A novel humanized cutaneous lupus erythematosus mouse model mediated by IL-21-induced age-associated B cells

Cutaneous lupus erythematosus (CLE) is a relapsing autoimmune disease, but key elements that drive disease initiation and progression remain elusive. To date, the lack of ideal murine model which resemble human cutaneous lupus makes it extremely challenging for moving mechanistic discoveries and novel therapeutics. Here, we prompt a humanized murine model to develop an inducible rapid-onset murine that performs cutaneous rather than systemic lupus, depending on the successful human immune system reconstruction from active lupus patients and UVB irradiation as for essentially pathogenic triggers. In addition, we demonstrate a newly discovered population of B cell with a unique phenotype, that of the age-associated B cell (ABC, T-bet⁺ CD11b⁺), exhibits B cell clusters in humanized cutaneous lupus. In the response of IL-21 and TLR7/9 signals, recruitment of autoreactive B cells to the position of inflammation with subsequent localized antibody production of IgG2a, IgG2b, IgG3, has the potential to exacerbate ongoing inflammation and thus driving lupus-like autoimmunity in a B-cell-dominant fashion. Overall, our model provides a relevant system for exploring the pathophysiology of cutaneous lupus, a suitable model for drug development, as well as updating a potential role of IL-21 and TLR7/9 to be targeted by biologics.