Abstract
Abstract: :
Purpose: Sjögren’s Syndrome (SjS) is characterized by lymphocytic infiltration, functional quiescence, and eventual destruction of the lacrimal and salivary epithelia. Evidence indicates that vesicular traffic between the lacrimal epithelial cell endomembrane network and plasma membrane constitutively secretes autoantigens to the underlying tissue. Accordingly, autoimmune disease may result when physiological or environmental perturbations disrupt immunoregulatory networks that maintain normal self tolerance. Methods: Soluble (Si), membrane–associated (Pi), and nuclear/debris (Po) fractions were obtained from mouse tissues. Acinar cells from rabbit lacrimal glands were maintained ex vivo with and without chronic carbachol (CCh) stimulation, then analyzed by density gradient centrifugation and phase partitioning. Western blots were probed with sera from diseased male NOD mice and from NOD females without established diabetes. Results: IgG from both males and females labeled 92 kDa and 52 kDa bands from rabbit acinar cells and mouse exocrine glands and kidney. IgG from males, but not non–diseased females, also labeled bands at 35 kDa, 30 kDa, and 22 kDA. All autoantigens were preferentially located in Pi, rather than Si, and primarily associated with biosynthetic and lysosomal compartments. The 30 kDa and 22 kDa autoantigens were additionally present in a secretory vesicle (SV)–related compartment from control cells, but accumulated in biosynthetic compartments and appeared in endosomes during chronic CCh stimulation. Conclusions: Functional and immunological similarities between autoimmune exocrinopathy in humans and NOD mice suggest the NOD mouse is an appropriate model for the pathogenesis of Sjs. Homologues to a number of NOD autoantigens are present in rabbit lacrimal glands and are recognized by mouse IgG. Like previously recognized SjS autoantigens, the autoantigens detected in this study are concentrated in endomembrane compartments. The disease–related autoantigens appear to reflux to the Golgi complex and endosomes during the aberrant membrane traffic program activated by chronic CCh stimulation. Since chronic CCh stimulation also causes catalytically active cathepsins to reflux to the Golgi complex and endosomes, we suggest the aberrant traffic program leads to aberrant autoantigen processing that might generate previously cryptic epitopes.
Keywords: autoimmune disease • lacrimal gland • antigen presentation/processing