SLE is a clinically heterogenous, challenging to evaluate autoimmune disease. Improved objective standards for global assessment of disease activity and evaluation of therapeutic interventions are needed. In addition, individualized measures of organ-specific damage should be defined as they could lead to the identification of "predictors" to implement earlier therapeutic interventions and prevent irreversible damage. Thus, there is an important need to develop objective, simple and robust SLE biomarkers. Pediatric and adult SLE patients display unique blood biosignatures that reflect the alterations in cellular and cytokine pathways that contribute to disease pathogenesis. These biosignatures can be used to assess disease activity. Most adult lupus studies have focused on the use of IFN alpha-induced transcripts and/or proteins as biomarkers of disease activity. IFN activity, however, has been shown to decrease in lupus patients with age, underscoring the need for more global approaches to identify useful lupus biomarkers that can be used in all age groups. We have developed a series of genomic and bioinformatics tools that allow the systematic evaluation of robust blood transcriptionahmodules displaying unique behaviors in patients with immune mediated diseases, including SLE. Transcriptionally co-regulated genes span not only those induced by type I IFN, but also those derived from a broader array of cell types and biological pathways. "Genomic scores" obtained using simple multivariate analysis that integrate several of these transcriptional modules perform well in longitudinal studies of pediatric SLE patients compared to validated disease activity measures. We now propose to establish a reference database for the assessment of SLE disease activity in adults using genomic scoring. We will next design a state of the art inexpensive and focused "lupus microarray" for monitoring patients in the clinical setting. Our objectives are 1) to establish and follow a longitudinal cohort of adult SLE and CLE patients, 2) to identify transcriptional markers for the assessment of disease activity and organ damage in these patients, with the ultimate goal of 3) designing and validating a cost-effective and practical assay for monitoring patients in the clinical setting.

Public Health Relevance

The development of a streamlined genomics assay to assess global and organ-specific activity in patients with lupus would be of great value in clinical settings to improve the management of patient care. It would also constitute an effective tool for the monitoring of drug efficacy and safety in the context of clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082715-04
Application #
8377374
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
2012-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$208,309
Indirect Cost
$48,479
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
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Caielli, Simone; Athale, Shruti; Domic, Bojana et al. (2016) Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 213:697-713
Blanco, Patrick; Ueno, Hideki; Schmitt, Nathalie (2016) T follicular helper (Tfh) cells in lupus: Activation and involvement in SLE pathogenesis. Eur J Immunol 46:281-90
Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-95
Ueno, Hideki; Banchereau, Jacques; Vinuesa, Carola G (2015) Pathophysiology of T follicular helper cells in humans and mice. Nat Immunol 16:142-52
Schmitt, Nathalie; Ueno, Hideki (2015) Regulation of human helper T cell subset differentiation by cytokines. Curr Opin Immunol 34:130-6
Turner, Jacob A; Bolen, Christopher R; Blankenship, Derek M (2015) Quantitative gene set analysis generalized for repeated measures, confounder adjustment, and continuous covariates. BMC Bioinformatics 16:272
Jacquemin, Clément; Schmitt, Nathalie; Contin-Bordes, Cécile et al. (2015) OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response. Immunity 42:1159-70
Bentebibel, Salah-Eddine; Jacquemin, Clement; Schmitt, Nathalie et al. (2015) Analysis of human blood memory T follicular helper subsets. Methods Mol Biol 1291:187-97
Schmitt, Nathalie (2015) Role of T Follicular Helper cells in Multiple Sclerosis. J Nat Sci 1:e139

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