Mechanisms and molecular actors of the intestinal response to infection in the context of HLA-B27

Principal Investigator: Isabelle Guénal

Keywords: spondylitis, HLA-B27, innate immunity, intestinal homeostasis, BMP, TGF-β, Drosophila

We have acquired expertise in using Drosophila to explore the molecular and cellular mechanisms underlying human pathologies. Part of our work, therefore, focuses on studying a major genetic factor predisposing individuals to ankylosing spondylitis. Spondyloarthritis (SpA) is a group of chronic inflammatory joint disorders. They have a significant hereditary component, the HLA-B27 allele of the major histocompatibility complex (MHC). However, the mechanisms by which HLA-B27 contributes to SpA remain poorly understood, despite 50 years of research. This research has highlighted the non-canonical effects of the HLA-B27 antigen, independent of its role in adaptive immunity. In collaboration with Prof. Breban's team (U1173, INSERM-UVSQ), we have developed a Drosophila model that allows us to study, in vivo, the effects of HLA-B27 at the cellular level and on innate immunity. A genetic approach has enabled us to show that HLA-B27 interacts with TGFβ signaling pathway receptors, which could disrupt the differentiation and regulation of CD4+ T cells (Grandon et al. 2019, Lauraine et al. 2024). This interaction has been found in patient cells. The continuation of this ANR-funded work has enabled us to develop the genetic tools needed to study the effect of HLA-B27 in the intestine. Our ongoing work aims to understand why this rheumatic disease is strongly associated with inflammatory bowel disease (IBD).

Grandon et al. (2019) Annals of the Rheumatic Diseases, doi: 10.1136/annrheumdis-2019-215832 (hal-02975533)

Lauraine et al. (2024) Arthritis Research and Therapy, doi: 10.1186/s13075-024-03370-1. ⟨hal-04362225⟩