Systemic lupus erythematosus is a chronic relapsing autoimmune disease of unclear etiology. The heterogeneity and unpredictable course of lupus, and the lack of reliable biomarkers to assist in predicting disease flares add to the challenge faced by physicians treating patients with this complex systemic disease. Our data suggest that a demethylated CD4+CD28+KIR+CD11a hi T cell subset correlates with disease activity in lupus patients. Since T cell DNA demethylation is more pronounced in active compared to inactive lupus patients, and because demethylation precedes T cell activation, we hypothesize that the size of the CD4+CD28+KIR+CD11a hi T cells subset correlates with disease activity in lupus and will be a useful biomarker to predict disease flares in lupus patients. We will test this hypothesis using a cross sectional and a longitudinal multicenter collaborative approach. We propose to determine the relationship between CD4+CD28+KIR+CD11a hi T cell subset expansion, total genetic risk, and the SLEDAI score in lupus patients, and to test the CD4+CD28+KIR+CD11a hi T cell subset size as a novel prognostic biomarker for disease progression and remission in a multicenter longitudinal study.
We identified a unique CD4+CD28+KIR+CD11a hi T cell subset in patients with active but not inactive lupus, and a similar subset causes lupus in mice. This proposal will test the relationship between the subset size, total lupus genetic risk, and the SLEDAI score in lupus patients, and examine this subset as a prognostic biomarker for disease progression. These studies may provide a personalized approach to the prediction of lupus flares in any given individual, based on subset size and the level of their genetic risk for lupus.
|Gensterblum, Elizabeth; Renauer, Paul; Coit, Patrick et al. (2018) CD4+CD28+KIR+CD11ahi T cells correlate with disease activity and are characterized by a pro-inflammatory epigenetic and transcriptional profile in lupus patients. J Autoimmun 86:19-28|
|Ray, Donna; Strickland, Faith M; Richardson, Bruce C (2018) Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells. Clin Immunol 196:97-102|
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|Dozmorov, Mikhail G; Coit, Patrick; Maksimowicz-McKinnon, Kathleen et al. (2017) Age-associated DNA methylation changes in naive CD4+ T cells suggest an evolving autoimmune epigenotype in aging T cells. Epigenomics 9:429-445|
|Teruel, Maria; Sawalha, Amr H (2017) Epigenetic Variability in Systemic Lupus Erythematosus: What We Learned from Genome-Wide DNA Methylation Studies. Curr Rheumatol Rep 19:32|
|Tsou, Pei-Suen; Sawalha, Amr H (2017) Unfolding the pathogenesis of scleroderma through genomics and epigenomics. J Autoimmun 83:73-94|
|Strickland, Faith M; Patel, Dipak; Khanna, Dinesh et al. (2016) Characterisation of an epigenetically altered CD4(+) CD28(+) Kir(+) T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry. Lupus Sci Med 3:e000147|
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