Development of proteoglycan‐induced arthritis is critically dependent on Fcγ receptor type III expression

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Fc receptors for IgG (FcγR) have been implicated in the development of arthritis. However, the precise contribution of the individual FcγR to joint pathology is unclear. In this study, the role of the different FcγR was assessed both in an active and in a passive mouse model of arthritis by analyzing disease development in double and triple knockout (KO) offspring from crosses of FcγRI KO, FcγRIII KO, FcγRI/III double KO, or FcR γ-chain KO with the FcγRII KO on C57BL6 background, which is susceptible for collagen-induced arthritis (CIA). In the active CIA model, onset was significantly delayed in the absence of FcγRIII, whereas incidence and maximum severity were significantly decreased in FcγRI/II/III triple KO but not in FcγRII/III double KO and FcγRI/II double KO mice as compared with FcγRII KO animals. Remarkably, fully destructive CIA developed in FcγRI/II/III triple KO mice. In contrast, FcR γ/FcγRII double KO mice were resistant to CIA. These findings were confirmed with the passive KRN serum-induced arthritis model. These results indicate that all activating FcγR play a role in the development of arthritis, mainly in the downstream effector phase. FcγRIII is critically required for early arthritis onset, and FcγRI can substantially contribute to arthritis pathology. Importantly, FcγRI and FcγRIII were together dispensable for the development of destructive arthritis but the FcR γ-chain was not, suggesting a role for another FcR γ-chain associated receptor, most likely FcγRIV. In addition, FcγRII plays a negative regulatory role in both the central and effector phase of arthritis.

Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 83%

Destructive Arthritis in the Absence of Both FcγRI and FcγRIII

Boross

Lent²,

Martín-Ramírez

et al. 2008

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“…In BALB/c mice, immunization with human PG protein induces a form of arthritis (PGinduced arthritis [PGIA]) that recapitulates many clinical aspects of human RA (7,8). PGIA is a T cell-dependent and B cell-/Abmediated autoimmune disease (9)(10)(11)(12).…”

mentioning

confidence: 99%

“…In PGIA, Th17 cells contribute to pathology (31), but they may not be essential for the induction of disease (32). Furthermore, although their putative role in EAE has remained unclear (33), B cells play an important dual role in PGIA: they are required as APCs for the induction of severe clinical symptoms (11,34,35) and for the production of pathological autoantibodies (9,11,36,37). The overall aim of the present study was to examine whether DEC205 + DC-targeted tolerogenic vaccination with a single immunodominant peptide of PG is suitable to protect against PGIA.…”

mentioning

confidence: 99%

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

Spiering

Margry

Keijzer

et al. 2015

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.

“…In RA, the presence of RF and anti-cyclic citrullinated peptide autoantibodies in the serum are an early predictor of disease in 50% of RA patients by an average of 7.5 years (14). Autoantibodies bind to target epitopes, forming immune complexes that activate complement components and Fc receptor-bearing cells that contribute to RA pathogenesis (15,16). In several murine models of RA, autoantibodies are pathogenic, particularly the K/BxN and collagen-induced arthritis (CIA) models where disease is initiated by transfer of autoantibodies to GPI and collagen respectively (17)(18)(19)(20).…”

Section: R Heumatoid Arthritis (Ra)mentioning

confidence: 99%

Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4+ T Cell Reactivity

Hamel¹,

Doodes²,

Cao

et al. 2008

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B cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) since the discovery of RA as an autoimmune disease. There is renewed interest in B cells in RA based on the clinical efficacy of B cell depletion therapy in RA patients. Although, reduced titers of rheumatoid factor and anti-cyclic citrullinated peptide Abs are recorded, the mechanisms that convey clinical improvement are incompletely understood. In the proteoglycan-induced arthritis (PGIA) mouse model of RA, we reported that Ag-specific B cells have two important functions in the development of arthritis. PG-specific B cells are required as autoantibody-producing cells as well as Ag-specific APCs. Herein we report on the effects of anti-CD20 mAb B cell depletion therapy in PGIA. Mice were sensitized to PG and treated with anti-CD20 Ab at a time when PG-specific autoantibodies and T cell activation were evident but before acute arthritis. In mice treated with anti-CD20 mAb, development of arthritis was significantly reduced in comparison to control mAb-treated mice. B cell depletion reduced the PG-specific autoantibody response. Furthermore, there was a significant reduction in the PG-specific CD4+ T cell recall response as well as significantly fewer PG-specific CD4+ T cells producing IFN-γ and IL-17, but not IL-4. The reduction in PG-specific T cells was confirmed by the inability of CD4+ T cells from B cell-depleted mice to adoptively transfer disease into SCID mice. Overall, B cell depletion during PGIA significantly reduced disease and inhibited both autoreactive B cell and T cell function.