title: Post-streptococcal auto-antibodies inhibit protein disulfide isomerase and are associated with insulin resistance.
abstract: 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.
authors.affiliation: Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, United States of America.
authors.forename: Adi
authors.initials: A
authors.lastname: Aran
authors.forename: Karin
authors.initials: K
authors.lastname: Weiner
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Laurel Ann
authors.initials: LA
authors.lastname: Finn
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Greco
authors.forename: Paul
authors.initials: P
authors.lastname: Peppard
authors.forename: Terry
authors.initials: T
authors.lastname: Young
authors.forename: Yanay
authors.initials: Y
authors.lastname: Ofran
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D019704:Protein Disulfide-Isomerases / Q000276:immunology*; D013290:Streptococcal Infections / Q000150:complications / Q000201:enzymology / Q000276:immunology*; D013291:Streptococcus / Q000276:immunology*; D055815:Young Adult
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001323:Autoantibodies; D007328:Insulin; D019704:Protein Disulfide-Isomerases