Cambridge Institute for Medical Research

Professor Linda Wicker

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Identification of Molecular and Cellular Mechanisms in Autoimmune Disease

Our group is focused on understanding the molecular and cellular mechanisms of autoimmune syndromes such as type 1 diabetes (T1D) by identifying and characterising the function of genes that contribute to disease susceptibility in both humans and mice.  Although the MHC region remains the major genetic determinant causing the destruction of insulin-producing beta cells in the pancreas of humans and nonobese diabetic (NOD) mice, the identification of non-MHC genes contributing to T1D susceptibility has made enormous progress in recent years.  It is now apparent that a conservative estimate of the number of T1D regions is at least 100 in both species, with most regions having plausible candidate genes that could alter immune function.  Importantly, overlap with T2D causal regions has not been observed whereas overlapping gene associations are present in the case of other autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.  Humans and NOD mice have variations in some of the same T1D genes or gene pathways and there are data in both species that the early autoimmune response to insulin and other beta cell proteins is caused by a partial failure in central and peripheral tolerance mechanisms.  In addition to sharing structural aspects of the MHC class II molecules that confer T1D susceptibility or resistance, variation in the PTPN22, CTLA-4 and IL-2/CD25 pathways are also associated with T1D in both species.  All of these pathways are critical for the development and regulation of immune and autoimmune responses; PTPN22 is a phosphatase that negatively regulates signalling in many subsets of immune cells and CTLA-4 is a negative regulator that is particularly critical for the function of FOXP3+CD25+CD4+ regulatory T cells, a cell subset that is essential for immune homeostasis.  The interaction of IL-2 with its trimeric receptor, which includes the IL-2 receptor alpha chain (IL-2Ra, also called CD25), is also necessary for the function of FOXP3+CD25+CD4+ regulatory T cells.

To link the gene variants that cause autoimmune disease with their biological effects within the human immune system, we study immune cells purified from the peripheral blood of healthy volunteers accessed through the Cambridge BioResource.  The genotypes of our donors at genes causing T1D are determined and correlated with phenotypes ranging from the expression of the protein encoded by the putative disease-causing gene to parameters of immune cell activation and differentiation.  One phenotype for which we have discovered a genotype correlation is the expression level of CTLA-4 in FOXP3+CD25+CD4+ regulatory T cells; donors having a genotype conferring protection from T1D have higher CTLA-4 expression levels in this T cell subset.  In other studies that we have recently published, CD25 expression was shown to vary by genotype on memory CD4 T cells (higher on cells having a protective haplotype) and IL-2 production by these memory T cells following activation was positively correlated with CD25 expression.  We also discovered that there is expression of CD25 on a subset of naïve CD4 T cells in many individuals and that this expression increases with age and is decreased in individuals having a second protective IL2RA haplotype (in this case the protective allele is also associated with protection from multiple sclerosis).  Reduced upregulation of CD25 on naïve CD4 T cells following stimulation was determined also by this same T1D/MS protective allele. 

Funding

• Juvenile Diabetes Research Foundation
• Wellcome Trust
• National Institutes of Health (USA)

Group Members