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.”
_____
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
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