WHY we work in this area
Autoimmune diseases are caused by a complex combination of genetic and environmental factors. For example, genetic studies in the past 15 years have identified almost 100 different relevant genes for rheumatoid arthritis (see this recent review http://www.ncbi.nlm.nih.gov/pubmed/24276088). A major problem is that the mechanism of action of most of these genes in human autoimmunity is currently unknown. Understanding the effect of disease-associated genetic variations on gene function is important because it might pave the way to targeting these genes or other components of the pathways to which the genes belong for novel therapies. In addition, genes are partially responsible for the fact that not all therapies work in all patients. Thus studying the function of such genes will enable development of more efficient personalized therapies that are tailored on the specific mechanism that causes disease in each patient.
WHAT we are doing in this area
Two major autoimmunity genes, PTPN22 and PTPN2 encode for enzymes with tyrosine phosphatase activity. Dr. Bottini reported the initial discovery that a single nucleotide substitution in PTPN22 significantly increases the risk of autoimmunity in human carriers (see http://www.ncbi.nlm.nih.gov/pubmed/15004560). Part of the Bottini laboratory is dedicated to understanding the mechanism of action of PTPN22 in autoimmunity. PTPN22 currently ranks as the second most important gene in rheumatoid arthritis, and the third in type 1 diabetes. It also increases the risk of other connective tissues diseases including systemic lupus erythematosus and systemic sclerosis. The laboratory uses a range of approaches from manipulation of PTPN22 expression in human cell lines and cells from human subjects, to modeling of the gene function in mice affected by autoimmune disease. Since PTPN22 plays a major role in autoimmune diabetes, this is an area of major interaction with the LJI Type 1 Diabetes Center.
HOW we support our work in this area
Work on the genetics of autoimmune diseases in the laboratory is currently supported by donations to the LJI Type 1 Diabetes Center, the JDRF, the Rheumatology Research Foundation, and the NIAID.
EXAMPLES of PUBLICATIONS from our laboratory in this area
http://www.annualreviews.org/doi/abs/10.1146/annurev-immunol-032713-120249 A recent review on the immunology of PTPN22 in autoimmunity.
http://www.ncbi.nlm.nih.gov/pubmed/23871208 In collaboration with Drs. Erik Peterson at University of Minnesota and Klaus Ley at LJI, the Bottini laboratory discovered that PTPN22 –which was believed to operate mainly if not exclusively at the level of B and T cells- also plays an important role in signaling in myeloid cells.
http://www.ncbi.nlm.nih.gov/pubmed/20538612 Biochemical work on PTPN22 showed that the phosphatase can be regulated by phosphorylation in a portion of the molecule that affects the activity of the enzyme. The common and autoimmune predisposing variants of the phosphatase are differentially regulated.
http://www.ncbi.nlm.nih.gov/pubmed/18981062 The Bottini laboratory discovered a second mutation in PTPN22, which leads to reduced function and protects humans from systemic lupus erythematosus and rheumatoid arthritis.
http://www.ncbi.nlm.nih.gov/pubmed/16273109 Biochemical work in cell lines and cells from human carriers of the autoimmune-predisposing mutation shows that the common and autoimmune predisposing variants of the phosphatase differentially regulate intracellular signaling in T cells.
KEY COLLABORATORS OUTSIDE LJI
Michel Tremblay, PhD, McGill University, Montreal, Canada
Tony Tiganis, PhD, Monash University, Victoria, Australia