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Developmental Biology - The Immune System

Gene Helps Heart Grow/Slows Immune System Aging

A gene playing a key role in fetal heart development also plays a key role in our immune system...

A gene with the cryptic abbreviation CRELD1 has so far been a mystery to science. It is known to play an important role in the development of the heart in the embryo. However, the CRELD1 gene also remains active after birth.
Studies show that CRELD1 is regularly produced in practically all cells of the body. However, for what purpose was completely unknown.

A recent study led by the University of Bonn (Germany) reflects the gene is not very active, and as the immune defense system undergoes characteristic changes — it loses its effectiveness. Doctors often refer to an 'aging immune system' as a similar result can often be seen in older people. The University of Bonn results may indicate how CRELD1 contributes to age-related losses. The study is published in the journal Nature Immunology.

The Bonn researchers used a novel approach to answer their question.

Nowadays, scientific studies with human participants often include so-called transcriptome analyses. By these means, scientists can determine which genes are active, and to what extent in a respective test subject. Researchers are also increasingly making data they obtain available to colleagues, to use in work on completely different matters.
"And this is exactly what we did in our study. This information provided us with the activity of the genetic material, including the gene, in a total of 4,500 test subjects. In addition, the data for these participants included information on certain immunological parameters, such as the number of different immune cells in their blood."

Anna Aschenbrenner PhD, LIMES Institute, University of Bonn and member of the ImmunoSensation² Cluster of Excellence.

Aschenbrenner is doing her post doctural research with the Genomics and Immunoregulation team of Prof. Dr. Joachim Schultze. Together with her colleagues, she combined transcriptome data from three different studies.

CRELD1 Less Active In Some People

These researchers discovered a surprising correlation when analyzing all of this information: 4,500 analyzed test subjects included some in whom the CRELD1 gene was, for some reason, significantly less active. Interestingly, the blood of those donors was found to contain only very few T cells. T cells play an important role in fighting infections; some of them detect virus-infected cells and kill them before they can infect other cells.

Researchers investigated this relationship further using mice.
Their results showed that genetic loss of the CRELD1 gene was indeed the cause for the loss of T cells. T cells without the CRELD1 gene largely lose their ability to propagate and die early.

According to Aschenbrenner: "We see similar changes in people with an 'aged' immune system."

This phenomenon, called immunosenescence, is mainly observed in older people. Those affected are much more susceptible to infections. Currently discussed in regards to COVID-19, it is possibly related to all age-related diseases such as cancer or Alzheimer's.

The activity of numerous genes in the blood is altered in a characteristic way. Experts refer to it as the signature of immunological aging. Aschenbrenner: "We found precisely this signature among participants with low CRELD1 activity."

Centenarians With Young Immune Systems

Surprisingly, some people'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.

Researchers now hope the CRELD 1 gene will provide them a key to better understanding causes of immunological aging.
"The long-term goal is to slow down — or halt this process. This could perhaps significantly reduce the risk of illness in seniors."

Anna Aschenbrenner PhD

CRELD1 is a pivotal factor for heart development, the function of which is unknown in adult life. We here provide 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 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.

Lorenzo Bonaguro, Maren Köhne, Lisa Schmidleithner, Jonas Schulte-Schrepping, Stefanie Warnat-Herresthal, Arik Horne, Paul Kern, Patrick Günther, Rob ter Horst, Martin Jaeger, Souad Rahmouni, Michel Georges, Christine S. Falk, Yang Li, Elvira Mass, Marc Beyer, Leo A. B. Joosten, Mihai G. Netea, Thomas Ulas, Joachim L. Schultze and Anna C. Aschenbrenner

The authors thank K. Händler, M. Kraut, H. Theis and M. Thielisch for technical assistance and K. Baßler, F. Gondorf, S. Burgdorf and M. Embgenbroich for technical advice. Furthermore, we acknowledge the assistance of the Flow Cytometry Core Facility at the Institute of Experimental Immunology, University of Bonn. We thank M. Hoch for his continuous support of our work; P. Rosenstiel, F. Berberich-Siebelt, M. Väth, D. Cantrell, D. Littmann and L. Fülle for helpful discussion of our work; and M. Davis, S. Turner, L. Klein, J. Bluestone and J. Riley for critically reading our manuscript. A.C.A. was supported by an intramural grant from the Department of Genomics & Immunoregulation at the LIMES Institute. The work was supported by the German Research Foundation (DFG) to J.L.S. under Germany’s Excellence Strategy (EXC2151-390873048) as well as under SCHU 950/8-1; GRK 2168, TP11; SFB704, the BMBF-funded excellence project Diet–Body–Brain (DietBB) and the EU project SYSCID under grant number 733100. M.G.N. was supported by a Spinoza grant of the Netherlands Organization for Scientific Research and an ERC Advanced Grant (833247). E.M. was supported by the DFG under Germany’s Excellence Strategy EXC2151-390873048, the Daimler and Benz Foundation and the Fritz Thyssen Foundation. S.R. and M.G. are supported by the University of Liège (ARC and Fonds Spéciaux) and Fonds de la Recherche Scientifique de Belgique (F.R.S.-FNRS) under grant number EOS 30770923. C.S.F. was supported by the DFG (SFB738/TP3).

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Nov 12 2020   Fetal Timeline   Maternal Timeline   News

Image above shows cells in which Creld1 is labeled with yellow dye
indicating localization within the cell. CREDIT Lorenzo Bonaguro.

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