Reduced levels of CD99 on Leukocytes without chromosome Y

Avani Dave, Jai Hind College

Background

In more than 30% of 60–80-year-old men with Mosaic loss of chromosome Y (LOY), a fraction of circulating immune cells lack the Y chromosome, and this aberration is evident in at least 10% of peripheral blood cells. A previous study of men over the age of 90 demonstrated that more than half of the participants had LOY in their blood leukocytes. Furthermore, single-cell tests of blood cells of old men diagnosed with Alzheimer’s revealed leukocytes lacking chromosomal Y. 

These findings confirm mosaic LOY as the most frequent somatic mutation in aged men’s hematopoietic lineages. Successively, in serially investigated men, the frequency of LOY-positive blood cells tends to rise over time. In peripheral blood cells, age, germline, genetic predisposition, and environmental exposures such as smoking are all repeated risk factors for LOY. Men with LOY have a higher chance of death from any cause; this increased risk of pathology and mortality linked with LOY could be one of the reasons why males live 5 years less than women on average. Up to 156 risk variants for LOY have been found in genome-wide association studies. 

A recent study conducted by Mattisson, J., et al. established a correlation between Leukocytes with LOY showing a reduced amount of surface immunoprotein CD99 enabling the identification of the underlying mechanism by which LOY in the blood might cause pathology. 

Discussion

The CD99 gene, which is located in pseudoautosomal region 1 (PAR1) of chromosomes X and Y, is one of the immunological genes that shows persistent downregulation in LOY cells. Females are immune to X-inactivation, emphasizing the relevance of CD99’s balanced expression. CD99 is a transmembrane glycoprotein present in most organs at low levels but significantly expressed in hematopoietic progenitor cells, peripheral blood cells, and endothelial cells. Since in vitro studies of hematopoietic progenitors reveal a role for CD99 in normal immune cell differentiation, selection, and death, it’s plausible that altered cell differentiation is linked to LOY-associated dysregulation of CD99. Progressing in the course of this study, fresh blood samples were collected to study the abundance of CD99 cell surface protein as well as CD99 mRNA in single cells with and without LOY. 

Conclusion

In conclusion, men who have circulating immune cells without the Y chromosome have a higher risk of disease and death. The results of the study reveal that single cells with LOY have a lower amount of CD99 protein, which is encoded by a gene on chromosomes X and Y. This cell surface immunoprotein is important for leukocyte features like transendothelial motility, adhesion, differentiation, apoptosis, and intracellular trafficking of immune surveillance proteins. These findings confirm the theory that LOY in leukocytes is directly linked to reduced immune activities via disruption of physiological CD99 biology and provide proof-of-concept for detecting a disease-associated protein on single cells with LOY. Nonetheless, establishing LOY as a predictive biomarker would benefit from a direct effect of LOY in immune cells on increased disease vulnerability in affected individuals; a hypothesis that would require more research and functional validation.

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Reference: 

1. Mattisson, J., Danielsson, M., Hammond, M. et al. Leukocytes with chromosome Y loss have reduced abundance of the cell surface immunoprotein CD99. Sci Rep11, 15160 (2021). https://doi.org/10.1038/s41598-021-94588-5

Author’s Info: Patient Decision Aid: Managing acute Achilles tendon rupture

Avani Dave is currently in the final year of her bachelor’s degree, majoring in Life Sciences. She holds a good academic and extra-curricular record. She is on a constant journey of acquiring exposure in her field of interest. However, she does not limit herself to just that. Avani likes studying Diseases and Syndromes and everything under this umbrella!

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

Publications in BioXone:

• Dave, A. (2021). Did the “Good cholesterol” get even better? BioXone. https://bioxone.in/news/worldnews/did-the-good-cholesterol-get-even-better/
• Dave, A. (2021). Unveiling the features of within-host dynamics in malaria. BioXone. https://bioxone.in/news/worldnews/unveiling-the-features-of-within-host-dynamics-in-malaria/
• Dave, A. (2021). A dash of sugar kelp for better health. BioXone. https://bioxone.in/news/worldnews/a-dash-of-sugar-kelp-for-better-health/

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