ArticleArthritis research & therapy2015
The HLA-B*35 allele modulates ER stress, inflammation and proliferation in PBMCs from Limited Cutaneous Systemic Sclerosis patients.
Article in Arthritis research & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed, 18 citations in OpenAlex.
- Article
- Pulmonary toxicity of immune checkpoint immunotherapy.The Journal of clinical investigation · 2024Review
- Unveiling the shared genes between systemic sclerosis and lung cancer.Frontiers in medicine · 2024Article
- Allelic imbalance of HLA-B expression in human lung cells infected with coronavirus and other respiratory viruses.European journal of human genetics : EJHG · 2022Article
- Fibrillary Glomerulonephritis, DNAJB9, and the Unfolded Protein Response.Glomerular diseases · 2022Review
- Describing the Clinical and Laboratory Features and HLA-B Pattern of Adult-Onset Idiopathic Autoimmune Uveitis at a Tertiary Hospital in South India: A Cross-Sectional Study.TheScientificWorldJournal · 2022Article
- Differential Levels of Endoplasmic Reticulum Stress in Peripheral Blood Mononuclear Cells from Patients with Sudden Sensorineural Hearing Loss.Medical science monitor : international medical journal of experimental and clinical research · 2020Article
- Endoplasmic Reticulum Stress, a Driver or an Innocent Bystander in Endothelial Dysfunction Associated with Hypertension?Current hypertension reports · 2017Review
- Association of serum 25-hydroxyvitamin D concentration with HLA-B, -DRB1 and -DQB1 genetic polymorphisms.European journal of clinical nutrition · 2017Article
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
introductionHLA-B*35 is associated with increased risk of developing pulmonary hypertension in SSc patients. We previously reported that HLA-B*35 induces endothelial cell dysfunction via activation of ER stress/UPR and upregulation of the inflammatory response. Because PBMCs from lcSSc-PAH patients are also characterized by activation of ER stress/UPR and inflammation, the goal of this study was to assess whether the presence of HLA-B*35 contributes to those characteristics.
methodsPBMCs were purified from healthy controls (n = 49 HC) and lcSSc patients, (n = 44 with PAH, n = 53 without PAH). PBMCs from each group were stratified for the presence of HLA-B*35. Global changes in gene expression in response to HLA-B*35, HLA-B*8 or empty lentivirus were investigated by microarray analysis in HC PBMCs. Total RNA was extracted and qPCR was performed to measure gene expression.
resultsER stress markers, in particular the chaperones BiP and DNAJB1 were significantly elevated in PBMC samples carrying the HLA-B*35 allele. IL-6 expression was also significantly increased in HLA-B*35 lcSSc PBMCs and positively correlated with ER stress markers. Likewise, HMGB1 was increased in HLA-B*35-positive lcSSc PBMCs. Global gene expression analysis was used to further probe the role of HLA-B*35. Among genes downregulated by HLA-B*35 lentivirus were genes related to complement (C1QB, C1QC), cell cycle (CDNK1A) and apoptosis (Bax, Gadd45). Interestingly, complement genes (C1QC and C1QB) showed elevated expression in lcSSc without PAH, but were expressed at the low levels in lcSSc-PAH. The presence of HLA-B*35 correlated with the decreased expression of the complement genes. Furthermore, HLA-B*35 correlated with decreased expression of cyclin inhibitors (p21, p57) and pro-apoptotic genes (Bax, Gadd45) in lcSSc B35 subjects. FYN, a tyrosine kinase involved in proliferation of immune cells, was among the genes that were positively regulated by HLA-B*35. HLA-B*35 correlated with increased levels of FYN in lcSSc PBMCs.
conclusionsOur study demonstrates that HLA-B*35 contributes to the dysregulated expression of selected ER stress, inflammation and proliferation related genes in lcSSc patient PBMCs, as well as healthy individuals, thus supporting a pathogenic role of HLA-B*35 in the development of PAH in SSc patients.
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