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Grant category: Research Grants in open competition

Year: 2023

Geography: Norway

Ludvig Sollid’s project aims to improve the understanding of the pathogenic immune responses in dermatitis herpetiformis and hereby design and investigate potential new therapeutics for the disease.

Dermatitis Herpetiformis (DH) is a chronic autoimmune bullous skin disease characterised by itchy blisters localised at specific surfaces of the body. DH can be considered a cutaneous manifestation of the gluten sensitive condition Coeliac Disease (CeD). The treatment for DH, as it is for CeD, is a life-long gluten-free diet and therefore novel treatments are sought for.

The diagnosis of DH is made by detection of granular IgA deposits in the dermis layer of the skin. These IgA deposits are immune complexes involving the autoantigen transglutaminase 3 (TG3) which is expressed in the epidermis, the outmost layer that sits above the dermis.

In this project Ludvig Sollid and his team aim to dissect the immunopathogenesis of DH, specifically addressing the mechanism for the generation of TG3 autoantibodies. Based on a model for the generation of autoantibodies to another transglutaminase (transglutaminase 2, TG2) in CeD, they will explore whether B cells carrying B-cell receptors isolated from DH patients, can bind complexes of TG3 and gluten peptides and thereby present gluten peptides to T cells so that T-cell help is provided.

Specifically, they will characterise the substrate binding site of TG3, identify the preferred gluten peptide substrates for TG3, and also characterise, in detail, the structural basis for binding of DH autoantibodies including antibodies that augment TG3 activity.

Based on these new insights, the team will design TG3 inhibitors which have potential therapeutic usage for treatment of DH along with a TG2 inhibitor which recently proved efficacious for treatment of CeD.