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Streptococcal infections are known to trigger autoimmune disorders, affecting millions worldwide. Recently, we found an association between post-streptococcal autoantibodies against Protein Disulphide Isomerase (PDI), an enzyme involved in insulin degradation and insulin resistance. This led us to evaluate associations between post-streptococcal antibodies and metabolic syndrome, as defined by the updated National Cholesterol Education Program definition, 2005. Metabolic data (HDL, triglycerides, fasting glucose, blood pressure, waist circumference, BMI, smoking), post-streptococcal antibodies (anti-Streptolysin O (ASO) and anti-PDI), and C-reactive protein (CRP, as a general inflammatory marker), were assessed in 1156 participants of the Wisconsin Sleep Cohort Study. Anti-PDI antibodies were found in 308 participants (26.6%), ASO≥100 in 258 (22.3%), and 482 (41.7%) met diagnostic criteria for metabolic syndrome. Anti-PDI antibodies but not ASO were significantly associated with metabolic syndrome [n = 1156, OR 1.463 (95% CI 1.114, 1.920), p = 0.0062; adjusted for age, gender, education, smoking]. Importantly, the anti-PDI-metabolic syndrome association remained significant after adjusting for CRP and fasting insulin. Post-streptococcal anti-PDI antibodies are associated with metabolic syndrome regardless of fasting insulin and CRP levels. Whereas these data are in line with a growing body of evidence linking infections, immunity and metabolism, additional studies are necessary to establish the post-streptococcal-metabolic syndrome association.

Post-streptococcal autoimmunity affects millions worldwide, targeting multiple organs including the heart, brain, and kidneys. To explore the post-streptococcal autoimmunity spectrum, we used western blot analyses, to screen 310 sera from healthy subjects with (33%) and without (67%) markers of recent streptococcal infections [anti-Streptolysin O (ASLO) or anti-DNAse B (ADB)]. A 58 KDa protein, reacting strongly with post-streptococcal sera, was identified as Protein Disulfide Isomerase (PDI), an abundant protein with pleiotropic metabolic, immunologic, and thrombotic effects. Anti-PDI autoantibodies, purified from human sera, targeted similar epitopes in Streptolysin O (SLO, P51-61) and PDI (P328-338). The correlation between post-streptococcal status and anti-human PDI auto-immunity was further confirmed in a total of 2987 samples (13.6% in 530 ASLO positive versus 5.6% in 2457 ASLO negative samples, p<0.0001). Finally, anti-PDI auto-antibodies inhibited PDI-mediated insulin degradation in vitro (n = 90, p<0.001), and correlated with higher serum insulin (14.1 iu/ml vs. 12.2 iu/ml, n = 1215, p = 0.039) and insulin resistance (Homeostatic Model Assessment (HOMA) 4.1 vs. 3.1, n = 1215, p = 0.004), in a population-based cohort. These results identify PDI as a major target of post-streptococcal autoimmunity, and establish a new link between infection, autoimmunity, and metabolic disturbances.