Conjunctival Inflammation in Thrombospondin-1 Deficient Mouse Model of Sjögren’s Syndrome

Laura Contreras-Ruiz,James Kearns,Sharmila Masli,Fayaz Ahmad Mir,Birgit Regenfuss

doi:10.1371/journal.pone.0075937

Abstract

Lacrimal gland inflammation during autoimmune Sjögren’s syndrome (SS) leads to ocular surface inflammation – Keratoconjunctivitis sicca (KCS). This condition afflicts both the cornea and conjunctiva that form the ocular surface. Thrombospondin-1 (TSP-1) deficiency in mice results in lacrimal gland and corneal inflammation that resembles the human disease. In this study we report conjunctival pathology in this mouse model of SS. We found that TSP-1 null mice develop inflammation in the conjunctiva and associated loss of goblet cell function similar to that seen in patients with SS. Increased expression of Th1 (IFN-γ, TNF-α) and Th17 (IL-6, IL-17A) inflammatory cytokines and related transcription factors (Tbet and RORγt) were detected in TSP-1 null conjunctiva as well as their draining lymph nodes (LNs). The conjunctival inflammation was also accompanied by an increase in local lymphatic vessels. Interestingly, migration of antigen-bearing dendritic cells (DCs) from the ocular surface to the LNs was dependent on the TSP-1 available in the tissue. These results not only reveal potential immunopathogenic mechanisms underlying KCS in SS but also highlight the therapeutic potential of TSP-1.

Highlights

Sjögren’s syndrome (SS) is the second most common autoimmune rheumatic disease and afflicts an estimated 2-4 million individuals in the United States [1]
At 12 weeks, TSP-1 null conjunctiva displayed a marked thickening of the outer epithelial layers, a relative decrease in goblet cell numbers and a prominent infiltration of inflammatory cells, while no such alterations were detectable in WT conjunctiva
In this study we report that, as in SS, inflammatory damage in TSP-1 null mice is detected in the conjunctiva

Summary

Introduction

Sjögren’s syndrome (SS) is the second most common autoimmune rheumatic disease and afflicts an estimated 2-4 million individuals in the United States [1] It is an autoimmune exocrinopathy involving chronic inflammation and progressive functional loss of exocrine glands – salivary and lacrimal glands. The secretory deficit of these glands affects the target organ protected by their secretions resulting in clinical manifestations of xerostomia (dry mouth) and xerophthalmia (dry eye). The latter condition is referred to as Keratoconjunctivitis sicca (KCS) indicating the dryness and inflammation of the cornea and conjunctiva of the eye that form the ocular surface. An animal model that recapitulates most pathologic features of the disease can serve as a useful tool to reveal underlying mechanisms and to develop comprehensive therapeutic approaches that target multiple pathologic aspects of the disease

Methods

Results

Conclusion