Format

Send to

Choose Destination
Front Immunol. 2019 Oct 21;10:2160. doi: 10.3389/fimmu.2019.02160. eCollection 2019.

Characterization of cxorf21 Provides Molecular Insight Into Female-Bias Immune Response in SLE Pathogenesis.

Author information

1
Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.
2
Departments of Pathology and Medicine, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
3
Division of Rheumatology, School of Medicine, University of Colorado, Aurora, CO, United States.
4
Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, United States.
5
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
6
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
7
United States Department of Veterans Affairs Medical Center, Cincinnati, OH, United States.
8
Medical and Research Services, Oklahoma City Department of Veterans Affairs Health Care Center, Oklahoma City, OK, United States.

Abstract

Background: Ninety percent of systemic lupus erythematosus (SLE) patients are women. X chromosome-dosage increases susceptibility to SLE and primary Sjögren's syndrome (pSS). Chromosome X open reading frame 21 (CXorf21) escapes X-inactivation and is an SLE risk gene of previously unknown function. We undertook the present study to delineate the function of CXorf21 in the immune system as well as investigate a potential role in the sex bias of SLE and pSS. Methods: Western blot protein analysis, qPCR, BioPlex cytokine immunoassay, pHrodo™ assays, as well as in vitro CRISPR-Cas9 knockdown experiments were employed to delineate the role of CXorf21 in relevant immunocytes. Results: Expressed in monocytes and B cells, CXorf21 basal Mrna, and protein expression levels are elevated in female primary monocytes, B cells, and EBV-transformed B cells compared to male cells. We also found CXorf21 mRNA and protein expression is higher in both male and female cells from SLE patients compared to control subjects. TLR7 ligation increased CXorf21 protein expression and CXorf21 knockdown abrogated TLR7-driven increased IFNA1 mRNA expression, and reduced secretion of both TNF-alpha and IL-6 in healthy female monocytes. Similarly, we found increased pH in the lysosomes of CXorf21-deficient female monocytes. Conclusion: CXorf21 is more highly expressed in female compared to male cells and is involved in a sexually dimorphic response to TLR7 activation. In addition, CXorf21 expression regulates lysosomal pH in a sexually dimorphic manner. Thus, sexually dimorphic expression of CXorf21 skews cellular immune responses in manner consistent with expected properties of a mediator of the X chromosome dose risk in SLE and pSS.

KEYWORDS:

Interferon-inducible; X-chromosome; innate immunity; sex-bias; systemic lupus erythematosus

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center