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J Exp Med. 2019 Nov 14. pii: jem.20190860. doi: 10.1084/jem.20190860. [Epub ahead of print]

B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2.

Author information

1
K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway l.m.sollid@medisin.uio.no fleur.du.pre@rr-research.no.
2
Department of Immunology, Oslo University Hospital, Oslo, Norway.
3
Department of Immunology, University of Oslo, Oslo, Norway.
4
K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway.
5
Department of Informatics, University of Oslo, Oslo, Norway.
6
Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology and Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
7
Department of Experimental Medicine, TOR, University of Rome "Tor Vergata", Rome, Italy.
8
K.G. Jebsen Coeliac Disease Research Centre, University of Oslo, Oslo, Norway l.m.sollid@medisin.uio.no.

Abstract

Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient-derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2 -/- mice. Autoreactive B cells in Tgm2 +/+ mice were indistinguishable from their naive counterparts in Tgm2 -/- mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten-TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help.

PMID:
31727780
DOI:
10.1084/jem.20190860

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