Immunogenetics: CRELD1 Gene Plays A Critical Role In Immune System Even In The Context Of COVID-19 And Neurodegenerative Diseases Like Alzheimer's
: Researchers from the University of Bonn-Germany and the Radboud University Medical Center, Nijmegen-Netherlands have in a new study found a genetic disposition that plays a key role in the development of the heart in the embryo also appears to play a key role in the human immune system. When the gene identified as CRELD1 is not active enough, the immune defense system undergoes characteristic changes, causing it to lose its effectiveness. Physicians speak of an aging immune system, as a similar effect can often be observed in older people.
According to the study abstract, CRELD1 is a pivotal factor for heart development, the function of which was unknown in adult life until now.
The study team provides evidence that CRELD1 is an important gatekeeper of immune system homeostasis. Exploiting expression variance in large human cohorts contrasting individuals with the lowest and highest CRELD1 expression levels revealed strong phenotypic, functional and transcriptional differences, including reduced CD4+ T cell numbers.
These study findings were validated in T cell–specific Creld1-deficient mice. Loss of Creld1 was associated with simultaneous overactivation and increased apoptosis, resulting in a net loss of T cells with age. Creld1 was transcriptionally and functionally linked to Wnt signaling.
Collectively, gene expression variance in large human cohorts combined with murine genetic models, transcriptomics and functional testing defines CRELD1 as an important modulator of immune homeostasis.
The study findings were published in the peer reviewed journal : Nature Immunology. https://www.nature.com/articles/s41590-020-00811-2
These study findings can in the medium term contribute to reduce these age-related losses.
This mysterious gene with the cryptic abbreviation CRELD1 has so far been a puzzle to science and genetics. It was known to play an important role in the development of the heart in the embryo but nothing else was ever known about it till now.
The CRELD1 gene remains active after birth: Studies show that it is regularly produced in practically all cells of the body. For what purpose, however, was previously completely unknown.
The German and Dutch researchers used a novel approach to answer this question.
These days, scientific studies with human participants often include so-called transcriptome analyses. By these means, one can determine which genes are active to what extent in the respective test subjects.
Corresponding author, Dr Anna Aschenbrenner, from the Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn-Germany told Thailand Medical News, “Scientists are also increasingly making the data they obtain available to colleagues, who can then use it to work on completely different matters. And this is exactly what we did in our study."
Dr Aschenbrenner is a member of the ImmunoSensation² Cluster of Excellence
Aschenbrenner is doing her habilitation in the Genomics and Immunoregulation team of Pr
ofessor Dr Joachim Schultze.
The study team combined transcriptome data from three different studies.
She explained, "This provided us with information on the activity of the genetic material, including the CRELD1 gene, of a total of 4,500 test subjects. In addition, the data for these participants also included information on certain immunological parameters, such as the number of different immune cells in their blood."
Surprisingly, the study team discovered a correlation when analyzing this information ie the 4,500 analyzed test subjects included some in whom the CRELD1 gene was significantly less active for some reason.
Significantly, the blood of these donors was found to contain only very few of the so-called T cells. These cells play an important role in fighting infections; some of them detect virus-infected cells and kill them before they can infect other cells.
The study team further investigated this relationship in mouse experiments.
The study findings showed that the genetic loss of the CRELD1 gene was indeed the cause for the loss of T cells.
It was noted that T cells lacking the CRELD1 gene largely lose their ability to propagate and die earlier
Dr Aschenbrenner stressesed, "We see similar changes in individuals with an 'aged' immune system, this phenomenon, also called immunosenescence, is mainly observed in older people.”
Importantly those affected are much more susceptible to infections, as currently discussed in the context of COVID-19, but possibly also to age-related diseases such as cancer or Alzheimer's.
To date it is known that the activity of numerous genes in the blood is altered in a characteristic way, which experts also refer to as an immunological aging signature.
Dr Aschenbrenner added, "Importantly we found precisely this signature among participants with low CRELD1 activity."
It has been found that some individual's immune system ages much faster than others. For instance, there are centenarians who, immunologically speaking, are several decades younger. With others, the power of the body's own disease defense system already diminishes significantly in the middle of life.
The study team now hopes that CRELD1 will provide them with a key to better understand the causes of immunological aging.
Dr Aschenbrenner added, "The long-term goal is to slow down or halt this process. This could perhaps significantly reduce the risk of illness in seniors."
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