RNA exosomes play key role in B cell development, UTSW study finds

New research from UT Southwestern suggests that RNA exosomes – the cellular machinery that breaks down old RNA molecules – play a key role in the development of B cells, which are essential for the immune system’s ability to protect against infection. The findings, published in Sciences Immunologyexplain why patients with rare mutations in a gene that codes for this machinery are often immunocompromised and could offer new approaches to treating autoimmune diseases.

It was quite a surprise to us to find that this gene, whose role was well known as part of an RNA disposition system, is also critical for a very important part of our immune system. .

Nan Yan, Ph.D., study leader, professor of immunology and microbiology at UT Southwestern and member of the Harold C. Simmons Comprehensive Cancer Center

Many patients with a rare disease linked to a deficiency in RNA exosomes, known as trichohepato-enteric syndrome (THES), also develop B-cell immunodeficiency and suffer from recurrent infections. Although researchers have long known that THES is associated with mutations in genes encoding exosomes known as SKIV2L and TTC37, the molecular basis of the disease is unknown.

To better understand the role of SKIV2L in THES, Dr. Yan’s research team in the Department of Immunology and colleagues at UTSW’s Primary Immunodeficiency Clinic and Dallas Children’s Medical Center studied a patient THES carried this mutation and was part of a clinical research study led by Christian Wysocki, MD, Ph.D., associate professor of pediatrics. In addition to the usual clinical features of THES, a multi-organ disorder with symptoms such as short birth size, intractable diarrhea, distinctive “woolly” hair, and liver disease, this patient had low B-cell blood counts very weak.

The researchers then generated mice that had the SKIV2L gene deleted in the bone marrow stem cells that generate B cells. The animals also had B cell deficiencies; further research showed that B cells never matured because a key part of their development – in which progenitor cells randomly recombine genetic material to create a diverse pool of B cells – did not mature. product.

Dr. Yan explained that this appears to be related to SKIV2L’s role in RNA degradation. In a separate finding published in the same issue of Science Immunology, researchers at Columbia University showed that mutations in other components of the RNA exosome also cause B cell deficiency. non-functional RNA exosomes, causing cells to selectively retain RNA, especially the non-coding form that does not produce proteins. When B cell progenitors are clogged with excess non-coding RNA, they cannot become functional B cells.

Taken together, the findings suggest that THES could be treated with a bone marrow transplant, replacing defective B-cell progenitors carrying a genetic mutation with healthy progenitors. They also suggest that SKIV2L could offer a new target to fight autoimmune diseases such as lupus, in which overactive B cells play a key role. By inhibiting the activity of this gene, Dr. Yan explained, it may be possible to control the number of B cells, thereby reducing the intensity of the autoimmune attack.

Dr. Yan is the Rita C. and William P. Clements, Jr. Scholar in Medical Research.

Other UTSW researchers who contributed to this study include Kun Yang (first author), Jie Han, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, and Tracey Wright. Mr. Teresa de la Morena of the University of Washington also contributed.

This research was supported by grants from the National Institutes of Health (AI153576) and the Burroughs Wellcome Fund.