Autoimmune disease affects over 25 million Americans, and has an economic impact of over 100 billion dollars per year. These disorders result from a break down of the intrinsic regulatory pathways that limit T cell activation and differentiation, and from a failure of regulatory T cells (Treg) to extrinsically suppress conventional T cell (Tconv) proliferation and effector function. Genetic studies in both humans and mice strongly implicate the cytokine IL-2 in the risk of developing Grave's disease, rheumatoid arthritis, celiac disease, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and type 1 diabetes (T1D). The majority of the disease-associated single nucleotide polymorphisms (SNP) are located in the ~100 kb or intergenic space between the IL2 and IL21 genes, and the molecular basis for the genetic link between IL2 and autoimmunity is not understood. We have new evidence that distal, intergenic cis-regulatory elements contribute to the regulation of IL2. We find that CD28 costimulation induces looping between a distal element and the il2 promoter, and this distal element can greatly enhance IL2 transcription in promoter-reporter assays. The research proposed in this application will explore and establish the long-range regulatory architecture of the IL2 locus, paving the way for an important new understanding of the genetic basis for autoimmune disease.

Public Health Relevance

Autoimmune disease results from a breakdown of the 'checks and balances'that normally limit activation of the cells of the immune system. Genetic studies in both humans and mice strongly implicate the immune hormone IL-2 in the risk of developing Grave's disease, rheumatoid arthritis, celiac disease, multiple sclerosis, psoriasis, Crohn's disease, ulcerative colitis, and type 1 diabetes (T1D), autoimmune disorders that together affect over 25 million Americans and have an economic impact of over 100 billion dollars per year. Despite this, the molecular basis for the genetic link between IL2 and autoimmunity is not understood, as most of the single nucleotide polymorphisms (SNP) associated with disease occur within the vast intergenic space upstream of the IL2 gene. We have new evidence that this region of the genome is not 'junk DNA', but rather contains a previously undiscovered array of potential regulatory elements that can contribute to IL2 expression, and potentially to regulation of the next closest gene encoding another important cytokine, IL-21. The research proposed in this application will explore and establish the 'regulatory architecture'of the IL2 locus, paving the way for an important new understanding of the genetic basis for autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI110179-01
Application #
8656204
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Peyman, John A
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$226,800
Indirect Cost
$91,800
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104