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Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis.

ABSTRACT: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance.To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used.Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naïve mice ameliorated the development of CII-induced arthritis.Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.

SUBMITTER: Andersson SE

PROVIDER: S-EPMC4908726 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis.

Andersson Sofia E M SE Eneljung Tove T Tengvall Sara S Jirholt Pernilla P Stern Anna A Henningsson Louise L Liang Bibo B Thorarinsdottir Katrin K Kihlberg Jan J Holmdahl Rikard R Mårtensson Inga-Lill IL Gustafsson Kenth K Gjertsson Inger I

Arthritis research & therapy 20160614 1

<h4>Background</h4>The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance.<h4>Methods</h4>To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used.<h4>Results</h4>Present ...[more]

PMID: 27301320

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Project description:Regulatory T (Treg) cells have anti-inflammatory functions and heighten immune tolerance. The proportion and functions of Treg cells are perturbed in rheumatoid arthritis (RA), contributing to the excessive immune activation associated with this disease. We therefore hypothesized that supplementation with foreign Treg cells could be used to treat RA. To investigate the therapeutic effects of exogenous Treg cells on RA and its mechanism, we used human Treg cells to treat collagen-induced arthritis (CIA) in a rat model to observe whether exogenous Treg cells can treat the disease across species. Successful treatment would indicate that Treg cell transplantation in humans is more likely to affect RA. In the present study, human Treg cells were collected from healthy human peripheral blood and culture-expanded in vitro. Induced human Treg cells were injected into CIA rats via the tail vein. The rats' lymphocyte subtypes, cytokines, and Th1/Th2 ratios were measured using flow cytometry. In the rats, following injection of the human Treg cells, the severity of CIA was significantly reduced (P < 0.01), the proportion of endogenous Treg cells increased in the peripheral blood and spleen (P = 0.007 and P < 0.01, respectively), and the proportion of B cells decreased (P = 0.031). The IL-5 level, IL-6 level, and Th1/Th2 ratio in the peripheral blood were decreased (P = 0.013, 0.009, and 0.012, respectively). The culture-expanded human Treg cells were also cultured with synovial fibroblast cells from RA patients (RASFs). After coculture with Treg cells, RASFs showed reduced proliferation (P < 0.01) and increased apoptosis (P = 0.037). These results suggest that exogenous and induced Treg cells can produce a therapeutic effect in RA and CIA by increasing endogenous Treg cells and RASF apoptosis and reducing B cells, the Th1/Th2 ratio, and secretion levels of IL-5 and IL-6. Treg cell transplantation could serve as a therapy for RA that does not cause immune rejection.

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Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis.

Publications

Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis.

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