Systemic lupus erythematosus (SLE) afflicts more than a million Americans, primarily women, and presents with symptoms resulting from the involvement of practically every organ. The origin of the disease involves diverse factors which probably contribute variably to the expression of the disease in each patient. Understanding of the molecular underpinnings that lead to an aberrant immune response through this line of research has helped us identify novel treatment targets and biomarkers. Engagement of the CD3/T cell receptor complex in SLE T cells results in early and enhanced signaling response which has been linked to decreased presence of the CD3?, aggregated lipid rafts and increased expression of the adhesion molecule CD44. Study of CD3? deficient mice revealed parallels to human SLE T cells and a noted infiltration of T cells in to various tissues including the kidney. The new information compelled the address the testable hypothesis that decreased expression of CD3? in T cells forces the formation of aggregated lipid rafts, the expression of CD44, the production of interferon-? and the ability to infiltrate target tissues. I two sets of experiments using novel engineered mice we will understand the mechanisms whereby decreased or absent expression of CD3? renders T cells able to infiltrate tissues and how manipulation of lipid rafts can mitigate organ damage resulting from T cell infiltration. In parallel, in a prospective study of SLE patients the expression of CD44 and the use of a homemade expression array of genes claimed important in the immunopathogenesis of SLE will be test their ability to serve as disease biomarkers. The significance of the proposed studies lies with the identification of novel targets and the development of biomarkers. The study of the contribution of T cells to tissue inflammation in SLE using novel engineered mice presents a unique opportunity. Furthermore, the use of our gene expression array opens the way to personalized approach to SLE.

Public Health Relevance

Systemic lupus erythematosus afflicts more than a million Americans, primarily women, and presents with symptoms resulting from the involvement of practically every organ. The origin of the disease involves diverse factors which probably contribute variably to the expression of the disease in each patient. Understanding of the molecular underpinnings that lead to an aberrant immune response through this line of research will help us identify novel treatment targets and biomarkers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI042269-17
Application #
8579573
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Johnson, David R
Project Start
1998-07-15
Project End
2018-05-31
Budget Start
2013-06-20
Budget End
2014-05-31
Support Year
17
Fiscal Year
2013
Total Cost
$408,900
Indirect Cost
$173,900
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Comte, Denis; Karampetsou, Maria P; Kis-Toth, Katalin et al. (2016) Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus. Proc Natl Acad Sci U S A 113:9321-6
Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin et al. (2016) Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production. J Immunol 196:4915-24
Suárez-Fueyo, Abel; Bradley, Sean J; Tsokos, George C (2016) T cells in Systemic Lupus Erythematosus. Curr Opin Immunol 43:32-38
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Comte, D; Karampetsou, M P; Tsokos, G C (2015) T cells as a therapeutic target in SLE. Lupus 24:351-63
Bradley, Sean J; Suarez-Fueyo, Abel; Moss, David R et al. (2015) T Cell Transcriptomes Describe Patient Subtypes in Systemic Lupus Erythematosus. PLoS One 10:e0141171
Deng, Guo-Min; Tsokos, George C (2015) Pathogenesis and targeted treatment of skin injury in SLE. Nat Rev Rheumatol 11:663-9
Walter, Jolan E; Lo, Mindy S; Kis-Toth, Katalin et al. (2015) Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol 135:272-3
Moulton, Vaishali R; Gillooly, Andrew R; Perl, Marcel A et al. (2015) Serine Arginine-Rich Splicing Factor 1 (SRSF1) Contributes to the Transcriptional Activation of CD3ζ in Human T Cells. PLoS One 10:e0131073

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