Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.
Journal: 2003/May - Proceedings of the National Academy of Sciences of the United States of America
ISSN: 0027-8424
Abstract:
Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression "signature" served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.
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Proc Natl Acad Sci U S A 100(5): 2610-2615

Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus

+3 authors
Departments of Medicine, Computer Science and Engineering, and Veterinary Pathobiology, University of Minnesota, Minneapolis, MN 55455; and Center for Genomics and Human Genetics, North Shore Long Island Jewish Research Institute, Manhasset, NY 11030
To whom correspondence should be addressed. E-mail: ude.nmu@100erheb.
Communicated by Martin G. Weigert, Princeton University, Princeton, NJ
Communicated by Martin G. Weigert, Princeton University, Princeton, NJ
Received 2002 Sep 4; Accepted 2002 Dec 17.

Abstract

Systemic lupus erythematosus (SLE) is a complex, inflammatory autoimmune disease that affects multiple organ systems. We used global gene expression profiling of peripheral blood mononuclear cells to identify distinct patterns of gene expression that distinguish most SLE patients from healthy controls. Strikingly, about half of the patients studied showed dysregulated expression of genes in the IFN pathway. Furthermore, this IFN gene expression “signature” served as a marker for more severe disease involving the kidneys, hematopoetic cells, and/or the central nervous system. These results provide insights into the genetic pathways underlying SLE, and identify a subgroup of patients who may benefit from therapies targeting the IFN pathway.

Abstract

Systemic lupus erythematosus (SLE) is a chronic, inflammatory autoimmune disease characterized by the production of antibodies with specificity for a wide range of self-antigens (1). SLE autoantibodies mediate organ damage by directly binding to host tissues and by forming immune complexes that deposit in vascular tissues and activate cells of the immune system. Organs commonly targeted in SLE include the skin, kidneys, joints, lungs, various blood elements, and the central nervous system (CNS). The severity of disease, the spectrum of clinical involvement, and the response to therapy vary widely between patients, and this leads to significant challenges in the diagnosis and management of lupus.

Genes implicated in human SLE include HLA Class II DRB and DQB alleles (e.g., DRB1*1501/DQB1*0602, and DRB1*0301/DQB1*0201) (2), and early components of the complement cascade (e.g., C1q, C4) (3). Gene mapping efforts in families enriched for SLE have identified several additional susceptibility loci (4, 5); however, the relevant genes are not yet isolated. Studies in lupus-prone mice have also identified a number of candidate loci, genes, and pathways that contribute to SLE-like autoimmunity (5, 6). Together, these studies suggest that SLE is a complex genetic disease with multiple genes influencing the clinical phenotype.

Genome-wide gene expression profiling using microarrays is a powerful emerging technology that allows the simultaneous measurement of thousands of mRNA transcripts in a biologic sample (7). This approach has been applied successfully to the classification and prediction of outcome of human malignancies (e.g., lymphoma, leukemia, melanoma, breast, colon, and prostate carcinoma), and to the identification of genes and pathways dysregulated in diseased human tissues (8, 9). In this study we explore the hypothesis that gene expression profiling of peripheral blood mononuclear cells (PBMCs), which are comprised of monocytes/macrophages, B and T lymphocytes, and natural killer cells, may provide new insights into the pathophysiology of SLE.

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Acknowledgments

We are grateful to all of the SLE patients for their participation. We thank L. Staudt for advice and encouragement. This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Minnesota Lupus Foundation, and the Alliance for Lupus Research.

Acknowledgments

Abbreviations

SLEsystemic lupus erythematosus
PBMCperipheral blood mononuclear cell
ADaverage difference
ACRAmerican College of Rheumatology
Abbreviations

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