New research by UT Southwestern suggests that RNA exosomes, the cellular machines that break down ancient RNA molecules, play a key role in the development of B cells, which are critical to the ability of the immune system. to protect yourself from infection. The findings, published in Science Immunology, explain why patients with rare mutations in a gene encoding this machinery are often immunodeficient and could offer new approaches to treating autoimmune diseases.
It was a surprise to us to find that this gene, whose role was well known as part of an RNA clearance system, is also critical to 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 RNA exosome deficiency, known as tricohepatoenteric syndrome (THES), also develop B-cell immunodeficiency and experience 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 has been unknown.
To better understand the role of SKIV2L in THES, Dr. Yan in the Department of Immunology and colleagues at the USSW Primary Immunodeficiency Clinic and Dallas Children’s Medical Center studied a THES patient who carried this mutation and was part of a clinical research study. . directed by Christian Wysocki, MD, Ph.D., Associate Professor of Pediatrics. In addition to the usual clinical features of THES, a multiorgan disorder with symptoms that include small birth size, intractable diarrhea, distinctive “woolly” hair, and liver disease, this patient had a very low B-cell blood count.
The researchers then generated mice whose SKIV2L gene had been suppressed in bone marrow-generating bone marrow stem cells. The animals also had B-cell deficiencies; Subsequent research showed that B cells never matured because a key part of their development did not occur, in which the progenitor cells randomly recombine the genetic material to create a diverse set of B cells.
Dr. Yan explained that this appears to be related to the role of SKIV2L in RNA degradation. In an independent 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. RNAs do not work, causing cells to selectively retain RNA, especially the non-coding form that does not produce proteins. When B-cell progenitors sink with an excess of non-coding RNA, they cannot mature into functional B-cells.
Taken together, the findings suggest that THES could be treated with a bone marrow transplant, replacing defective B-cell progenitors that carry a genetic mutation with healthy ones. They also suggest that SKIV2L could offer a new target for fighting autoimmune diseases such as lupus, in which hyperactive B cells play a key role. By inhibiting the activity of this gene, explained Dr. Yan, it may be possible to control the number of B cells, decreasing the intensity of the autoimmune attack.
Dr. Yan is Professor Rita C. and William P. Clements, Jr. Scholar in Medical Research.
Other USSW researchers who contributed to this study include Kun Yang (lead author), Jie Han, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, and Tracey Wright. M. 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.
Source:
UT Southwestern Medical Center
Magazine reference:
Yang, K., et al. (2022) The mammalian SKIV2L RNA exosome is essential for early B cell development. Science Immunology. doi.org/10.1126/sciimmunol.abn2888.