Immunity to the G1 globular domain of the cartilage proteoglycan aggrecan can induce inflammatory erosive polyarthritis and spondylitis in BALB/c mice but immunity to G1 is inhibited by covalently bound keratan sulfate in vitro and in vivo.

Leroux, Jean-Yves; Guerassimov, Alexei; Cartman, Annie; Delaunay, Nathalie; Webber, C; Rosenberg, Lawrence; Banerjee, Subhashis; Poole, A R

doi:10.1172/jci118458

Cited by 60 publications

(52 citation statements)

References 43 publications

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“…27 Removal of chondroitin 28 or keratin sulphate chains significantly enhances the immunogenicity of aggrecan and distinct regions within the N-terminal, globular (G)1 domain, have been linked with arthritis induction. 29 In particular, amino acids 84-103 from this region have been shown to contain the arthritogenic CD4 + T cell epitope (GRVRVNSAY) in both PGIA and in patients with rheumatoid arthritis. 30 Importantly, recent studies have shown that the activation of aggrecan-specific CD4 + T cells following B cell-mediated antigen presentation is crucial for the full development of PGIA.…”

Section: Discussionmentioning

confidence: 99%

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

Hine

Pradipta

et al. 2012

Immunology

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Summary Effective immune responses require antigen uptake by antigen‐presenting cells (APC), followed by controlled endocytic proteolysis resulting in the generation of antigen‐derived peptide fragments that associate with intracellular MHC class II molecules. The resultant peptide–MHC class II complexes then move to the APC surface where they activate CD4+ T cells. Dendritic cells (DC), macrophages and B cells act as efficient APC. In many settings, including the T helper type 1 (Th1) ‐dependent, proteoglycan‐induced arthritis model of rheumatoid arthritis, accumulating evidence demonstrates that antigen presentation by B cells is required for optimal CD4+ T cell activation. The reasons behind this however, remain unclear. In this study we have compared the activation of CD4+ T cells specific for the proteoglycan aggrecan following antigen presentation by DC, macrophages and B cells. We show that aggrecan‐specific B cells are equally efficient APC as DC and macrophages and use similar intracellular antigen‐processing pathways. Importantly, we also show that antigen presentation by aggrecan‐specific B cells to TCR transgenic CD4+ T cells results in enhanced CD4+ T cell interferon‐γ production and Th1 effector sub‐set differentiation compared with that seen with DC. We conclude that preferential CD4+ Th1 differentiation may define the requirement for B cell APC function in both proteoglycan‐induced arthritis and rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 99%

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

Hine

Pradipta

et al. 2012

Immunology

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“…A number of experimental models and clinical studies indicate that autoimmunity directed against fibrocartilage proteins/proteoglycans, including aggrecan, can induce enthesitis and spondylitis (50)(51)(52)(53). The strong HLA-B27 association with AS indicates that autoimmunity is important in human AS, especially at sites of fibrocartilage (31).…”

Section: Molecular Mechanisms Pertaining To Immune Activation In Enthmentioning

confidence: 99%

Report on the Second International Enthesitis Workshop

McGonagle¹,

Marzo‐Ortega²,

Benjamin³

et al. 2003

Arthritis & Rheumatism

106

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“…ϩ T cells recognize epitopes on the G1 domain of aggrecan (20,21) and on the separate globular link protein (22). In a recent study, Zou et al (23) examined the CD4 ϩ immune response of synovial T cells to the G1 domain in AS and rheumatoid arthritis patients, indicating that the G1 domain of aggrecan might play a pathogenetic relevant role in the cellular autoimmune response in AS and rheumatoid arthritis.…”

Section: Identification Of Novel Human Aggrecan T Cell Epitopes In Hlmentioning

confidence: 99%

Identification of Novel Human Aggrecan T Cell Epitopes in HLA-B27 Transgenic Mice Associated with Spondyloarthropathy

Kuon

Kuhne

Busch

et al. 2004

The Journal of Immunology

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The pathology of ankylosing spondylitis, reactive arthritis, and other spondyloarthropathies (SpA) is closely associated with the human leukocyte class I Ag HLA-B27. A characteristic finding in SpA is inflammation of cartilage structures of the joint, in particular at the site of ligament/tendon and bone junction (enthesitis). In this study, we investigated the role of CD8+ T cells in response to the cartilage proteoglycan aggrecan as a potential candidate autoantigen in BALB/c-B27 transgenic mice. We identified four new HLA-B27-restricted nonamer peptides, one of them (no. 67) with a particularly strong T cell immunogenicity. Peptide no. 67 immunization was capable of stimulating HLA-B27-restricted, CD8+ T cells in BALB/c-B27 transgenic animals, but not in wild-type BALB/c mice. The peptide was specifically recognized on P815-B27 transfectants by HLA-B27-restricted CTLs, which were also detectable by HLA tetramer staining ex vivo as well as in situ. Most importantly, analysis of the joints from peptide no. 67-immunized mice induced typical histological signs of SpA. Our data indicate that HLA-B27-restricted epitopes derived from human aggrecan are involved in the induction of inflammation (tenosynovitis), underlining the importance of HLA-B27 in the pathogenesis of SpA.

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Immunity to the G1 globular domain of the cartilage proteoglycan aggrecan can induce inflammatory erosive polyarthritis and spondylitis in BALB/c mice but immunity to G1 is inhibited by covalently bound keratan sulfate in vitro and in vivo.

Abstract: Earlier work from this laboratory showed that the human proteoglycan aggrecan from fetal cartilages can induce a CD4

Cited by 60 publications

References 43 publications

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

Report on the Second International Enthesitis Workshop

Identification of Novel Human Aggrecan T Cell Epitopes in HLA-B27 Transgenic Mice Associated with Spondyloarthropathy

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Immunity to the G1 globular domain of the cartilage proteoglycan aggrecan can induce inflammatory erosive polyarthritis and spondylitis in BALB/c mice but immunity to G1 is inhibited by covalently bound keratan sulfate in vitro and in vivo.

Abstract: Earlier work from this laboratory showed that the human proteoglycan aggrecan from fetal cartilages can induce a CD4

Cited by 60 publications

References 43 publications

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4+ T helper type 1 subset differentiation

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4+ T helper type 1 subset differentiation

Report on the Second International Enthesitis Workshop

Identification of Novel Human Aggrecan T Cell Epitopes in HLA-B27 Transgenic Mice Associated with Spondyloarthropathy

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Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation

Presentation of the candidate rheumatoid arthritis autoantigen aggrecan by antigen‐specific B cells induces enhanced CD4⁺ T helper type 1 subset differentiation