Researchers identify over 140 genes linked to immune system regulation

First extensive immune profiling of mice reveals a vast catalogue of genes that regulate the immune system and model human disease

Scientists from the Wellcome Sanger Institute and King’s College London have led a major multicentre analysis of over 500 genetically modified mouse lines to explore the effect of disrupting single genes on the immune system.

The immune system is increasingly implicated in many functions of the body beyond infection, with involvement documented in cancer, obesity, and neurodegeneration. However, there is only a very limited understanding of the genes and pathways that regulate the immune system.

Published today (16th December) in Nature Immunology, researchers developed a set of systematic and high-throughput tests for mouse strains to reproducibly and comprehensively identify roles for individual genes in the immune system.

The researchers created and analysed 530 genetic variant mouse lines in the study. They found more than 140 genes involved in controlling the number or activity of immune cells, or the response to infection by pathogens including salmonella and the flu. Many of these genes had not been associated with the immune system before. The screen also swiftly picked up the genes Arpc1b, Cog6, and Bach2, which have since been found to be altered in patients with immune system disorders.

“In this study we made no assumptions a priori about the relevance of the genes we analysed to immunology. This permitted us to uncover 80 new genes with immune regulatory functions, that had never previously been implicated in immunology.”
Professor Adrian Hayday Co-senior author, from the School of Immunology & Microbial Sciences, Kings College London

“Our study is helping us to understand the immune system. We were delighted to find several genes that impact the immune system which have now also been associated with immune disorders in humans.”
Dr David Adams Co-senior author from the Wellcome Sanger Institute   

The next steps in this research are to investigate the pathways by which the identified genes regulate the immune system, and to investigate the potential of these as diagnostics or therapeutics in the clinic.

“The datasets we have generated serve as a resource that can be mined for years to come. In vivo models are critically important for validating the link between human genetics and disease genes and for the generation of new treatments.”
Dr Adam Laing School of Immunology & Microbial Sciences, Kings College London

More information

All of the data can be viewed on 3i Consortium website.

Publication:

L. Abeler-Dörner, A.G. Laing, A. Lorenc et al. (2019) High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation. Nature Immunology. DOI: 10.1038/s41590-019-0549-0

Funding:

The 3i consortium was funded by Wellcome and included investigators from the Universities of Oxford, Cambridge and Manchester, Imperial College London, and the Francis Crick institute. Please see the paper for their full funding information.