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.
Highlights
Beta hemolytic streptococcal infections, typically pharyngitis and skin infections, are usually benign, but can lead to serious autoimmune complications such as rheumatic heart disease, Sydenham chorea, and glomerulonephritis [1]
We found that post-streptococcal sera reacted,6 times more frequently than control sera with a 58 KDa protein (Figure 1A), present in all tested tissues with highest affinity in the colon, liver, and urinary bladder (26.4% versus 4.3% of control sera in colon, n = 310, p,0.0001)
SLO is a highly immunogenic streptococcal toxin that induces anti-Streptolysin O (ASLO) antibodies in a majority of subjects following streptococcal pharyngitis, its clinical utility as a marker
Summary
Typically pharyngitis and skin infections, are usually benign, but can lead to serious autoimmune complications such as rheumatic heart disease, Sydenham chorea, and glomerulonephritis [1]. We found a positive correlation between the onset of narcolepsy and the levels of post-streptococcal antibodies [7]. This led us to search for novel post-streptococcal autoantibodies. PDI is primarily associated with the endoplasmic reticulum (ER) where it participates in protein folding during biosynthesis. It is found on the cell membrane and may be actively secreted by various cell types [9,10]. Extracellular PDI has been shown to regulate a number of activities including: cellular adhesion [11], pathogen entry (notably HIV) [12,13], platelet aggregation and secretion [14], tissue factor pro-coagulant activity (the limiting step in activation of the coagulation cascade) [15,16,17,18], intracellular nitric oxide delivery [19], and insulin degradation [20,21]
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