Autoimmune diseases afflict a significant portion of the US population, with the most common age of onset being during young adulthood leading to increased morbidity, early mortality and accrual of damage with associated disability, oftentimes early in life. Many of the systemic autoimmune diseases are characterized by a waxing and waning, or relapsing/remitting, course. These periods of increased disease activity, oftentimes with permanent organ-damage, are interspersed on a background of clinical suppression or quiescence. Although shared across many of the systemic autoimmune diseases, the mechanisms or predictors of disease flares are very poorly understood or not understood at all. This application will focus on understanding mechanisms of disease flare in SLE and then collaborating with other ACE centers, to expand these studies and evaluate which of these mechanisms are common across a number of autoimmune diseases or are disease specific. Over the past funding cycle, our Oklahoma ACE has established and expanded a number of patient collections which have provided insights or samples which will be relevant to understanding mechanisms of SLE disease flare. In preliminary studies of European American SLE patients who exhibited a disease flare within 6 or 12 weeks of baseline assessment compared to patients who did not flare, alterations in 27 soluble mediators {p<0.01) were found at baseline compared to non-flare patients, with significantly higher levels of pro-inflammatory mediators several weeks before clinical flare. Regulatory cytokines were increased at baseline in non-flare SLE patients. Nearly all of these abnormalities were also found in the SLE patients during their flare year compared to samples from these individuals in a non-flare year. Based upon these and other presented preliminary data, we hypothesize that critical alterations in cellular activation, TNF receptor shedding, innate and adaptive mediators of inflammation, and regulatory immune cell pathways are present immediately preceding SLE disease flare. We will test these hypotheses through the following specific aims: 1) determine alterations in innate and adaptive immune cell populations, functional responses and serologic biomarkers in SLE patients immediately before flare compared to matched SLE patients who do not flare, as well as in longitudinal samples;2) evaluate parent cellular populations, levels, locations and functional consequences of shed TNF and other immune receptors in SLE patients temporally preceding a clinical disease flare;and 3) assess the frequency and function of regulatory B and T cells temporally preceding SLE disease flare.

Public Health Relevance

Autoimmune diseases affect 5-7% of the population and often have has periods of disease flares interspersed with disease suppression. This project aims to identify mechanisms responsible for disease flare and predictors of disease flare that are currently unknown or poorly understood to help aid earlier diagnosis, design appropriate clinical trials, develop new directed therapeutic agents and help guide therapy selection to improve the lives of patients with autoimmune diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Oklahoma Medical Research Foundation
Oklahoma City
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St Clair, E William; Baer, Alan N; Wei, Chungwen et al. (2018) Clinical Efficacy and Safety of Baminercept, a Lymphotoxin ? Receptor Fusion Protein, in Primary Sjögren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheumatol 70:1470-1480
Koelsch, Kristi A; Cavett, Joshua; Smith, Kenneth et al. (2018) Evidence of Alternative Modes of B Cell Activation Involving Acquired Fab Regions of N-Glycosylation in Antibody-Secreting Cells Infiltrating the Labial Salivary Glands of Patients With Sjögren's Syndrome. Arthritis Rheumatol 70:1102-1113
Hinks, Anne; Marion, Miranda C; Cobb, Joanna et al. (2018) Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idiopathic Arthritis Resembles That of Adult Rheumatoid Arthritis. Arthritis Rheumatol 70:957-962
Pelikan, Richard C; Kelly, Jennifer A; Fu, Yao et al. (2018) Enhancer histone-QTLs are enriched on autoimmune risk haplotypes and influence gene expression within chromatin networks. Nat Commun 9:2905
Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :
Kheir, Joseph M; Guthridge, Carla J; Johnston, Jonathon R et al. (2018) Unique clinical characteristics, autoantibodies and medication use in Native American patients with systemic lupus erythematosus. Lupus Sci Med 5:e000247
Young, K A; Munroe, M E; Harley, J B et al. (2018) Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus. Lupus 27:1524-1531
Jog, Neelakshi R; Chakravarty, Eliza F; Guthridge, Joel M et al. (2018) Epstein Barr Virus Interleukin 10 Suppresses Anti-inflammatory Phenotype in Human Monocytes. Front Immunol 9:2198
Fu, Yao; Tessneer, Kandice L; Li, Chuang et al. (2018) From association to mechanism in complex disease genetics: the role of the 3D genome. Arthritis Res Ther 20:216
Hanscombe, Ken B; Morris, David L; Noble, Janelle A et al. (2018) Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Hum Mol Genet 27:3813-3824

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