Background/Purpose: Non-obese diabetic (NOD) mice repeatedly exposed to ultraviolet (UV) light and Toll-like receptor-7 (TLR7) agonist cream (imiquimod) develop lupus-like disease, modeling a possible cutaneous trigger for systemic lupus erythematosus (SLE) in genetically predisposed individuals. T-follicular helper (TFH) cells are known to support B cell maturation in germinal centers, leading to auto-antibody production in the context of SLE. Increased frequency of circulating TFH cells in the peripheral blood of human SLE patients has been associated with more severe disease, characterized by more lupus-associated auto-antibodies and end-organ manifestations. High-mobility group protein B1 (HMGB1) is a pro-inflammatory cytokine, which facilitates auto-antibody production in SLE both locally and systemically. HMGB1 release from the cell nucleus in skin occurs early in sun-induced lesions, and correlates with the progression of SLE disease. We sought to characterize TFH cells and B cells in skin-draining lymph nodes of NOD mice treated with UV and topical imiquimod cream (TLR7 agonist).

Methods: NOD and Balb/C mice received weekly UVB radiation (5000 J/m²) and 25 μg of topical imiquimod cream. Skin-draining lymph nodes were analyzed by flow cytometry after four treatments to determine the activation status and number of TFH cells and B cells. Serum was collected to measure inflammatory cytokines such as TNFa, IL-6, and IFNg. Extra-nuclear expression of HMGB1 was evaluated in skin samples from both strains after four treatments.

Results: There was expansion of both TFH and B cells, as well as increased expression of the B cell activation marker CD40 in skin-draining lymph nodes of NOD mice following combined UV and imiquimod therapy, in contrast to Balb/C mice. Extra-nuclear expression of HMGB1 was greater in NOD mice, whereas expression in Balb/C mice was largely limited to the nucleus.

Conclusion: Skin-draining lymph node TFH cell expansion is an early event after UV and TLR7 agonist therapy and is correlated with auto-antibody production. HMGB1 redistribution in the skin also correlates with auto-antibody production. Quantification of circulating TFH cells and local HMGB1 expression may serve as markers for predicting SLE onset in genetically predisposed individuals.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/activation-of-t-follicular-helper-cells-and-b-cells-in-ultraviolet-light-induced-murine-model-of-systemic-lupus-erythematosus/