‘Molecular Switch’ that Causes Mucosal Autoimmune Diseases Discovered

According to an international team of researchers led by University College London and King’s College London, the discovery of a ‘molecular switch’ that causes the mucosal inflammatory diseases ulcerative colitis, Crohn’s disease, and celiac disease, could lead to effective new treatments for these autoimmune conditions. The discovery is reported in the journal PLoS Genetics.

According to Soderquest et al, T-bet plays an important role in coordinating the body’s immune responses. Image credit: Werbe Fabrik.

For the first time, researchers have a specific target for the treatment of these life-changing conditions by identifying an immune molecule called T-bet (TBX21) as the key control point that regulates the genetic risk in specific diseases.

“Our research outlines a specific focus for the development of new treatments for these diseases which have such a profound effect on sufferers,” explained Professor Graham Lord, co-senior author on the study and Director of the National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London.

In the study, Prof. Lord and his colleagues examined how genetic variation affects T-bet binding to DNA, as a key regulatory mechanism in the immune response.

“Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases,” the researchers said.

“The majority of these polymorphisms are located within non-coding distal regulatory elements.”

“It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined.”

The researchers found that T-bet binding sites are specifically enriched in genetic variants associated with the mucosal autoinflammatory diseases.

They also identified genetic variants that alter T-bet binding and gene expression.

“We show that SNPs associated with the mucosal inflammatory diseases Crohn’s disease, ulcerative colitis and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T-bet binding sites,” the authors said.

“Furthermore, we identify disease-associated variants that alter T-bet binding in vitro and in vivo.”

“Our results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding,” they said.

“Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.”

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K. Soderquest et al. 2017. Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. PLoS Genet 13 (2): e1006587; doi: 10.1371/journal.pgen.1006587