Malfunctioning immune system

Inflammatory bowel disease (IBD) is a chronic disorder of the gut caused by dysfunction of the immune system. The most common forms are Crohn’s disease and ulcerative colitis. IBD is growing in prevalence and is believed to affect more than 6.5 million people worldwide.

Genetic, immunological and environmental factors are implicated in the development of IBD, but the exact causes have been unclear.

Treatment challenges

The advent of immunomodulators in the 1990’s and anti-TNF biologics in the 2000’s have improved outcomes for patients. However, IBD is still often chronic and progressive with a massive impact on quality of life. There is an urgent need for more medication options. However, only 10% of the drugs that enter clinical development actually end up becoming treatments. In part, this is because the mechanisms underpinning IBD have been poorly understood.

New scientific approaches

Development of powerful new molecular biology techniques in recent years are helping to change that. ‘Omics technologies and CRISPR gene knockout techniques allow scientists to employ a ‘functional genomics’ approach. Beyond just identifying the genes associated with a disease like IBD, these techniques allow researchers to understand the dynamic aspects of the genetics and identify factors that affect gene and protein functions. For example, they can identify factors that regulate the expression of a gene, i.e., the rate at which its DNA instructions get decoded in a cell to produce proteins and downstream effects, both negative and positive.

Change on chromosome 21 directs macrophage inflammation through the ETS2 gene

A recent paper in the journal Nature describes a comprehensive study that has done exactly this with exciting results.

The work was led by researchers at the Francis Crick Institute in London and the Charité–Universitätsmedizin in Berlin in collaboration with colleagues at other world-class research institutes.

They were able to identify a change (or haplotype) in a region on chromosome 21 (chr21q22) that affects expression of a gene called ETS2.

Chr21q22 lies in what is called a ‘gene-desert’ or non-coding region and yet it has profound effects. The change in chr21q22 causes enhanced ETS2 expression in macrophage cells.

Macrophages are the immune cells that recognize, engulf and destroy infected or damaged cells. They gobble up bacteria by phagocytosis. They also present antigens to the T-cells of the immune system and initiate inflammation by releasing cytokines and other chemicals.

Enhanced ETS2 expression in macrophages causes these responses to go into overdrive. The researchers found that chr21q22 causes enhanced ETS2 expression in macrophage cells leading to increased phagocytosis, increased production of pro-inflammatory cytokines and the release of reactive oxygen species (an oxidative-burst) that can damage pathogens, but also surrounding tissues. These diverse effects of ETS2 are likely achieved through metabolic reprogramming of other genes associated with inflammation.

Crazily, they even found a possible feedback loop to multiply the effect, since the ETS2 (the product of the ETS2 gene) also binds at the chr21q22 enhancer site,

These effects mimic the disease state of IBD and indeed the researchers found that the genes regulated by ETS2 were prominently expressed in IBD diseased tissues.

How common is this risk factor?

The researchers estimate that the genetic risk factor is common with a frequency of around 75% in Europeans and >90% in Africans and has been present for over 500,000 years. Clearly there must be an interaction beyween the genetic risk factor and enviromental factors, since not all carriers of the chr21q22 variant go on to develop IBD.

But, why does this harmful pathway persist, why hasn’t it been removed by natural selection over our evolutionary history?

Well, ETS2 expression in macrophages and their precursors is linked to effective responses against bacteria. It’s beneficial effects in fighting pathogens has balanced out the disadvantages of increased IBD risk.

New treatment options

Often better understanding of the biology of a disease leads to new treatment options to explore and that is the case here.

Using a database of cellular signatures, the researchers identified drugs that might modulate the pathway. The largest class of drugs was MEK inhibitors, which are currently used to treat other diseases.

Multiple MEK1/2 inhibitors downregulated the ETS2-target genes, and this method of inhibition affects multiple cytokines, including TNF and IL-23, which are targets of existing therapies, and IL-1β, which is linked to treatment resistance. However, long-term MEK inhibitor use may not be ideal owing to the harmful effects of MEK in other tissues.

Selectively delivering MEK inhibitors to macrophages through combined antibody–drug conjugates could overcome this problem.

An alternative, safer means of blocking ETS2-driven inflammation could involve targeting ETS2 directly through a targeted protein degrader (PROTAC).

The same region on chromosome 21 is linked to 3 other auto-immune/inflammatory diseases (ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis) offering hope for new therapeutic approaches to combat these too.

It may take a number of years for the apprpach to bear fruit, but understanding the underlying disease mechanim being targeted gives greater hope of success.

Reference:

Stankey, C. T., Bourges, C., Haag, L. M., et al. (2024). A disease-associated gene desert directs macrophage inflammation through ETS2. Nature, 630(8016), 447–456. https://doi.org/10.1038/s41586-024-07501-1

Written by: Noisy Guts co-founder Dr Mary Webberley. Mary has a background in biology, with two degrees from the University of Cambridge and post-doctoral research experience. She spent several years undertaking research into the diagnosis of IBS and IBD. She was the winner of the 2018 CSIRO Breakout Female Scientist Award.