Rare gene mutation eliminates immune cell population

A collaborative study has allowed researchers to identify a rare human gene mutation that removes a population of immune cells, called mucosal-associated invariant T (MAIT) cells.

A man gazes at the complex protein structures of his own immune system, and the rare genetic mutations that caused his illness, leading scientists to a dramatic discovery. Image Credit: (C) Erica Tandori.

The study involved Monash Health, the Australian Genomics Health Alliance (AGHA), and scientists from the Monash Biomedicine Discovery Institute (Monash BDI).

The journey of this study first started with a patient of Dr Samar Ojaimi from Monash Health. This patient had complained about a mild primary immunodeficiency with an unknown cause.

He was later identified as a suitable candidate for the Genetic Immunology Flagship of AGHA headed by Professor Matthew Cook from the Centre for Personalised Immunology at the Australian National University. The university focuses on detecting genetic causes for immunological disorders.

The AGHA team performed genome sequencing that revealed a rare mutation in the gene that encodes a protein known as MR1. This protein usually helps trigger an inflammatory reaction from a population of immune cells known as MAIT cells.

But when researchers from Monash BDI and headed by Dr Lauren Howson further analyzed this mechanism, they found that the population of immune cells was fully eliminated, while the remaining immune system continued to be intact.

We studied the patient’s MR1 protein structure and found that the mutation prevented MR1 from being able to bind the vitamin metabolite it normally presents in order to activate MAIT cells. This led us to look at the patient's immune system to see what effect the mutation had on the MAIT cell population and we were surprised to find it completely gone.”

Dr Lauren Howson, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute

The study, published in the Science Immunology journal, shows the power of interdisciplinary association to expose the effect of a single gene mutation and help diagnose rare immune diseases.

The study also advances the research fields of MR1 and MAIT cell biology and also shows how discovery-based studies can have a considerable impact when integrated with genetic and clinical research, creating a means for sophisticated personalized medicine for rare immune and genetic diseases.

This occurrence of a single immune cell population loss in a person gives us invaluable insight into the important role that this cell type plays in human immune responses.”

Dr Lauren Howson, Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute

“Human genomics is a powerful method for advancing our understanding of the complexity of immunity. Genome sequencing has emerged as a crucial tool for both diagnosis and discovery of immune-mediated disease,” Professor Cook concluded.