights into the generation of T sub(Reg) cells, their involvement in disease and the molecular basis of the dominant tolerance exerted by FOXP3 super(+) T sub(Reg) cells that could permit their safe and specific manipulation in humans.

Autoreactive CD8 super(+) regulatory T cells (Tregs) play important roles as modulators of immune responses against self, and numerical and functional defects in CD8 super(+) Tregs have been linked to autoimmunity. Several subsets of CD8 super(+) Tregs have been described. However, the origin of these T cells and how they participate in the natural progression of autoimmunity remain poorly defined. We discuss several lines of evidence suggesting that the autoimmune process itself promotes the development of autoregulatory CD8 super(+) T cells. We posit that chronic autoantigenic exposure fosters the differentiation of non-pathogenic autoreactive CD8 super(+) T cells into antigen-experienced, memory-like autoregulatory T cells, to generate a \"negative feedback\" regulatory loop capable of countering pathogenic autoreactive effectors. This hypothesis predicts that approaches capable of boosting autoregulatory T cell memory will be able to blunt autoimmunity without compromising systemic immunity.

ObjectivesTo analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.MethodsThe Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed.ResultsWe included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69).ConclusionsThis study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.