title: Regulatory B Cells Are Functionally Impaired in Patients Having Hemophilia A With Inhibitors.
abstract: Development of inhibitors remains a major clinical complication in patients with hemophilia A receiving replacement therapy with factor VIII (FVIII). Understanding the immune mechanisms involved in the development of inhibitors can provide valuable information about pathways to human tolerance. Recent evidence indicates that B regulatory (Breg) cells play a pivotal role in controlling the production of antibodies (Abs) while promoting follicular T helper (Tfh) cells and monocytes, expressing the low-density lipoprotein receptor-related protein (LRP/CD91), which is involved in FVIII intake from the circulation. We studied circulating levels of Breg cells along with Tfh cells and the expression of LRP/CD91 on monocytes in patients with hemophilia A using 8-color flow cytometry and cell culture. Compared to healthy controls, patients with hemophilia A with inhibitors showed a severe reduction in levels of Breg cells and produced less interleukin-10 when activated via the CD40 signaling pathway. In addition, patients with hemophilia A with inhibitors exhibited an overexpression of LPR/CD91 on monocytes and normal levels of Tfh cells. Levels of Breg cells were not significantly related to LPR/CD91 although negative associations were evidenced. Collectively, these results provide new insights into the role of Breg cells and LPR/CD91 in the development of inhibitors in patients with hemophilia A.
authors.affiliation: 1 Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.|2 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: Mohamed-Rachid
authors.initials: MR
authors.lastname: Boulassel
authors.affiliation: 1 Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
authors.forename: Maryam
authors.initials: M
authors.lastname: Al-Ghonimi
authors.affiliation: 2 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: Badriya
authors.initials: B
authors.lastname: Al-Balushi
authors.affiliation: 1 Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Naamani
authors.affiliation: 1 Department of Allied Health Sciences, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Al-Qarni
authors.affiliation: 3 Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.|4 Faculty of Medicine, Pediatric Department, Alexandria University, Alexandria Governorate, Egypt.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Wali
authors.affiliation: 3 Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.|4 Faculty of Medicine, Pediatric Department, Alexandria University, Alexandria Governorate, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elshinawy
authors.affiliation: 3 Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: Maryam
authors.initials: M
authors.lastname: Al-Shezawi
authors.affiliation: 2 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: Hamad
authors.initials: H
authors.lastname: Khan
authors.affiliation: 3 Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.|4 Faculty of Medicine, Pediatric Department, Alexandria University, Alexandria Governorate, Egypt.
authors.forename: Hanan
authors.initials: H
authors.lastname: Nazir
authors.affiliation: 3 Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.|4 Faculty of Medicine, Pediatric Department, Alexandria University, Alexandria Governorate, Egypt.
authors.forename: Doaa
authors.initials: D
authors.lastname: Khater
authors.affiliation: 2 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: Anil
authors.initials: A
authors.lastname: Pathare
authors.affiliation: 2 Department of Haematology, College of Medicine and Health Sciences, Sultan Qaboos University Hospital, Muscat, Oman.
authors.forename: Salam
authors.initials: S
authors.lastname: Al-Kindi
mesh_terms: D000293:Adolescent; D060151:B-Lymphocytes, Regulatory / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006467:Hemophilia A / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping / Q000379:methods*; D007223:Infant; D008297:Male
keywords: B regulatory cells; LPR; follicular cells; hemophilia A; inhibitors