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.
Highlights
systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by several simultaneous abnormalities, such as B cell hyperactivation, autoantibody production, and interferon signature
This was supported by our quantitative real-time PCR data, which showed that the Chromosome X open reading frame 21 (CXorf21) mRNA was highly expressed in antigen presenting cells, such as primary CD14+ monocytes, and CD19+ B cells (Figure 1)
We have previously shown that CXorf21 protein was increased in healthy female monocytes, B cells, and Lymphoblastoid cell lines (LCLs) compared to healthy male samples [23], we assessed whether SLE-affected and unaffected subjects, with and without Xchromosomal aneuploidies, have increased expression of CXorf21 (Figures 2A,B)
Summary
SLE is a chronic systemic autoimmune disease characterized by several simultaneous abnormalities, such as B cell hyperactivation, autoantibody production, and interferon signature. We have proposed an X-chromosome gene dose effect due to the difference in the number of X chromosomes between women (46,XX) and men (46,XY) as a mechanism for the female sex bias found in SLE and pSS, as well as for differences in overall immune responses [3,4,5]. Immune-related Xlinked genes, such as TLR7, CD40L, DDX3X, and IL3RA, escape inactivation in female immune and somatic cell populations, as previously reported [7,8,9,10]. Such disparity in immune-related protein-coding gene expression could provide an explanation for differences in male and female immune responses, as well as the susceptibility of women to autoimmune disease. We undertook the present study to delineate the function of CXorf in the immune system as well as investigate a potential role in the sex bias of SLE and pSS
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