Systemic lupus erythematosus (SLE) is a complex, prototypic, systemic autoimmune disease of great interest to the Autoimmunity Center of Excellence network. However, by the time patients receive the devastating SLE diagnosis, the majority have ongoing aggressive inflammatory processes and oftentimes damage that cannot be reversed. Once these autoimmune cascades are underway, dissecting the basic concepts of disease initiation, perpetuation and direct pathogenesis from the complications of end-organ damage can be quite difficult. Our Oklahoma ACE builds on unique populations and experimental systems to address early events in systemic autoimmunity. Few repositories exist that allow researchers to investigate SLE development before clinical manifestations. Through our collaboration with the US Department of Defense, we have identified 240 patients who developed SLE while serving in the US military and who had serum samples that were provided before SLE classification. We previously obtained serial samples from the DoDSR for 130 of these patients, as well as four matched controls for each patient. Initial studies with these samples found that autoantibodies precede clinical illness by many years, that the Sm and Ro (alone) systems begin by targeting a single antigenic structure then become progressively more complicated and that a few autoantibodies are detectable before their associated clinical manifestations. In addition, we now have in house the samples from an additional 100 SLE patients and their matched controls and are seeking ACE funding to examine temporal associations of key targetable pathways in the pre-clinical stages to support or refute rationale use of interventions directed against interferon alpha or vitamin D supplementation for SLE patients. Further elucidation of the etiology and early pathogenesis of SLE will also provide improved biomarkers regarding select aspects of autoantibodies that correlate with onset of clinical disease features, and identify autoantibody subsets that help predict disease and allow identification of """"""""high risk"""""""" populations for potential interventional trials.
Our specific aims will address the following key clinical questions: 1) Does vitamin D deficiency precede lupus autoimmunity and/or clinical disease onset? 2) Does an increase in interferon activity occur before or concurrently with the onset of lupus autoimmunity or clinical disease? 3) Does non-specific autoimmunity precede onset of lupus-specific autoimmunity and thereby serve as a predictor of disease? 4) Does autoantibody concentration, specificity or affinity change with symptom onset and can these changes help direct therapeutic decisions?

Public Health Relevance

Understanding the initial targets and pre-clinical features of SLE will provide the basis for the development of lupus-specific diagnostic tests, evaluation of candidate pathways to target for SLE therapies, assessment of temporal associations to examine surrogates of causation for select biomarkers, and the determination of patients with the highest likelihood of response to specific therapies and for recruitment to potential prevention trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082714-02
Application #
8078070
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
2
Fiscal Year
2010
Total Cost
$288,249
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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

Showing the most recent 10 out of 133 publications