Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells

Murakami, Masaaki; Okuyama, Yuko; Ogura, Hideki; Asano, Shogo; Arima, Yasunobu; Tsuruoka, Mineko; Harada, Masaya; Kanamoto, Minoru; Sawa, Yukihisa; Iwakura, Yoichiro; Takatsu, Kiyoshi; Kamimura, Daisuke; Hirano, Toshio

doi:10.1084/jem.20100900

Cited by 95 publications

(89 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, although we saw similar levels of IL-17 in LN and spleens of mice with CIA whether or not they were transferred with the HCF4Vβ7 line, more IL-17–producing HCF4Vβ7 + cells were present in the synovium of mice with CIA, indicating a local effect of the cells in an already inflamed environment. An alternative explanation for enhanced arthritis in this study is that HCF4Vβ7 + CD4 T cells act as a local source of IL-17 in the joint, as reported previously (61). However, in our studies, OVA-specific CD4 T cells also produced IL-17 in response to OVA and trafficked to spleens, LN, and synovium when transferred into mice with CIA, but arthritis was not increased in these animals.…”

Section: Discussionsupporting

confidence: 68%

A Citrullinated Fibrinogen-Specific T Cell Line Enhances Autoimmune Arthritis in a Mouse Model of Rheumatoid Arthritis

Cordova

Willis

Haskins

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Citrullinated proteins, derived from the conversion of peptidyl-arginine to peptidyl-citrulline, are present in the joints of patients with rheumatoid arthritis (RA), who also uniquely produce high levels of anti-citrullinated protein Abs. Citrullinated fibrinogen (CF) is abundant in rheumatoid synovial tissue, and anti-citrullinated protein Ab-positive RA patients exhibit circulating immune complexes containing CF. Thus, CF is a potential major target of pathogenic autoimmunity in RA. T cells are believed to be involved in this process by initiating, controlling, and driving Ag-specific immune responses in RA. In this study, we isolated a CD4 T cell line specific for CF that produces inflammatory cytokines. When transferred into mice with collagen-induced arthritis (CIA), this T cell line specifically enhanced the severity of autoimmune arthritis. Additionally, pathogenic IgG2a autoantibody levels to mouse type II collagen were increased in mice that received the T cells in CIA, and levels of these T cells were increased in the synovium, suggesting the T cells may have had systemic effects on the B cell response as well as local effects on the inflammatory environment. This work demonstrates that CD4 T cells specific for CF can amplify disease severity after onset of CIA.

show abstract

Section: Discussionsupporting

confidence: 68%

A Citrullinated Fibrinogen-Specific T Cell Line Enhances Autoimmune Arthritis in a Mouse Model of Rheumatoid Arthritis

Cordova

Willis

Haskins

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…A process of “epitope spreading” has been described in a number of autoimmune settings (45), and it is possible that IL-17-secreting 6.5 − CD4 + T cells cause disease because they utilize endogenous TCRs that recognize joint-specific self-peptides, including cryptic self-peptides that might be presented by unconventional APCs such as synoviocytes that become MHC class II-positive in the inflamed joint (46). However, a recent study suggested that any Th17 cells that are able to traffic to the joints (regardless of antigen specificity) can induce arthritis development by acting as a local source of IL-17, and that direct recognition of joint antigens may not be required for arthritis to develop in such a setting (47). In this case, then, the key role of the 6.5 TCR in disease development could be in establishing conditions that favor Th17 cell formation; these could include the lymphopenic environment that develops in young TS1×HACII mice as a consequence of severe thymocyte deletion (22), since lymphopenic environments have been found to contribute to Th17 cell formation in the SKG model of arthritis (34).…”

Section: Discussionmentioning

confidence: 99%

Requirement for Diverse TCR Specificities Determines Regulatory T Cell Activity in a Mouse Model of Autoimmune Arthritis

Aitken²,

Simons³

et al. 2012

The Journal of Immunology

View full text Add to dashboard Cite

CD4+CD25+Foxp3+ regulatory T cells (Tregs) are required to restrain the immune system from mounting an autoaggressive systemic inflammatory response, but why their activity can prevent (or allow) organ-specific autoimmunity remains poorly understood. We have examined how TCR specificity contributes to Treg activity using a mouse model of spontaneous autoimmune arthritis, in which CD4+ T cells expressing a clonotypic TCR induce disease by an IL-17-dependent mechanism. Administration of polyclonal Tregs suppressed Th17 cell formation and prevented arthritis development; notably, Tregs expressing the clonotypic TCR did not. These clonotypic Tregs exerted antigen-specific suppression of effector CD4+ T cells using the clonotypic TCR in vivo, but failed to mediate bystander suppression and did not prevent Th17 cells using nonclonotypic TCRs from accumulating in joint-draining lymph nodes of arthritic mice. These studies indicate that the availability of Tregs with diverse TCR specificities can be crucial to their activity in autoimmune arthritis.

show abstract

“…However, it remains to be elucidated whether infection is a cause or a consequence (or neither) of the numerous immune aberrations displayed by RA patients. Do infections play a pathogenic role by evoking immune reactions, for example resulting from molecular mimicry with a specific microbe or from repeated exposures to a multitude of foreign agents triggering a wear and tear type of immune defence?8…”

Section: Introductionmentioning

confidence: 99%

A transient peak of infections during onset of rheumatoid arthritis: a 10-year prospective cohort study

et al. 2014

View full text Add to dashboard Cite

ObjectivesThe role of infection in rheumatoid arthritis (RA) has not been determined. We aimed to document the infectious burden and some aspects of antibacterial immunity in a large and prospective cohort study of RA patients in the early and late stages of the disease and in their relatives predisposed to RA.SettingClinical and laboratory examination of all individuals enrolled in the study was performed in the Republican Clinical Hospital, Kazan, Russia.Participants376 patients with RA, 251 healthy first-degree relatives and 227 healthy controls without a family history of autoimmune disease (all females) were examined twice annually over more than 10 years.Primary and secondary outcome measuresThe following parameters were investigated: type, duration and frequency of infections, bacterial colonisation and serum levels of IgG to bacteria, serum levels of total Ig, plasma cytokine levels, granulocyte reactive oxygen species production, lysozyme activity and phagocytosis.ResultsThere were no significant differences in infection rate between healthy controls (median 14 days/year) and RA patients (13). However, infection rates were higher (p<0.001) in healthy relatives (53) and early stage patients (62), which groups also showed heavy bacterial skin colonisation. In contrast, late stage patients had fewer infection days (12; p<0.001) than healthy controls, although bacterial colonisation was still heavy. Phagocyte function and antibacterial antibody generation, together with compensatory cytokine production, were observed to be subnormal in the healthy relatives as well as in RA patients.ConclusionsWe observed a marked increase in overall infections at the time of RA onset, and signs of a defective antibacterial defence mechanism, contrasting with fewer infections in the late RA stage. It can be speculated that frequent early infections initiate a compensatory immune hyper-reactivity which reduces the infection load while stimulating the development of RA in predisposed individuals.

show abstract

Local microbleeding facilitates IL-6– and IL-17–dependent arthritis in the absence of tissue antigen recognition by activated T cells

Abstract: Local microbleeding induces the accumulation of Th17 cells and the development of IL-17– and IL-6–dependent arthritis in the absence of cognate antigen recognition by CD4+ T cells.

Cited by 95 publications

References 70 publications

A Citrullinated Fibrinogen-Specific T Cell Line Enhances Autoimmune Arthritis in a Mouse Model of Rheumatoid Arthritis

A Citrullinated Fibrinogen-Specific T Cell Line Enhances Autoimmune Arthritis in a Mouse Model of Rheumatoid Arthritis

Requirement for Diverse TCR Specificities Determines Regulatory T Cell Activity in a Mouse Model of Autoimmune Arthritis

A transient peak of infections during onset of rheumatoid arthritis: a 10-year prospective cohort study

Contact Info

Product

Resources

About