IL-17A-producing MAIT cells and epidermolyis bullosa inflammation

Background: Recessive Dystrophic Epidermolysis Bullosa (RDEB) is characterized by wounds chronically colonized with Staphylococcus aureus associated with local and systemic inflammation. This study aimed to clarify how the immune response is shaped by S. aureus in RDEB patients with focus on Mucosal-Associated invariant T (MAIT) cells. Methods: Fifteen RDEB children (moderate phenotype n=5; severe phenotype n=10) and controls (n=18) were enrolled. A novel proteomic pipeline was used to evaluate over 800 proteins in plasma. Patient-specific cytokine, immune T cell and S. aureus signatures were evaluated. The effect of the patient's S. aureus strain on T-cell function was analyzed in vitro and correlated with the bacterial secretome. Findings: We detected a unique plasma proteomic signature that enabled the differentiation of RDEB children and controls. Profiling of immune cells (n= 30 subsets and cytokine-producing cells) and cytokines (n=38) identified a severe inflammatory response and activation of CD4+ T and MAIT cells in severe RDEB patients with increased frequency of IL-17A-producing CD4+ T and MAIT cells. Positive S. aureus cultures from the skin of 12 of the 15 RDEB patients allowed whole-genome sequencing of patient strains, assessment of the primary keratinocyte response to bacterial challenge, and identification of potential immunomodulatory bacterial determinants. Conditioned media from keratinocytes challenged with S. aureus strains of severe RDEB patients induced a strong Th17 response. Interpretation: This study uncovers a huge systemic inflammatory response associated with a high level of circulating IL-17A-producing CD4+ T and MAIT cells in RDEB patients and supports the involvement of patient S. aureus strains in biasing the host immune response.