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Abstract Number: 108

Sex-Specific Expression of CXorf21 Provide Molecular Explanation for the Fundamental Difference in Male and Female Immune Response: An Explanation for Female-Bias SLE Pathogenesis

R. Hal Scofield1, Valerie M Harris2, Biji T. Kurien3 and Kristi A. Koelsch4, 1Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 2Oklahoma Medical Research Foundation, Oklahoma City, OK, 3University of Oklahoma Health Sciences Center, Oklahoma City, OK, 4Section of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Okalahoma City, OK

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: B cells, SLE, X chromosome and monocytes

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Session Information

Date: Sunday, October 21, 2018

Title: Systemic Lupus Erythematosus – Etiology and Pathogenesis Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Systemic lupus erythematosus (SLE) is complex autoimmune disorders characterized by B cell hyperactivity resulting in autoantibody and cytokine production. Approximately 90% of patients are female. We have produced data an X-chromosome gene dose effect increases susceptibility. Therefore, our objective is to functionally describe an X-linked protein which escapes X-inactivation, Chromosome X open reading frame 21 (CXorf21), to uncover any role this protein may have in the pathogenesis or susceptibility to SLE. Publicly available data predict CXorf21 is a dehydrogenase/reductase expressed almost exclusively in monocytes, B cells, and and other antigen-presenting cells. Additional studies show that CXorf21, a SLE risk allele, directly interacts with another SS/SLE-associated risk allele, Slc15a4. SLC15a4, a lysosomal proton-oligopeptide co-transporter, is necessary for endolysosomal antigen processing, TLR7- and NOD1-mediated cytokine as well as antibody production in dendritic cells and B cells.

Methods: We used quantitative real-time PCR, Western blot protein analysis, Bio-plex cytokine immunoassay, and pHrodo™ assay, as well as, in vitro CRISPR-Cas9 knockdown experiments to examine the role of CXorf21 in monocytes and B cell immunity.

Results: Our data show that CXorf21 basal gene and protein expression is elevated in female primary monocytes and B cells compared to male cells. We also found CXorf21 mRNA expression was higher in both male and female SLE-affected EBV-transformed B cells and female primary Sjogren’s Syndrome patient’s PBMC subsets compared to healthy male controls. Additionally, we found that following activation by TLR7 (Imiquimod) and NOD1 (iE-DAP) agonists CXorf21, IFN-alpha, and NFkappaB expression increases, in addition to an increase IL-6 and TNF-alpha cytokine production. This response is exaggerated in a female-specific manner. Successful knockdown of CXorf21, using CXorf21-specific gRNA (CRISPR-Cas9), abrogated both the expression levels and cytokine response in the female samples, but had not affect in male subjects. pHrodo™ lysosomal pH experiments revealed that knockdown of CXorf21 protein in healthy female monocytes resulted in an increased lysosomal pH. As result of the increase from acidic to a more alkaline lysosomal environment in the female samples (auto)antigen processing is perceived to be disrupted.

Conclusion: CXorf21 is over-expressed in female immune cells compared to male cells and is involved in a sex-dependent dimorphic response to activation through TLR7 and NOD1. We propose that CXorf21 via interaction with the lysosome proton cotransporter, SLC15a4, maintains the lysosomal pH gradient necessary for monocyte and B cell immune response. Thus, sexual dimorphic expression of CXorf21, based on escape of X chromosome inactivation, skews (auto)antigen processing and immune response by women compared to men. CXorf21 may be a major contributor to TLR7 disease pathogenesis, and sex bias of the diseases based on an X chromosome dosage effect.


Disclosure: R. H. Scofield, NIH, ept Veran Affirs,Lupus esearch Institute, 2,Dept of Veterans Affairs, Universiy of Oklahoma, 3,Boston Pharmacueticals, 5; V. M. Harris, None; B. T. Kurien, None; K. A. Koelsch, None.

To cite this abstract in AMA style:

Scofield RH, Harris VM, Kurien BT, Koelsch KA. Sex-Specific Expression of CXorf21 Provide Molecular Explanation for the Fundamental Difference in Male and Female Immune Response: An Explanation for Female-Bias SLE Pathogenesis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/sex-specific-expression-of-cxorf21-provide-molecular-explanation-for-the-fundamental-difference-in-male-and-female-immune-response-an-explanation-for-female-bias-sle-pathogenesis/. Accessed .
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