Identifying the Cells Breaching Self-Tolerance in Autoimmunity

Benson, Robert A.; Patakas, Agapitos; Conigliaro, Paola; Rush, Catherine M.; Garside, Paul; McInnes, Iain B.; Brewer, James M.

doi:10.4049/jimmunol.0903951

Cited by 40 publications

(37 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We then investigated whether this failure of T cell help for B cells and the subsequent Ab response were recapitulated in a novel OVA-driven model of RA. We previously described the suggested mode of action of this model in detail (21,(48)(49)(50). Briefly, we think that by transferring a large number of activated Th1 cells of an irrelevant specificity and inducing a local inflammatory stimulus in the joint, the normal regulatory mechanisms are overwhelmed and breach of self-tolerance occurs.…”

Section: Discussionmentioning

confidence: 99%

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Platt

Gibson

Patakas

et al. 2010

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Abatacept modulates CD28-mediated T cell costimulation and is efficacious in the treatment of rheumatoid arthritis (RA). Its mechanism of action has not been fully elucidated but will likely reveal critical pathologic pathways in RA. We show that abatacept substantially modulated Ag-specific T and B cell responses in vivo. Ag-specific T cell proliferation was reduced, and the acquisition of an activated phenotype, characterized by upregulation of CD69, OX40, ICOS, and programmed death-1 and downregulation of CD62L, was suppressed. Furthermore, abatacept suppressed the production of inflammatory cytokines, such as IFN-γ and IL-17. These effects were associated with a failure of Ag-specific T cells to acquire the CXCR5+ICOS+ T follicular helper cell phenotype. This, in turn, led to a failure of these cells to enter B cell follicles, resulting in reduced specific Ab responses, despite normal B cell clonal expansion. To test the pathologic significance of this, we used a novel model of RA associated with breach of self-tolerance to self-Ag and demonstrated that abatacept prevented the emergence of self-reactivity. Thus, CD28-dependent signaling is required for optimal T follicular helper cell maturation and expansion, and its inhibition prevents loss of self-tolerance in a model of articular pathology. Thus, we provide a novel mode of action for abatacept with profound implications for its potential usefulness in early inflammatory arthropathies associated with autoantibody expression.

show abstract

Section: Discussionmentioning

confidence: 99%

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Platt

Gibson

Patakas

et al. 2010

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…DCs are a very heterogeneous population of cells, and different subsets can have very distinct functions. They are important in the breaching of self-tolerance in autoimmunity,10 and plasmacytoid (p)DCs play an important anti-inflammatory role in the context of articular breach of tolerance 11. It was recently shown that compounds that selectively deplete DCs can ameliorate arthritis12 and that blocking tyrosine kinases may have beneficial effects in arthritis by modulating DC numbers 13.…”

Section: Introductionmentioning

confidence: 99%

Absence of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling protects against collagen-induced arthritis

et al. 2013

View full text Add to dashboard Cite

ObjectiveComprehending the mechanisms that regulate activation of autoreactive T cells and B cell antibody production is fundamental for understanding the breakdown in self-tolerance and development of autoimmunity. Here we studied the role of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling in the pathogenesis of collagen-induced arthritis (CIA).MethodsCIA was induced in mice lacking Flt3L (Flt3L−/−) and wild-type (WT) littermates (C57/BL6, 8–10 weeks old). Mice were killed in the initial phase (acute phase: experiment 1) and late phase (chronic phase: experiment 2) of the disease. Arthritis severity was assessed using a semiquantitative scoring system (0–4), and histological analysis of cellular infiltration, cartilage destruction and peptidoglycan loss was performed. Phenotypic and functional analysis of T and B cells, FoxP3 expression, activation and lymphocyte costimulatory markers, and cytokine production were performed ex vivo by flow cytometry in lymph nodes. Serum collagen type II (CII)-specific antibodies were measured by ELISA.ResultsFlt3L−/− mice showed a marked decrease in clinical arthritis scores and incidence of arthritis in both acute and chronic phases of CIA compared with WT mice. Moreover, decreased synovial inflammation and joint destruction was observed. Both the magnitude and quality of T cell responses were altered in Flt3L−/−. In the acute phase, the amount of CII-specific IgG2a antibodies was lower in Flt3L−/− than WT mice.ConclusionsThese results strongly suggest a role for Flt3L signalling in the development of arthritis.

show abstract

“…Thus, a possible explanation for the failure to induce arthritis by serum passive transfer could be related to the greater magnitude of anti-CII response than OVA-mediated arthritis and the different antibody specificity rather than the affinity. However, we cannot exclude the possibility that other autoantibodies are required to induce disease or that other cell types, such as T cells or dendritic cells (41), may be necessary to induce arthritis.…”

Section: Discussionmentioning

confidence: 99%

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

Conigliaro¹,

Benson²,

Patakas³

et al. 2011

Arthritis & Rheumatism

Self Cite

View full text Add to dashboard Cite

Objective. Type II collagen (CII)-specific B cell responses have been recognized in human rheumatoid arthritis (RA) and in collagen-induced arthritis (CIA). An important limitation of the CIA model is that the CII response and the disease are stimulated by exogenously injected collagen. A model of experimental ovalbumin (OVA)-mediated acute arthritis has been established in which autoimmunity is spontaneous and elicited by antigen-specific T cells. This study was undertaken to create a new model of chronic autoimmune polyarthritis and characterize the associated CII-specific B cell response.Methods. Secondary challenge with OVA or CII in adjuvant was used to elicit chronic disease. CII-specific B cell responses against the epitopes U1, J1, C1, and citrullinated C1, together with the antibody affinity, were investigated in OVA-mediated arthritis.Results. Chronic autoimmune polyarthritis was induced and was dependent on the antigen used in the secondary challenge. U1 was the major CII epitope recognized, and antibodies showed the same affinity as those in CIA.Conclusion. Our findings indicate that the development and severity of chronic disease is dependent on the antigen and is associated with an increased autoreactive B cell response directed against a specific CII epitope (U1). OVA-mediated chronic arthritis exhibits anti-CII antibodies (against U1), resembling human RA and murine CIA.

show abstract

Identifying the Cells Breaching Self-Tolerance in Autoimmunity

Abstract: Material Supplementary 1.DC1http://www.jimmunol.org/content/suppl/2010/04/21/jimmunol.090395

Cited by 40 publications

References 48 publications

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

Absence of Fms-like tyrosine kinase 3 ligand (Flt3L) signalling protects against collagen-induced arthritis

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

Contact Info

Product

Resources

About