Ultraviolet light-mediated induction of systemic lupus ...
LUPUS
Activation of T-Follicular Helper Cells and B Cells in Ultraviolet Light-Induced Murine Model of Systemic Lupus Erythematosus
Misha Zarbafian1, Mehran Ghoreishi2 and Jan Dutz2, 1Medicine, University of British Columbia Vancouver Fraser Medical Program, Vancouver, BC, Canada, 2University of British Columbia Department of Dermatology and Skin Science, Vancouver, BC, Canada
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. Previous research has supported that T-follicular helper (TFH) cells 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 has been found to correlate 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.
Immunohistochemical characterization of acute and chronic discoid lupus erythematosus skin lesions
Jack C. O’Brien, BS1, Gregory A. Hosler, MD1,2, Benjamin F. Chong, MD, MSCS1
1University of Southwestern Medical Center, Department of Dermatology, Dallas, TX
2ProPath, Dallas, TX
Background: Cells of both the innate and adaptive immune system have been implicated in the pathogenesis of discoid lupus erythematosus (DLE). The inflammatory cell infiltrate in DLE has been described as containing CD4+ and CD8+ T cells, B cells, macrophages, and plasmacytoid dendritic cells. Histologically, DLE skin lesions can be thought of as having two phases, “acute” and “chronic,” which can be distinguished based on the absence or presence of dermal sclerosis. Characterizing the changes in the composition of the inflammatory cell infiltrate of acute and chronic DLE lesions would elucidate the disease course of DLE.
Objective: To characterize the inflammatory infiltrate in acute and chronic DLE skin lesions using immunohistochemistry.
Methods: We identified 25 skin biopsies from untreated DLE skin lesions from DLE patients seen at UT Southwestern Medical Center and Parkland Memorial Hospital between 2006 and 2015. Patients were classified as having acute (N=7) or chronic (N=18) DLE based on the presence or absence of deep dermal fibrosis, respectively. Immunostains for T cells (CD3, CD4, CD8), B cells (CD20), plasmacytoid dendritic cells (CD123), macrophages (CD163), neutrophils (MPO), and plasma cells (CD138) were performed. Two independent observers graded the overall intensity of the infiltrate in three areas, interfollicular interface, perifollicular, and perivascular, on a 0 to 3 scale (0 = none, 1 = mild, 2 = moderate, 3 = marked). Each immunostain was graded on a 0 to 3 scale based on percentage of positive-staining cells (0 = ................
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