Autoantigen Discovery in Scleroderma Subsets: Possible Targeting of the Neural Crest in Patients with Severe Gastrointestinal Disease

Livia Casciola-Rosen, PhD
Zsuzsanna McMahan, MD, MHS
Johns Hopkins University School of Medicine

Project Summary:

Scleroderma is a systemic autoimmune disease that is characterized by inflammation, scarring of the skin, damage to internal organs, and an immune response to specific cellular proteins. Patients with scleroderma have several characteristic features, including gastrointestinal failure, loss of pigment in the skin, and disfigurement of the face that are common among scleroderma patients, but not patients with other autoimmune connective tissue diseases. These unique characteristics may provide insight into the biology of the disease.

Interestingly, each of these tissues — the cells in the gastrointestinal tract responsible for motility, pigmentary cells of the skin, and craniofacial cartilage — are derived from a distinct lineage of stem cells known as the neural crest. Casciola-Rosen and McMahan hypothesize that cells derived from this lineage are specifically targeted by the autoimmune response in scleroderma, and that autoantibodies generated against such targets may be biomarkers of gastrointestinal complications in scleroderma.

Research Update:

Dr. McMahan identified a cohort of 20 carefully phenotyped scleroderma patients with severe gastrointestinal disease. Dr. Casciola-Rosen’s team then employed a newly developed technique, phage-immunoprecipitation sequencing, to look for new autoantibodies in sera from these patients. This technique allowed the researchers to identify several novel autoantibodies that were previously unrecognized in these patients. After validation, the team prioritized several of the antibodies that have not previously been linked to scleroderma patients with severe GI disease. The team plans to pursue further studies to define the specificity of these autoantibodies for the severe GI patient subset. Ultimately, the team will work to evaluate the role of these antibodies in the diagnostic and clinical risk stratification of patients.

Dr. Casciola-Rosen on Why Research Matters:

“Research is critical in diseases like scleroderma because the currently utilized therapies are inadequate in the prevention of disability and life-threatening complications, and existing therapies currently aimed at broadly suppressing the immune response have a high risk profile and contribute further to the development of clinical complications. Biomarkers that predict disease course, or that can be used to stratify response to therapy or readout treatment effectiveness, are critical. In addition, research aimed at understanding disease subsets and pathogenesis will provide data which will inform future studies related to the biology of the disease.” 

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