Mosaicism of XX and XXY cells accounts for high copy number of Toll like Receptor 7 and 8 genes in peripheral blood of men with Rheumatoid Arthritis.
Gabriel V MartinSami B KanaanMarie F HemonDoua F AzzouzMarina El HaddadNathalie BalandraudCécile Mignon-RavixChristophe PicardFanny ArnouxMarielle MartinJean RoudierIsabelle AugerNathalie C LambertPublished in: Scientific reports (2019)
The X chromosome, hemizygous in males, contains numerous genes important to immunological and hormonal function. Alterations in X-linked gene dosage are suspected to contribute to female predominance in autoimmunity. A powerful example of X-linked dosage involvement comes from the BXSB murine lupus model, where the duplication of the X-linked Toll-Like Receptor 7 (Tlr7) gene aggravates autoimmunity in male mice. Such alterations are possible in men with autoimmune diseases. Here we showed that a quarter to a third of men with rheumatoid arthritis (RA) had significantly increased copy numbers (CN) of TLR7 gene and its paralog TLR8. Patients with high CN had an upregulated pro-inflammatory JNK/p38 signaling pathway. By fluorescence in situ hybridization, we further demonstrated that the increase in X-linked genes CN was due to the presence of an extra X chromosome in some cells. Men with RA had a significant cellular mosaicism of female (46,XX) and/or Klinefelter (47,XXY) cells among male (46,XY) cells, reaching up to 1.4% in peripheral blood. Our results present a new potential trigger for RA in men and opens a new field of investigation particularly relevant for gender-biased autoimmune diseases.
Keyphrases
- toll like receptor
- copy number
- induced apoptosis
- rheumatoid arthritis
- genome wide
- inflammatory response
- signaling pathway
- peripheral blood
- nuclear factor
- immune response
- cell cycle arrest
- mitochondrial dna
- middle aged
- endoplasmic reticulum stress
- genome wide identification
- oxidative stress
- cell death
- type diabetes
- systemic lupus erythematosus
- dna methylation
- skeletal muscle
- mental health
- interstitial lung disease
- adipose tissue
- gene expression
- metabolic syndrome
- cell proliferation
- single molecule
- epithelial mesenchymal transition
- systemic sclerosis
- bioinformatics analysis