Characterization of the anticollagen antibody response in a new model of chronic polyarthritis

Conigliaro, Paola; Benson, Robert A.; Patakas, Agapitos; Kelly, Sharon M.; Valesini, Guido; Holmdahl, Rikard; Brewer, James M.; McInnes, Iain B.; Garside, Paul

doi:10.1002/art.30413

Cited by 13 publications

(17 citation statements)

References 40 publications

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“…All together, these data suggested that the adaptive immune response against autoantigens is initiated years before the clinical signs of the disease. Likewise, in certain murine models of arthritis, it has been observed an increase in antibody levels before the onset of clinical symptoms or before the relapse of arthritis [66,67]. Recently, anti-CarP antibodies were detected in mice with collagen-induced arthritis (CIA) and appeared after immunization, which caused local inflammation, combined with the notion that inflammation can induce carbamylation and lead to a break of B cell tolerance to carbamylated proteins [66].…”

Section: Preclinical Immunological Phase In Rheumatoid Arthritismentioning

confidence: 99%

“…Recently, anti-CarP antibodies were detected in mice with collagen-induced arthritis (CIA) and appeared after immunization, which caused local inflammation, combined with the notion that inflammation can induce carbamylation and lead to a break of B cell tolerance to carbamylated proteins [66]. Furthermore, in a model of chronic antigen-mediated polyarthritis the production of ACPA, RF, and anti-type II collagen (CII) antibodies was observed in the absence of clinical signs of arthritis and increased before the relapse of arthritis [67].…”

Section: Preclinical Immunological Phase In Rheumatoid Arthritismentioning

confidence: 99%

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Autoantibodies in inflammatory arthritis

Conigliaro

Chimenti

Triggianese

et al. 2016

Autoimmunity Reviews

102

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Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides

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Section: Preclinical Immunological Phase In Rheumatoid Arthritismentioning

confidence: 99%

Section: Preclinical Immunological Phase In Rheumatoid Arthritismentioning

confidence: 99%

Autoantibodies in inflammatory arthritis

Conigliaro

Chimenti

Triggianese

et al. 2016

Autoimmunity Reviews

102

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“…Actually, murine collagen-induced arthritis (CIA) has been a gold standard model of human rheumatoid arthritis (RA). However, an important limitation of the CIA model is that the collagen response and the disease are stimulated by exogenously injected collagen, whereas human RA is characterized by a spontaneous breach of selftolerance [15]. Thus, to be more applicable to the histologic and humoral features of human disease, we developed a model of ovalbumin- (OVA-) mediated polyarthritis, in which autoimmunity is spontaneous [15, 16].…”

Section: Discussionmentioning

confidence: 99%

Combination with Methotrexate and Cyclophosphamide Attenuated Maturation of Dendritic Cells: Inducing Treg Skewing and Th17 SuppressionIn Vivo

Wang²,

Luo³

et al. 2013

Clinical and Developmental Immunology

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Immune disorder is considered the main pathogenesis of autoimmune diseases, such as rheumatoid arthritis (RA). The balance of the two special subsets of CD4+T cells, T helper cell 17 (Th17), and Regulator T cell (Treg) is the key factor of maintaining a normal immune response. Dendritic cells (DCs), which are the most powerful antigen-presenting cells, play an important role in regulating the balance of Th17 and Treg. The combination of disease modifying antirheumatic drugs (DMARDs) is an important strategy of RA therapy. In this study, we investigated the effect of MTX and CTX on DC maturation in ovalbumin (OVA) immunized mice. Th17 inflammatory response is stronger, while the level of DCs maturity is higher. In contrast, the immunosuppression of Treg is stronger. We found that MTX combined with CTX significantly inhibited the DCs maturity and downregulated the antigen presenting capacity of DCs. As a result, it reestablished a balance of Th17 and Treg. Our study adds a novel mechanism and therapeutic target of MTX combined with CTX for autoimmune disease treatment.

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“…Mice were sacrificed four days later and cells were isolated from joint tissue and draining popliteal lymph nodes (pLN). The “late” model antigen induced inflammatory arthritis was modified from a model of chronic polyarthritis(21). 30 days after HAO administration described above, mice were given a second periarticular injection of 100µg of HAO in incomplete Freund’s adjuvant (IFA) (Sigma-Aldrich) or IFA alone as a control.…”

Section: Methodsmentioning

confidence: 99%

“…This will inform the development of more effective tolerogenic therapies by indicating the range of clones that would need to be targeted and the disease stage at which these therapies are most likely to be effective. In this study, we employed breach of self-tolerance models of antigen induced inflammatory arthritis (19,20) and chronic polyarthritis (21) in which autoreactive responses develop. These models also recapitulate the early and later stages of the disease – hereafter named the early and late phases respectively.…”

Section: Introductionmentioning

confidence: 99%

TCRβ Sequencing Reveals Spatial and Temporal Evolution of Clonal CD4 T cell Responses in a Breach of Tolerance Model of Inflammatory Arthritis

Al‐Khabouri

Benson

Prendergast

et al. 2020

Preprint

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ObjectivesDevelopment of effective tolerogenic therapies for Rheumatoid Arthritis (RA) relies on understanding the evolution of articular antigen specific CD4 T cell responses. TCR clonality of the endogenous CD4 T cell infiltrate in early inflammatory arthritis was assessed to monitor the evolution of the TCR repertoire in the inflamed joint and its associated popliteal lymph node (pLN).MethodsMouse models of antigen-induced breach of self-tolerance and chronic polyarthritis were used to recapitulate the early and late phases of RA reported in patients. The infiltrating endogenous, antigen experienced CD4 T cells in inflamed joints and pLNs were analysed using flow cytometry and TCRβ sequencing.ResultsTCR repertoires from pLNs displayed increased clonality and diversity with disease progression, while inflamed joints maintain similar TCR repertoire clonality and diversity with time. Repertoires from late phase pLNs accumulated clones with a diverse range TRBV genes, while inflamed joints at both phases contain clones expressing similar TRBV genes. Repertoires from pLNs and joints at the late phase displayed reduced CDR3β sequence overlap compared to the early disease phase, however correlation analysis revealed the most abundant clones in pLNs accumulate in the joint at the later phase.ConclusionsCD4 T cell clonality broadens and evolves with progression of inflammatory arthritis and is reflected in pLNs before potentially being mirrored in the joint. These observations imply that antigen specific tolerogenic therapies for RA will be more easily developed and more effective at earlier phases of the disease, when CD4 T cell clonality is least diverse.KEY MESSAGESSelective accumulation of CD4 T cell clones has been observed in arthritic joints of RA patients, indicating the presence of antigen driven accumulation of CD4 T cells in these patients.These antigen specific T cell clones are thought to be pathogenic and thus are targets for tolerogenic therapy.This study suggests that CD4 TCR clonality is restricted at the early phases of disease and broadens with disease progression. Moreover, changes in CD4 TCR clonality are first reflected in joint draining lymph nodes before being mirrored in the inflamed joint.Thus tolerogenic therapies will be more effective when CD4 TCR clonality is restricted i.e. at early disease stages.Changes in CD4 TCR clonality in the joint draining lymph node can also be a biomarker for disease state.

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Characterization of the anticollagen antibody response in a new model of chronic polyarthritis

Cited by 13 publications

References 40 publications

Autoantibodies in inflammatory arthritis

Autoantibodies in inflammatory arthritis

Combination with Methotrexate and Cyclophosphamide Attenuated Maturation of Dendritic Cells: Inducing Treg Skewing and Th17 SuppressionIn Vivo

TCRβ Sequencing Reveals Spatial and Temporal Evolution of Clonal CD4 T cell Responses in a Breach of Tolerance Model of Inflammatory Arthritis

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