Abstract
Celiac disease is an immune-mediated disorder in which mucosal autoantibodies to the enzyme transglutaminase 2 (TG2)1 are generated in response to the exogenous antigen gluten2 in individuals who express human leukocyte antigen HLA-DQ2 or HLA-DQ8 (ref. 3). We assessed in a comprehensive and nonbiased manner the IgA anti-TG2 response by expression cloning of the antibody repertoire of ex vivo–isolated intestinal antibody-secreting cells (ASCs). We found that TG2-specific plasma cells are markedly expanded within the duodenal mucosa in individuals with active celiac disease. TG2-specific antibodies were of high affinity yet showed little adaptation by somatic mutations. Unlike infection-induced peripheral blood plasmablasts4, the TG2-specific ASCs had not recently proliferated and were not short-lived ex vivo. Altogether, these observations demonstrate that there is a germline repertoire with high affinity for TG2 that may favor massive generation of autoreactive B cells. TG2-specific antibodies did not block enzymatic activity and served as substrates for TG2-mediated crosslinking when expressed as IgD or IgM but not as IgA1 or IgG1. This could result in preferential recruitment of plasma cells from naive IgD- and IgM-expressing B cells, thus possibly explaining why the antibody response to TG2 bears signs of a primary immune response despite the disease chronicity.
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Acknowledgements
We thank E. Mummert (Phadia) for providing recombinant human TG2 produced in Sf9 insect cells, C. Khosla (Stanford University) and L. Fesus (University of Debrecen) for providing plasmids encoding His-tagged recombinant TG2 for expression in Escherichia coli, M. Ráki for help in sample collection and immunofluorescence analysis, J. Jahnsen for providing biopsy samples from two subjects, and the staffs at the LIIPAT laboratory and the flow cytometry core facility (both at Oslo University Hospital-Rikshospitalet) for technical assistance. This work was supported by the Marie Curie Research and Training Network (European Commission) contract MRTN-CT-2006-036032, the European Research Council and grants from the Research Council of Norway to L.M.S., and US National Institutes of Health National Institute of Allergy and Infectious Disease grants U19 AI082724-01, R01 AI76585-03 and HHSN266200500026C to P.C.W. We thank M. Shlomchik and B. Jabri for discussion and critical reading of the manuscript.
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R.D.N. conceived the study, performed experiments, analyzed data and wrote the manuscript. L.M., N.-Y.Z., J.S., M.M., J.-H.L., M.H., R.I., M.F.d.P. and S.-W.Q. performed experiments. K.E.A.L. recruited study subjects and provided materials. P.C.W. supervised the study, analyzed data and revised the manuscript. L.M.S. conceived and supervised the study and wrote the manuscript.
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Di Niro, R., Mesin, L., Zheng, NY. et al. High abundance of plasma cells secreting transglutaminase 2–specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18, 441–445 (2012). https://doi.org/10.1038/nm.2656
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DOI: https://doi.org/10.1038/nm.2656
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