Systemic Lupus Erythematosus (SLE) is a devastating autoimmune disease that affects up to 0.5% of the US population. This disease is characterized by heterogeneous manifestations including severe rashes, organ- threatening nephritis, and an elevated risk of cardiovascular disease. Despite ongoing research into the pathogenesis of this disease, very little is understood about the mechanism of cutaneous lesion development or how skin inflammation may be able to influence systemic disease. This project proposes to take a systems biology approach to analyze the gene expression changes present in the most common cutaneous lupus subtypes by taking advantage of advances in RNA isolation from formalin-fixed paraffin-embedded tissue. Importantly, changes in gene expression and regulation of inflammatory networks will then be analyzed to determine pathways unique to cutaneous lupus associated with systemic disease. Further, comparisons with known dysregulated pathways in lupus nephritis biopsies will be made to develop an understanding of the overlap in the pathology between cutaneous and renal lupus. Importantly, cutaneous transcriptional changes will be analyzed in the context of available clinical data to determine if cutaneous biomarkers may exist that predict development of systemic lupus. Study Design: Using microarray analysis of subacute cutaneous (sCLE) and discoid lupus (DLE) skin biopsies, AIM 1 will develop a comprehensive understanding of the gene expression changes in sCLE and DLE compared with control skin. Using Ingenuity and Genomatix software, changes to biological pathways and transcriptional networks will be identified. Further, overlapping and unique transcriptional changes between the disease subsets will also be determined. The information gathered in AIM1 and additional biopsy subsets will then be used to compare cutaneous changes in gene expression in skin only CLE to CLE associated with systemic disease (Aim2a). Further, the pathways and networks unique to DLE, sCLE, skin- only CLE and CLE with systemic disease will be compared to those known to be dysregulated in kidney biopsies from lupus nephritis patients via TALE (Tool for Approximate LargE graph matching) analysis (AIM2b). This will allow for identification of overlapping expression changes and inflammatory networks between cutaneous and renal inflammation which may be important targets for further study and treatments.
AIM2 c will use Chi-squared and survival analysis to determine the extent to which gene expression changes and dysregulated networks identified in AIM 1 correlate with the development of systemic disease manifestations, either at the time of biopsy or over time. This would then allow for development of possible biomarkers of systemic disease risk and identify important targets for disease prevention and treatment strategies.

Public Health Relevance

Systemic Lupus Erythematosus is a devastating autoimmune disease that affects up to 0.5% of the US population. It results in severe organ damage, elevated risk of cardiovascular disease and disfiguring scars. This proposal is relevant to public health as it will develop an understanding of the inflammatory pathways active in lupus skin disease and determine the extent to which these serve as predictors of organ damage, particularly of lupus nephritis. This understanding will provide novel targets for both treatment o cutaneous lupus and also prevention of systemic disease activity following skin flares, leading to improved quality of life and reduced patient morbidity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR066337-02
Application #
8928966
Study Section
Special Emphasis Panel (ZAR1)
Program Officer
Mancini, Marie
Project Start
2014-09-30
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Swindell, William R; Beamer, Maria A; Sarkar, Mrinal K et al. (2018) RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature. Front Immunol 9:80
Stannard, Jasmine N; Reed, Tamra J; Myers, Emily et al. (2017) Lupus Skin Is Primed for IL-6 Inflammatory Responses through a Keratinocyte-Mediated Autocrine Type I Interferon Loop. J Invest Dermatol 137:115-122
Liang, Yun; Kahlenberg, J Michelle; Gudjonsson, Johann E (2017) A vestigial pathway for sex differences in immune regulation. Cell Mol Immunol 14:578-580
Liu, Jianhua; Berthier, Celine C; Kahlenberg, J Michelle (2017) Enhanced Inflammasome Activity in Systemic Lupus Erythematosus Is Mediated via Type I Interferon-Induced Up-Regulation of Interferon Regulatory Factor 1. Arthritis Rheumatol 69:1840-1849
Hile, Grace A; Lowe, Lori; Kahlenberg, J Michelle (2017) Cutaneous purpura of Sjögren syndrome successfully treated with hydroxychloroquine. JAAD Case Rep 3:326-328
Liang, Yun; Tsoi, Lam C; Xing, Xianying et al. (2017) A gene network regulated by the transcription factor VGLL3 as a promoter of sex-biased autoimmune diseases. Nat Immunol 18:152-160
Stannard, Jasmine N; Kahlenberg, J Michelle (2016) Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus. Curr Opin Rheumatol 28:453-9