Immune and metabolic disorders: two sides of the same coin?
A significant overlap has been identified in the functionalities of genes associated with immune and metabolic disorders, suggesting a fundamental frameshift is needed in our understanding of the two.
A team of researchers from Vanderbilt University Medical Center (TN, USA), led by Jeffrey Rathmell, has used CRISPR-screening methods to expose a significant overlap in the genes implicated in inherited metabolic and immune diseases, revealing new insights into the genetic underpinnings of these complex disorders. These recent findings could one day lead to improved treatments for patients with these conditions and highlight the need to explore potential disorders of immunometabolism.
Inherited disorders of metabolism, known as inborn errors of metabolism (IEM), are caused by genetic aberrations that disrupt the processes used by cells to convert nutrients into energy. Their immunological compatriots, known as inborn errors of immunity (IEI), result from genetic defects that impair the functionality of the immune system. Only a small number of genes have previously been identified as contributing to both conditions, which runs contrary to the numerous interwoven pathways that constitute immunometabolism.
To investigate this discrepancy, study first author Andrew Patterson employed CRISPR-based screening technology in mouse CD4 T cells to examine if genes associated with IEMs also had immunological functions and whether genes associated with IEIs had metabolic capabilities. Selecting a promising candidate from each set to thoroughly explore the mechanical pathways underlying their immunological or metabolic impacts, the team made some fascinating discoveries.
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The initial screen unmasked hundreds of genes that overlapped, impacting both the immune and metabolic systems. From the IEM-associated genes, the de novo hexosamine synthesis enzyme – Gfpt1 – was shown to be vital to T cell expansion and function. Meanwhile, the IEI gene screen highlighted the gene Bcl11b as stimulatory of mitochondrial activity as well as able to promote the expression of Mcl1, a key player in the prevention of metabolic stress.
Commenting on these findings, Rathmell emphasized that, “rather than different categories, these diseases are part of a continuum; there’s a gray zone between them and a potential new class of inborn errors of immunometabolism that intersects the two.” This represents a frameshift in our understanding of immune and metabolic disorders and suggests that if someone suffers from a metabolic disease, they may also have a previously unidentified immune system issue, and vice versa, which could help inform their treatment.
What’s more, the collection of genes identified represent hundreds of potential targets for drug discovery and for further exploration to better understand these disorders. Keen for their efforts to be built upon, the team has made their database containing these overlapping genes available online.
