B Cell Depletion Delays Collagen-Induced Arthritis in Mice: Arthritis Induction Requires Synergy between Humoral and Cell-Mediated Immunity

Abstract

Rheumatoid arthritis is a systemic autoimmune disease. B cells are likely to play a critical role in arthritis pathogenesis, although it is unclear whether they are necessary for disease induction, autoantibody production, or disease progression. To assess the role of B cells in inflammatory arthritis, B cells were depleted using mouse anti-mouse CD20 mAbs in a mouse model of collagen-induced arthritis. CD20 mAbs effectively depleted mature B cells from adult DBA-1 mice. When B cells were depleted using CD20 mAbs before collagen immunization, there was a delay in disease onset and autoantibody production, with significantly diminished severity of arthritis both clinically and histologically. B cell depletion further delayed disease onset if initiated before, as well as after, collagen immunization. However, in both cases, the eventual reappearance of peripheral B cells triggered autoantibody production and the subsequent development of arthritis in collagen-sensitized mice. By contrast, B cell depletion after collagen immunizations did not have a significant effect on arthritis progression or severity. Thus, disease symptoms were only induced when peripheral B cells and their autoantibody products were present in collagen-immunized mice, documenting a critical role for B cells during the elicitation phase of collagen-induced arthritis. These studies suggest that B cell depletion strategies will be most effective when initiated early in the development of inflammatory arthritis, with sustained B cell depletion required to inhibit the production of isotype-switched pathogenic Abs and the evolution of joint inflammation and destruction.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

“…The xid mutation in mice has been shown to suppress or partially suppresses disease in models of autoimmune disease (19,20,24), but these genetic experiments cannot distinguish Btk's developmental role from its role in mature B lymphocyte function in a disease caused by sustained generation of autoimmunity. PCI-32765 treatment led to a dose-dependent decrease in disease manifestation in both the collagen-induced arthritis and MRL-Fas(lpr) lupus models.…”

IL-10-producing regulatory B cells (B10 cells) in autoimmune disease

“…CIA and rheumatoid arthritis share in common an association with a limited number of MHC-II haplotypes that determine disease susceptibility [82,83]. B cells are important for initiating inflammation and arthritis since mature B cell depletion significantly reduces disease severity prior to CIA induction but does not inhibit established disease [84]. Several studies on CIA demonstrate the negative regulatory effects and therapeutic potential of B10 cells.…”

Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

“…These results indicate immunosuppressive and tolerogenic potential of ASCs in CIA mice. B cell depletion inhibits CIA, suggesting the involvement of B cells and autoantibodies in the pathogenesis of CIA (31). However, Bregs with the CD19 + CD1d hi CD5 + phenotype were shown to possess protective effect in autoimmune disease models (32).…”