Poster Presentation Lorne Infection and Immunity 2020

Molecular mimicry between bacterial and gluten derived peptides implicates bacteria as environmental risk factor in Celiac disease (#191)

Jan Petersen 1 2 , Laura Ciacchi 1 2 , Mai T Tran 1 , Khai-Lee Loh 1 , Yvonne Kooy-Winkelaar 3 , Nathan P Croft 1 , Melinda Y Hardy 4 , Zhenjun Chen 5 , James McCluskey 5 , Robert P Anderson 6 , Anthony W Purcell 1 , Jason A Tye-Din 4 , Frits Koning 3 , Hugh H Reid 1 2 , Jamie Rossjohn 1 2
  1. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University , Clayton, VIC, Australia
  2. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia
  3. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, ZA, The Netherlands
  4. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  5. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
  6. ImmusanT, Cambridge, MA, USA

The majority of T cell mediated autoimmune diseases is associated with both genetic and environmental risk factors. Particular Human Leukocyte Antigen (HLA) alleles and genes linked to immune recognition stand out as determinants of heritable risk, however the contributions of environmental risk factors are unclear. In the present study we investigated bacterial antigens as potential contributors to the induction of the immune response in celiac disease (CeD), a chronic T cell mediated inflammatory disorder of the small intestine. CeD is strongly associated with HLA-DQ2.5 and characterised by T cell reactivity towards deamidated gluten peptides derived from each of the sub-fractions of wheat gluten (a, b, g, and w gliadin; and glutenins) and homologous sequences in rye and barley . Guided by structural and functional data on consensus T cell receptor specificities, we identified bacteria-derived peptides that activate a-gliadin-specific, HLA-DQ2.5 restricted T cells from CeD patients. We show that a parental bacterial protein is naturally processed by antigen presenting cells and recognized by CeD patient derived T cells. Crystal structures of T cell receptors (TCRs) in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry forms the basis for the observed T cell cross-reactivity between bacterial and a-gliadin epitopes. Our data shows that gluten reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby implicating microbial exposure as an environmental factor in CeD.