The role of high endothelial venules in sex dimorphism in rheumatoid arthritis

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Summary/Abstract: The proposed study addresses the mechanisms of sex differences in rheumatoid arthritis; in particular, we focus on the high endothelial venules and their roles in female-biased disease development. Rheumatoid arthritis (RA) is the most common inflammatory arthropathy worldwide, and it is a chronic, complex, and heterogeneous autoimmune disease. The treatment mainly focuses on suppressing excess inflammation and slowing the disease progression to minimize joint damage and enhance physical function and quality of life. There's no cure for rheumatoid arthritis. The complex abnormal regulation of immunity causes auto-reactive inflammatory reactions, leading to persistent inflammation and articular destruction. RA is a well- known female-biased disease (3:1 ratio). Women have higher susceptibility, earlier onset, severer symptoms, and more exacerbated disease progression. Interestingly, juvenile idiopathic arthritis which sex hormones are negligible, also shows a female-biased disease prevalence, illuminating the genetic predispositions in rheumatoid arthritis in females. The majority of research focuses on the hormonal influences and dysregulation of immune cells caused by genetic disposition. Yet, the contribution of the tissue microenvironment to sex differences has remained elusive. In particular, blood vessels are the most critical gateway for the leukocytes to migrate into the joint synovial membrane. Research on the blood vessels will uncover the unknown mechanism for the disease development and female biases in RA. This project will focus on ectopic high endothelial venules (HEVs), specialized vessels for leukocyte recruitment which have been found in RA but not in osteoarthritis. HEVs play a critical role in the initiation of adaptive immunity in secondary lymphoid organs by recruiting naïve leukocytes. Previous single-cell data of HEVs shows the potential skewed X-inactivation and upregulation of X-linked genes. As a result of dose compensation at embryonic development, one X-chromosome in females is silenced. However, 15-23% of X- linked human genes escape from this X-inactivation, causing upregulation of X-linked genes. We will take two independent approaches to investigate if HEVs and their skewed X-inactivation are the major cause of sex bias in RA. Aim 1: To identify the skewed X-inactivation and upregulation of X-linked genes in HEVs in human RA. Aim 2: To perform a proof-of-concept study in animal models to demonstrate the cause of sex dimorphisms. This proposed project initiates investigating the X-linked genes in HEVs and seeking their potential impact on female-biased RA progression. The studies will also uncover the X-inactivation and bi-allelic gene expression in ectopic HEVs. Our new mouse models to perform a proof-of-concept study are useful for future investigation to examine the significance of skewed X-inactivation in non-circulating local tissues for sexual dimorphisms in RA.