The goal primary of this study is to determine if over-expression of the transcription factor ARID3a in a subset of systemic lupus erythematosus patients is a contributing factor to this disease. We previously showed that over-expression of the mouse orthologue of ARID3a in B lineage cells results in breaches of B cell tolerance. The over-expressing transgenic mice produce anti-nuclear antigen antibodies (a defining characteristic of lupus) by four weeks of age, accumulate immunoglobulin deposits in kidney glomeruli and exhibit shifts in numbers of peripheral blood B cell subsets. Our preliminary data indicate that ARID3a is aberrantly over-expressed in a large subset of lupus patients, but not in healthy age-matched individuals. We hypothesize that patients with aberrant expression may constitute a new subgroup of patients with similar underlying defects. Furthermore, we hypothesize that ARID3a over-expression facilitates disease development.
Three specific aims are proposed. First, we will determine if aberrant ARID3a expression is a stable characteristic of some patients, or if over-expression occurs as the result of drug treatment or immune response over time. Secondly, we will determine how aberrant ARID3a expression affects B cell functions which may pertain directly to breaches in B cell tolerance. Finally, we will identify the specific mechanisms which contribute to aberrant ARID3a expression in these cells. These data will provide the basis for directing future studies to determine how ARID3a contributes to autoimmunity. The ability to group patients by specific symptoms and to understand the underlying mechanisms which contribute to lupus could lead to better treatment regimens.

Public Health Relevance

Our published data indicate that over-expression of the transcription factor ARID3a/Bright in transgenic mouse B cells results in production of autoimmune antibodies. Preliminary new data suggest that ARID3a is inappropriately expressed in a subset of lupus patients. The goal of this study is to determine if how inappropriate ARID3a expression contributes to lupus pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Johnson, David R
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Oklahoma Medical Research Foundation
Oklahoma City
United States
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Ratliff, Michelle L; Mishra, Meenu; Frank, Mark B et al. (2016) The Transcription Factor ARID3a Is Important for In Vitro Differentiation of Human Hematopoietic Progenitors. J Immunol 196:614-23
Ward, Julie M; Ratliff, Michelle L; Dozmorov, Mikhail G et al. (2016) Human effector B lymphocytes express ARID3a and secrete interferon alpha. J Autoimmun 75:130-140
Ratliff, Michelle L; Templeton, Troy D; Ward, Julie M et al. (2014) The Bright Side of Hematopoiesis: Regulatory Roles of ARID3a/Bright in Human and Mouse Hematopoiesis. Front Immunol 5:113
Guthridge, Joel M; Lu, Rufei; Sun, Harry et al. (2014) Two functional lupus-associated BLK promoter variants control cell-type- and developmental-stage-specific transcription. Am J Hum Genet 94:586-98