Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by profound T cell effector dysfunction. The fundamental molecular mechanisms underlying T cell dysfunction remain largely unknown. Infection-related morbidity and mortality rates are high among patients with SLE and attributed to disease activity, the use of immunosuppressive drugs and deficient cell-mediated cytotoxic responses that are associated with decreased expression of interleukin-2 (IL-2). Besides the contribution to the increased rate of infections, decreased IL-2 production is involved in the defective activation-induced cell death that is important for the elimination of autoreactive T cells and the generation of T regulatory cells, which are believed to be decreased in SLE patients. Evidence suggests that the production of IL-2 is controlled at the gene transcription level. Specifically, it has been documented that SLE T cells have increased amounts of serine/threonine phosphatase 2A (PP2Ac) which limits the amounts of the phosphorylated (p) cAMP responsive element binding protein (CREB), a transcriptional enhancer. The increased expression of PP2Ac appears to be controlled at the transcriptional level through a CpG motif and single nucleotide polymprphisms (SNPs) located throughout the gene. In addition, certain regulatory B subunits of the PP2A trimolecular complex are aberrantly expressed in SLE T cells and account for specific T cell malfunction. Finally, a novel mouse over expressing PP2Ac in T cells produces increased amounts of IL-17 and is prone to glomerulonephritis. The hypothesis that PP2Ac represents a main contributor in the immunopathogenesis of SLE will be tested by determining genetic and epigenetic mechanisms that control the expression of PP2A in human SLE T cells;establishing the aberrant expression of B regulatory subunits in human SLE T cells and determining how each one of them contributes to a specific abnormal T cell function, and using the Cd2-Pp2ac mouse to establish the contribution of increased expression of PP2Ac in the autoimmune response and pathology. This line of research will generate novel information on the origin of T cell malfunction in SLE patients and will identify novel approaches to correct IL-2 production which will help decrease the rate of infections by restoring immune cell function.

Public Health Relevance

Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by profound T cell effector dysfunction. Infection-related morbidity and mortality rates are high among patients with SLE and it is attributed to disease activity, the use of immunosuppressive drugs and deficient cell- mediated cytotoxic responses that are associated with decreased expression of interleukin-2. Understanding the molecular mechanisms that account for the decreased production of interleukin-2 will generate novel information which will guide approaches to correct its production and help decrease the rate of infections by restoring immune cell function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068787-07
Application #
8424952
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2007-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
7
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
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