Defining the origins and effector function of AVB6-specific autoantibodies in ulcerative colitis

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Benaroya Research Institute At Virginia Mason $907,235 on September 1, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to define the origins and effector function of avβ6-specific autoantibodies in ulcerative colitis.

The research dissects the repertoire, biochemical activity, and pathogenic functions of avβ6-specific autoantibodies in ulcerative colitis, integrating patient-based and mechanistic model systems. Nearly all ulcerative colitis patients produce high-titer autoantibodies to the epithelial integrin avβ6, which precede clinical disease by up to ten years and associate with worse outcomes. The avβ6 integrin is the dominant epithelial activator of transforming growth factor beta-1, a master regulator of mucosal immune balance and epithelial barrier repair. Preliminary findings demonstrate that a subset of patient autoantibodies block avβ6-mediated TGF-β1 activation, functioning as de facto anti-cytokine antibodies, while other antibodies bind without blocking catalytic activity. The research tests whether multiple mechanisms—including blocking TGF-β1 activation, conformational locking, or Fc-dependent effector functions—converge to destabilize epithelial-immune cross-talk and promote inflammation.

Performance occurs in Seattle, Washington. The period of performance runs from September 1, 2026, through May 31, 2030. This is a Project Grant, the assistance type under the NIDDK extramural research program for investigator-initiated biomedical research.

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the colon that affects ~1 million americans. Current therapies suppress inflammation but are limited by incomplete efficacy, loss of response, and significant side effects. A recent breakthrough has been the discovery that nearly all UC patients produce high-titer autoantibodies to the epithelial integrin ΑVΒ6. These antibodies not only precede clinical disease by up to 10 years but are also associated with worse outcomes, raising the possibility that they represent not just biomarkers but active drivers of UC pathogenesis. Whether ΑVΒ6 autoantibodies directly cause disease, and by what mechanisms, remains unknown. Integrin ΑVΒ6 is the dominant epithelial activator of transforming growth factor (TGF)-Β1, a master regulator of mucosal immune balance and epithelial barrier repair. Our preliminary data demonstrate that a subset of UC patient autoantibodies block ΑVΒ6-mediated TGF-Β1 activation, effectively functioning as DE facto anti-cytokine antibodies. However, significant heterogeneity exists, with other antibodies binding without blocking catalytic activity. These findings suggest that multiple non-mutually exclusive mechanisms including blocking TGF-Β1 activation, conformational locking or FC-dependent effector functions may converge to destabilize epithelial-immune cross-talk and promote inflammation. Our long-term goal is to define how autoreactive b cell and antibody responses contribute to epithelial dysfunction and chronic intestinal inflammation. The objective of this application is to dissect the repertoire, biochemical activity, and pathogenic functions of ΑVΒ6-specific autoantibodies in UC, integrating patient-based and mechanistic model systems. Our central hypothesis is that ΑVΒ6 autoantibodies are active mediators of UC pathogenesis, with distinct functional subsets driving disease through TGF-Β1 blockade and FC-mediated epithelial injury. We will pursue two aims: 1) dissection of ΑVΒ6-specific autoantibody repertoires, epitopes, and effector functions in patients with ulcerative colitis, 2) determine the pathogenic mechanisms of ΑVΒ6-specific autoantibodies in colitis. This application is innovative in reframing UC as an autoantibody-driven disease and deploying state-of-the-art tools including patient-derived monoclonals, b cell tetramers, and structural immunology to interrogate pathogenic mechanisms. The proposed work is significant because IT will resolve whether ΑVΒ6 autoantibodies are biomarkers or active drivers of UC, define functional antibody subsets as candidates for biomarker-based patient stratification, and identify novel therapeutic targets for intervention. Ultimately, this project will establish a new paradigm of epithelial-directed autoimmunity in chronic intestinal inflammation.