A new model for autoantibody formation in systemic sclerosis
Grantee: Rasmus Iversen, Postdoc, Oslo University Hospital, Norway
Amount: DKK 3,966,274
Grant category: Research Grants in open competition
Year: 2024
Geography: Norway
Rasmus Iversen’s project explores the hypothesis that complex formation between self- and non-self-antigen can drive pathogenic T cell-B cell interactions and autoantibody formation in autoimmune diseases like Systemic Sclerosis (SSc). Inspired by previous work on celiac disease, Rasmus Iversen and his team will use the function of the B-cell antigen as a starting point to decipher disease mechanisms. In SSc, the T-cell antigen(s) are unknown, but there is disease-specific production of autoantibodies to centromere proteins (CENPs) with CENP-B being a major B-cell antigen. To investigate autoantibody formation, Rasmus Iversen and the team will isolate CENP-B-specific B cells from blood of SSc patients. In the first step (WP1), they will characterize the cells’ phenotypes in detail. The cells will then be used for generation of recombinant CENP-B-specific monoclonal antibodies (mAbs) in WP2. These mAbs will be used for studying interactions between the immune system, CENP-B and target DNA. In WP3, they aim to identify DNA fragments of commensal bacteria that can form complexes with CENP-B and potentially drive T cell-B cell interactions.
The results of Rasmus Iversen’s project may provide Insight into disease mechanisms and can potentially lead to discovery of new therapeutic targets in e.g. systemic sclerosis (SSc), which is a serious autoimmune disease that affects the skin and internal organs.
Dissecting the immunopathogenesis of Dermatitis Herpetiformis – a blistering skin disorder
Grantee: Ludvig Sollid, Professor, University of Oslo
Amount: DKK 3,996,277
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.