title: Immunologic human renal allograft injury associates with an altered IL-10/TNF-α expression ratio in regulatory B cells.
abstract: Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.
authors.affiliation: Renal Unit and Department of Transplant Immunology, St. James's University Hospital, Leeds, United Kingdom; drcherukuri2102@doctors.org.uk.
authors.forename: Aravind
authors.initials: A
authors.lastname: Cherukuri
authors.affiliation: Thomas E. Starzl Transplant Institute, Pittsburgh, Pennsylvania;
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.affiliation: Department of Transplant Immunology, St. James's University Hospital, Leeds, United Kingdom;
authors.forename: Brendan
authors.initials: B
authors.lastname: Clark
authors.affiliation: Department of Transplant Immunology, St. James's University Hospital, Leeds, United Kingdom;
authors.forename: Clive R
authors.initials: CR
authors.lastname: Carter
authors.affiliation: Faculty of Medicine and Health and.
authors.forename: Adam
authors.initials: A
authors.lastname: Davison
authors.affiliation: Nephrology and Transplantation, King's College London, London, United Kingdom;
authors.forename: Maria
authors.initials: M
authors.lastname: Hernandez-Fuentes
authors.affiliation: Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Hewitt
authors.affiliation: University College London Centre for Nephrology, Royal Free Hospital, London, United Kingdom.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.affiliation: Renal Unit and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Baker
mesh_terms: D000328:Adult; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology*; D007680:Kidney Neoplasms / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000276:immunology; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
keywords: chronic allograft rejection; immunology; renal function decline