T-cell recognition of differentially tolerated epitopes of cartilage proteoglycan aggrecan in arthritis

Buzás, Edit I.; Végvári, Anikó; Murad, Yanal; Finnegan, Alison; Mikecz, Katalin; Glant, Tibor T.

doi:10.1016/j.cellimm.2004.08.006

Cited by 36 publications

(67 citation statements)

References 46 publications

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“…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. 14,16 Materials and methods…”

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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“…Human PG exhibits a high degree of sequence homology with murine PG and shows substantial complexity with regard to contained T cell epitopes. Indeed, systemic immunization with whole PG protein leads to activation of a variety of PG-specific T cell clones, with the amino acids 70-84 of PG (PG [70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] ) representing an immunodominant epitope (27)(28)(29). Induction of EAE critically depends on self-reactive T effector (Teff) cells skewed toward the Th17 lineage (30).…”

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confidence: 99%

DEC205+ Dendritic Cell–Targeted Tolerogenic Vaccination Promotes Immune Tolerance in Experimental Autoimmune Arthritis

Spiering

Margry

Keijzer

et al. 2015

The Journal of Immunology

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Previous studies in mouse models of autoimmune diabetes and encephalomyelitis have indicated that the selective delivery of self-antigen to the endocytic receptor DEC205 on steady-state dendritic cells (DCs) may represent a suitable approach to induce Ag-specific immune tolerance. In this study, we aimed to examine whether DEC205+ DC targeting of a single immunodominant peptide derived from human cartilage proteoglycan (PG) can promote immune tolerance in PG-induced arthritis (PGIA). Besides disease induction by immunization with whole PG protein with a high degree of antigenic complexity, PGIA substantially differs from previously studied autoimmune models not only in the target tissue of autoimmune destruction but also in the nature of pathogenic immune effector cells. Our results show that DEC205+ DC targeting of the PG peptide 70–84 is sufficient to efficiently protect against PGIA development. Complementary mechanistic studies support a model in which DEC205+ DC targeting leads to insufficient germinal center B cell support by PG-specific follicular helper T cells. Consequently, impaired germinal center formation results in lower Ab titers, severely compromising the development of PGIA. Overall, this study further corroborates the potential of prospective tolerogenic DEC205+ DC vaccination to interfere with autoimmune diseases, such as rheumatoid arthritis.

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“…Transgenic BALB/c mice expressing a TCR specific for human cartilage proteoglycan (PG-TCR-Tg mice) have been described previously [22,23]. The majority of T cells in homozygous PG-TCR-Tg mice recognize the “5/4E8” immunodominant epitope ( 89 ATEGRVRVNSAYQDK 103 ) located in the first globular (G1) domain of human PG [23,24]. …”

Section: Methodsmentioning

confidence: 99%

“…We used an allophycocyanin (Apc)-labeled human PG (aggrecan)-specific tetramer (PG tetramer) composed of the human PG “5/4E8” peptide ( 89 ATEGRVRVNSAYQDK [22–24]) linked to I-A d (BALB/c haplotype-matched MHC class II molecule), and an irrelevant control Apc-labeled tetramer composed of a human class II-associated invariant chain peptide (CLIP; 103 PVSKMRMATPLLMQA) linked to I-A d (CLIP tetramer). Both tetramers were provided by the NIH Tetramer Core Facility at Emory University (Atlanta, GA, USA).…”

Section: Methodsmentioning

confidence: 99%

In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse model of rheumatoid arthritis

Kobezda

Ghassemi-Nejad

Glant

et al. 2012

Cellular Immunology

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Recent imaging studies on intact lymph nodes (LNs)1 of naïve T-cell receptor (TCR)-transgenic mice have reported that T cells reduce their motility upon contact with relevant antigen-presenting cells (APCs). Using in vivo two-photon imaging of T cells in joint-draining (JD) LNs, we examined whether similar changes in T cell motility are observed in wild type mice. Co-transfer of T cells from naïve mice and antigen-experienced T cells from mice with proteoglycan (PG)-induced arthritis into naïve or arthritic recipients resulted in prolonged interactions of antigen-experienced T cells with APCs upon intra-articular antigen (PG) injection, indicating that T cells from arthritic wild type mice recapitulate the motile behavior reported in naïve TCR-transgenic mice. However, naïve T cells also engaged in stable interactions with APCs in the JDLNs of arthritic recipients, suggesting an enhanced ability of APCs in the JDLNs of arthritic hosts to present antigen to either naïve or antigen-experienced T cells.

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T-cell recognition of differentially tolerated epitopes of cartilage proteoglycan aggrecan in arthritis

Cited by 36 publications

References 46 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

DEC205+ Dendritic Cell–Targeted Tolerogenic Vaccination Promotes Immune Tolerance in Experimental Autoimmune Arthritis

In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse model of rheumatoid arthritis

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T-cell recognition of differentially tolerated epitopes of cartilage proteoglycan aggrecan in arthritis

Cited by 36 publications

References 46 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

DEC205+ Dendritic Cell–Targeted Tolerogenic Vaccination Promotes Immune Tolerance in Experimental Autoimmune Arthritis

In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse model of rheumatoid arthritis

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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