Regenerating Gene Protein as a Novel Autoantigen in the Pathogenesis of Sjögren’s Syndrome

Takashi Fujimoto,Kiyomi Yoshimoto,Maiko Takeda,Asako Itaya-Hironaka,Takanori Fujimura,Shin Takasawa,Akiyo Yamauchi

doi:10.3390/antib4040409

Takashi Fujimoto, Kiyomi Yoshimoto + Show 5 more

Open Access

https://doi.org/10.3390/antib4040409

Copy DOI

Abstract

Sjögren’s syndrome, an autoimmune disease characterized by exocrine gland dysfunction leading to dry mouth and dry eye diseases, is typified by lymphoplasmacytic infiltrations and a progressive destruction of the salivary and lacrimal glands. Despite an ever-increasing focus on identifying the underlying etiology of Sjögren’s syndrome, the factors that initiate this autoimmune disease and the mechanisms that cause the subsequent exocrine gland dysfunction remain a mystery. The original explanatory concept for the pathogenesis of Sjögren’s syndrome proposed a specific, self-perpetuating, immune-mediated loss of acinar and ductal cells as the principal cause of salivary gland dysfunction. We highlight the possible involvement of regenerating gene (Reg) in the regeneration and destruction of salivary gland acinar and ductal cells in Sjögren’s syndrome. The Reg gene was originally isolated as a gene specifically overexpressed in regenerating pancreatic islets and constitutes a growth factor family (Reg family). We describe how salivary gland dysfunction is initiated and maintained and how it can be regenerated or progressed, mediated by the Reg gene, Reg protein, and anti-REG autoantibodies in Sjögren’s syndrome.

Highlights

Sjögren’s syndrome (SS) is a chronic inflammatory disease that affects the exocrine glands, the salivary and lacrimal glands, leading to xerostomia and xerophthalmia and characterized by the presence of a variety of autoantibodies directed against organ- and non-organ-specific autoantigens
The deletion down to position -141 did not attenuate IL-6-induced REG Iα promoter activity; an additional deletion to -117 caused a remarkable decrease in the IL-6-induced promoter activity of REG Iα [85]. These results indicated that the promoter region of -141 to -117 of the REG Iα gene was responsible for the REG Iα promoter activation in salivary ductal cells by IL-6
Our findings demonstrate that REG Iα overexpression in salivary ductal cells is induced by IL-6 but not by IL-8 at the transcriptional level, and this IL-6 stimulation enhanced REG Iα gene expression through STAT3 activation

Summary

Introduction

Sjögren’s syndrome (SS) is a chronic inflammatory disease that affects the exocrine glands, the salivary and lacrimal glands, leading to xerostomia and xerophthalmia and characterized by the presence of a variety of autoantibodies directed against organ- and non-organ-specific autoantigens. It is known that the production of autoantibodies is an antigen-driven immune response as certain autoantibodies are disease-specific, contain multiple epitopes, and the autoimmune response is perpetuated and augmented via intra- and inter-molecular spreading against the same or other autoantigens. It is unknown whether any of the autoantibodies has a direct pathogenic potential or if they merely participate in a secondary response to salivary glands that are already damaged by another process. REG Iα mRNA as well as its product (REG Iα protein) were overexpressed in ductal epithelial cells in the minor salivary glands (MSG) of primary SS (pSS) patients [13]. We aim to describe important pathogenetic mechanisms involved in the initiation and perpetuation of SS mediated by the regenerating gene, Reg, Reg protein, and autoantibodies against Reg protein

Pathogenesis of Sjögren’s Syndrome

General Aspects

Anti-REG Iα Autoantibodies

Gene Expression of REG Iα as an Auto-Antigen

Findings

Conclusions