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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Daniele Sblattero, University of Trieste, Italy
- Second opponent: Research Associate Luka Mesin, The Rockefeller University, USA
- Third member and chair of the evaluation committee: Associate professor Johanne Tracey Jacobsen, University of Oslo
Chair of the Defence
Associate Professor Olav Sundnes, University of Oslo
Principal Supervisor
Professor Ludvig Magne Sollid, University of Oslo
Summary
Dermatitis herpetiformis (DH), an inflammatory skin condition, is considered an extraintestinal manifestation of celiac disease (CeD). Individuals carrying HLA-DQ2.5, HLA-DQ8, or HLA-DQ2.2 are predisposed to both CeD and DH. In both conditions, harmful immune responses to dietary gluten are driven by presentation of deamidated peptides by these HLA-DQ allotypes to CD4+ T cells.
CeD is hallmarked by an autoantibody response to transglutaminase 2 (TG2), while DH patients develop autoantibodies to TG2 and also to transglutaminase 3 (TG3). Recent research on autoantibodies against TG2 has been extensive, but little is known about the anti-TG3 autoantibody response in DH. Our studies reveal that anti-TG2 and anti-TG3 autoantibodies are specific with no cross-reactivity. Anti-TG3 autoantibodies exhibit biased usage of IGHV2-5 heavy chains paired with IGKV4-1 light chains, suggesting selection of B cells for plasma cell development. Monoclonal antibodies generated from single TG3-specefic gut plasma cells recognize three epitope regions.
TG2 and TG3, both being Ca2+ dependent enzymes, modify peptide glutamine residues through deamidation or transamidation. Unlike TG2, active TG3 requires proteolytic cleavage to become catalytically active. X-ray crystallography analysis shows that catalytically active TG3 undergoes a conformational change detaching the C-terminal C1 and C2 domains and exposing the active site to react with substrate. DH-derived antibodies recognize the enzyme-substrate intermediate conformation of TG3 without the C1C2 domains, supporting a model for TG3-specific B cell activation via help from gluten specific CD4+ T cells facilitated by hapten-carrier like complexes of TG3 and gluten peptides.
We studied the naive TG2 binding B-cell receptor (BCR)-repertoire in CeD patients and healthy donors. Surprisingly, the naive BCR-repertoire does not fully reflect the BCR-repertoire of TG2 binding gut plasma cells in patients with active CeD. Our findings suggest that rare naive B cells binding to a specific TG2 epitope are selectively activated due to their superior interaction with gluten-specific CD4+ T cells through hapten-carrier mechanism.
In summary, our work provides mechanistic insight into autoantibody development against TG3 and TG2. Similar mechanisms may be involved in other autoantibody responses, inspiring future studies on other autoimmune diseases.
Additional information
Contact the research support staff.