LAUSR

Systemic sclerosis (SSc) is an autoimmune systemic vasculopathy that leads to wide-spread organ fibrosis. Gastrointestinal (GI) involvement in SSc is common and often results in debilitating symptoms that can lead to malnutrition and in severe cases dependence on total parenteral nutrition (TPN). There are multiple causes of GI symptoms in SSc, including dysfunction of the lower esophageal sphincter which can lead to chronic gastrointestinal reflux disease (GERD) and strictures, GI dysbiosis [1] including small intestinal bowel overgrowth (SIBO), food intolerance (e.g., fructose, lactose) [2, 3], and dysmotility of the GI tract (i.e., esophagus, stomach, small and large bowel). Our understanding of GI dysbiosis in medicine, and particularly in SSc, is still evolving, and the relationship between transit abnormalities and dysbiosis is still poorly understood. While gastric emptying tests are widely available, other more specialized imaging tests to evaluate for dysmotility throughout the GI tract are limited in availability and not well-studied in SSc. Serum biomarkers to diagnose and monitor GI disease in SSc are lacking, especially biomarkers that can reliably detect early GI disease activity. In addition, questions remain about how to identify subgroups at high risk for GI progression and whether the early application of promotility agents or immunomodulation prior to the development of progressive smooth muscle atrophy and GI fibrosis is beneficial for such patients. It is well-known that autoantibodies in SSc predict clinical phenotype [4]. Several studies have implicated anti-neuronal autoantibodies in SSc GI dysmotility, which are thought to reflect an immune response directed against the enteric nervous system. Autoantibodies targeting the myenteric plexus are present in a subset of SSc patients [5], as well as muscarinic-3 acetylcholine receptor autoantibodies (antiM3R) and anti-ganglionic acetylcholine receptor autoantibodies (anti-gAChR) which associate with severe GI involvement [6, 7]. However, these autoantibodies are not present in all SSc patients with GI disease, and so other autoantibodies likely remain to be discovered. Dr. Suliman and colleagues identify autoantibodies targeting the protein vinculin in a SSc cohort that associate with GI symptom severity. Vinculin is a cytoplasmic protein that binds to actin and is involved in cell adhesion. The authors demonstrate that anti-vinculin autoantibody levels are higher and these autoantibodies are more frequently identified in a SSc cohort enriched with GI disease compared with a healthy control population. Anti-vinculin autoantibody levels also associate with the severity of GI symptoms as measured by the GI-visual analogue score (GI-VAS). The presence of anti-vinculin autoantibodies in SSc is consistent with prior studies which have implicated vinculin as an important regulator of the enteric nervous system. Vinculin is notably involved in neuronal migration and axon growth, and vinculin deletion from mouse neocortical neurons results in attenuation of axon growth in vivo [8]. One study found an inverse association between anti-vinculin autoantibody titers and the density of interstitial cells of Cajal (ICC) in the myenteric plexus of human stomach from patients with gastric cancer [9]. The primary function of ICC is to serve as the pacemaker for gut motility by mediating neurotransmission between the autonomic nervous system and smooth muscle cells [10], and so the low density of ICC among patients with anti-vinculin autoantibodies suggests that gastric ICC may be affected by this aberrant immune response targeting vinculin. Some patients with SSc have reduced esophageal ICC [11], although the presence of anti-vinculin autoantibodies among these patients remains unknown. Autoantibodies targeting vinculin were first discovered in irritable bowel syndrome (IBS) [12], a GI dysmotility syndrome that is thought to be in part immunologically mediated * Brittany L. Adler [email protected]