Discovery of Novel Autoantigens in Scleroderma Patients with Gastrointestinal Dysmotility

Zsuzsanna McMahan, MD
Jay Pasricha, MD
Johns Hopkins University School of Medicine

Project Overview

Dr. McMahan and Dr. Pasricha: Gastrointestinal (GI) dysmotility is a common complication in systemic sclerosis (SSc), affecting over 90% of patients. Patients with SSc may have mild to severe GI symptoms, and dysmotility may be present anywhere from the esophagus through the colon. While it is recognized that the smooth muscle in the GI tract is weak in scleroderma, the reason why GI muscle weakness develops is poorly understood. We hypothesize that the smooth muscles cells (which control motility), enteric nerves (which stimulate muscle contraction), and/or the interstitial cells of Cajal (which facilitate communication between the nerves and muscles) are dysfunctional in SSc and this leads to decreased GI muscle strength and ultimately dysmotility. Using SSc patient serum to stain the longitudinal muscle and myenteric plexus in the GI tract (which is in charge of motility), we aim to identify and characterize novel proteins expressed in these cell populations that are targeted by the autoimmune response in patients with GI dysmotility.

Our preliminary data demonstrate that SSc sera bind distinct subsets of cells in the gut in 3 dominant patterns, which are not present when using normal control sera. In these studies, we plan to explore whether proteins uniquely expressed in (or whose expression is highly enriched in) subsets of smooth muscle, and the interstitial cells of Cajal (ICC) are also targeted by scleroderma sera and identify the distinct proteins in these cells that are recognized. Understanding the specific mechanistic relationship between staining patterns and GI dysmotility will be a focus of future studies.

How this work will impact patients

These studies will delineate the specific cellular targets of scleroderma sera in the GI tract. Identifying clusters of patients with similar patterns of staining in the gut will allow for the creation of a strong framework upon which to explore expression of specific autoantigens in human tissue, perform functional studies in animal models, and apply novel therapies in clearly defined patient subsets. Because GI dysmotility affects the majority of patients with scleroderma, understanding disease mechanisms in the GI tract may provide insight into scleroderma disease pathogenesis and ultimately lead to new therapeutic strategies.

Role of the Scleroderma Research Foundation

Funding by organizations like the Scleroderma Research Foundation is critical. The SRF provides support for scleroderma research across the country and is also one of the primary supporters of the Johns Hopkins Scleroderma Center. They provide funding for cutting edge science and make it possible for investigators like us to continue to do research, even when governmental funding is low. We depend on the SRF to keep scientific progress moving forward.

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