Immune-Intrinsic Myd88 Directs the Production of Antibodies With Specificity for Extracellular Matrix Components in Primary Sjögren’s Syndrome

Abstract

Primary Sjögren’s syndrome is an autoimmune disease that is predominantly seen in women. The disease is characterized by exocrine gland dysfunction in combination with serious systemic manifestations. At present, the causes of pSS are poorly understood. Pulmonary and renal inflammation are observed in pSS mice, reminiscent of a subset of pSS patients. A growing body of evidence indicates that inflammation mediated by Damage-Associated Molecular Patterns (DAMPs) contributes to autoimmunity, although this is not well-studied in pSS. Degraded extracellular matrix (ECM) constituents can serve as DAMPs by binding pattern-recognition receptors and activating Myd88-dependent signaling cascades, thereby exacerbating and perpetuating inflammatory cascades. The ECM components biglycan (Bgn) and decorin (Dcn) mediate sterile inflammation and both are implicated in autoimmunity. The objective of this study was to determine whether these ECM components and anti-ECM antibodies are altered in a pSS mouse model, and whether this is dependent on Myd88 activation in immune cells. Circulating levels of Bgn and Dcn were similar among pSS mice and controls and tissue expression studies revealed pSS mice had robust expression of both Bgn and Dcn in the salivary tissue, saliva, lung and kidney. Sera from pSS mice displayed increased levels of autoantibodies directed against ECM components when compared to healthy controls. Further studies using sera derived from conditional knockout pSS mice demonstrated that generation of these autoantibodies relies, at least in part, on Myd88 expression in the hematopoietic compartment. Thus, this study demonstrates that ECM degradation may represent a novel source of chronic B cell activation in the context of pSS.

The Role of Decorin in Autoimmune and Inflammatory Diseases

“…5 Journal of Immunology Research and kidney tissues of pSS mice [79]. Our study also found that decorin was significantly elevated in the salivary glands in the experimental Sjögren's syndrome model and pSS patients, and decorin induced the apoptosis of A253 cells and polarization of macrophages towards the M1 phenotype [54].…”

“…This indicates that decorin may have a different effect on different cytokines/chemokines and immune cells in SS. Further studies showed that although circulating levels of decorin were not different between NOD.B10 mice and control mice, autoantibodies against decorin were significantly elevated in pSS mice, and decorin was highly expressed in the salivary gland, lung, and kidney tissues of pSS mice [ 79 ]. Our study also found that decorin was significantly elevated in the salivary glands in the experimental Sjögren's syndrome model and pSS patients, and decorin induced the apoptosis of A253 cells and polarization of macrophages towards the M1 phenotype [ 54 ].…”

Autologous mesenchymal stem cells offer a new paradigm for salivary gland regeneration

“…While there is no difference in the expression of Bgn and Dcn in the SGs of healthy and SS control mice, Kiripolsky et al demonstrated that SS mice displayed increased levels of anti-Bgn and -Dcn autoantibodies relative to healthy controls. 36 Thus, emerging evidence suggests that degradation of the SG-ECM and basal lamina may precede (or take place in parallel with) the onset of inflammation, which is widely considered the ultimate cause of SS development. These findings suggest that potential therapies, which aim to restore a healthy SG microenvironment, may be a very promising, if relatively unexplored, therapeutic avenue.…”

Identification of Genetic Predisposition to Sjögren’s Syndrome by Whole Exome Sequencing

“…6). In the pathological state, ECM components can serve as damage-associated molecular patterns (DAMPs) that exacerbate and perpetuate inflammatory cascades and may provide a novel source of chronic B cell activation in SjS [63].…”