Inborn errors of immunity & corresponding protein interactions

Avani Dave, Jai Hind College

Inborn errors of immunity (IEI) are a group of approximately 400 monogenic diseases characterized by recurring, severe, or uncommon infections, as well as autoimmunity and autoinflammation. The synthesis of the clinical phenotype, the findings of immunological testing, and the results of genetic testing have identified the main pathogenic mutations required to make a diagnosis in these individuals(s). 

The technique of finding genetic variations has become much easier because of whole-exome and genome sequencing. When this method can’t locate a known pathogenic variation or even a known IEI gene, it shifts gears to see if a novel gene may be to blame for the illness phenotype. It’s an unresolved challenge to narrow down the list of thousands of genes and tens of thousands of variations in “non-clinical” genes/genes that haven’t yet been recognized as significant for a human illness. The list of variations can be whittled down to a few hundred genes by filtering out those that are prevalent in human populations. However, selecting genes and verifying their roles is a time-consuming procedure that follows this stage.

Every year, nearly a third of a dozen new IEI genes are identified. Although the correct gene is found, the procedure of verifying the biochemical and immunological effects of the discovered variant(s) is clearly defined, as time-consuming. A recent study conducted by Khan, H. A., et al. presents a list of IEI-related genes compiled by connecting known IEI proteins with novel IEI proteins.

Discussion: 

Using open-source datasets of protein-protein interactions, post-translational modifications, and transcriptional regulation, a new list of genes was delineated by connecting known IEI genes to new ones. The researchers further looked at the tolerance of genetic diversity in this new list of 2,530 IEI-related genes, as well as their expression levels in different immune cell types. This study presents a fresh list of potential genes that may play a role in as-yet-undiscovered IEIs by combining genes obtained from protein interactions of known IEI genes with transcriptional data. However, the lists do not address the issue of identifying non-redundant genes as the source of immunodeficiencies. This issue might be solved with better databases of immunological networks and tissue annotation.

The future prospects of the study:

In summary, the technique described during the study offers both a global and local perspective of proteins that may be important to query in future immunodeficiency research by combining 1:1 annotated protein interaction with broader, un-annotated protein interaction pathways. This study has enhanced the chance of genes from redundant, non-specific immune pathways being eliminated by further trimming the lists for cell-type expression. 

Notably, the findings discovered that a high probability of loss intolerance (pLI) or Gene damage indices (GDI) was ineffective in identifying the pathogenicity of a putatively new IEI gene, particularly those with recessive inheritance patterns. Furthermore, the findings build on prior research by combining transcriptional expression data with the list of IEI candidate genes obtained from protein interactions, ensuring that inquiries are answered based on clinical manifestations (e.g., T-cell lymphopenia) or diagnostic assumptions. This exploratory research in protein interaction is an extremely helpful tool for a comprehensive understanding of the underlying mechanisms.

Also read: Antifungal drug-delivery using micelles

Reference: Khan, H. A., & Butte, M. J. (2021). Expanding the potential genes of inborn errors of immunity through protein interactions. BMC Genomics, 22(1), 618. https://doi.org/10.1186/s12864-021-07909-3

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Author’s Info:

Avani Dave is currently in the final year of her bachelor’s degree, majoring in Life Sciences. Holding a good academic and extra-curricular record, she is on a constant journey of acquiring exposure in her field of interest while simultaneously not limiting herself to just that. Avani likes studying Diseases and Syndromes and everything under this umbrella! That being said, she is adept at working across departments and promises to deliver.

LinkedIn – https://www.linkedin.com/avani-dave/

Publications in BioXone:

• Dave, A. (2021). Hirschsprung disease patients show novel gene revelations! BioXone. https://bioxone.in/news/worldnews/hirschsprung-disease-patients-show-novel-gene-revelations/
• Dave, A. (2021). Autism Spectrum Disorder & its occurrence in Preterm Infants. BioXone. https://bioxone.in/news/autism-spectrum-disorder-its-occurrence-in-preterm-infants/
• Dave, A. (2021). HEI10: How do sex cells receive the right genetic mix? BioXone. https://bioxone.in/news/worldnews/hei10-how-do-sex-cells-receive-the-right-genetic-mix/