Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis (original) (raw)
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Rheumatology, 2007
Objective. In a large-scale ENU (N-ethyl-N-nitrosourea) mouse mutagenesis programme, we previously have identified and characterized a novel mutation Ali18 that causes inflammatory arthritis like lesions in peripheral joints. In this study, we analysed the immune system of Ali18 mice to understand mechanisms underlying the spontaneous inflammation. Methods. Humoral and cellular components of the immune system were phenotyped by ELISA and flow cytometry. The contribution of the immune system for phenotype expression was analysed in disease transfer experiments. The involvement of the adaptive immune system was investigated in Ali18;Rag1 double mutants and the influence of environmental factors was analysed in Ali18 mice reared under germ-free conditions. Results. Bone marrow cells from Ali18 mice were able to transfer the disease phenotype to naïve wild-type recipients suggesting that cellular components of the reconstituted immune system were sufficient to induce arthritis. Ali18 mice revealed abnormal leucocyte populations including lymphocytes and granulocytes, as well as increased plasma IL-5 and IgE levels. Ali18;Rag1 double homozygous mutants, which lack mature lymphocytes, still developed arthritis, suggesting that the phenotype is independent of the adaptive immune system. In addition, the arthritis phenotype appeared to be independent from environmental conditions as demonstrated in mice reared under germ-free conditions. Conclusions. The Ali18 mutation induces inflammatory arthritis through bone marrow-derived cells. However, non-pro-inflammatory cytokine cascades and mature lymphocyte independent-mechanisms are crucial for initiation and progression of the phenotype. Ali18 mice may thus represent a model to study mechanisms involved in seronegative arthritis induced by cells of the innate immune system.
Immunobiology, 2011
Objective-Dendritic cells (DCs) have long been recognized as potential therapeutic targets of rheumatoid arthritis (RA). Increasing evidence has showed that DCs are capable of suppressing autoimmunity by expanding FoxP3 + regulatory T cells (T reg), which in turn exert immunosuppression by increasing TGFβ-1. In the SKG mice, activated DC prime autoreactive T cells causing autoantibody production and an inflammatory arthritic response. Recently, we reported that CC-chemokine receptor-2 deficient (Ccr2 −/−) mice had impaired DCs migration and reduced CD8α + DCs in the C57Bl/6J mice strain and that these mice were more susceptible to collagen antibody-induced arthritis (CAIA), compared to wild type mice. To examine the mechanism by which DCs contribute to the increased susceptibility of arthritis in Ccr2 −/− mice, we tested the hypothesis that CD8α + DCs are protective (tolerogenic) against autoimmune arthritis by examining the role of CD8α + DCs in Ccr2 −/− and SKG mice. Methods-To examine the mechanism by which DCs defects lead to the development of arthritis, we used two murine models of experimental arthritis: collagen-induced arthritis (CIA) in DBA1/J mice and zymosan-induced arthritis in SKG mice. DBA1/J mice received recombinant Flt3L-injections to expand endogenous DCs populations or adoptive transfers of CD8α + DCs. Results-Flt3L-mediated expansion of endogenous CD8α + DCs resulted in heightened susceptibility of CIA. In contrast, supplementation with exogenous CD8α + DCs ameliorated arthritis in Ccr2 −/− mice and enhanced TGFβ1 production by T cells. Furthermore, SKG mice with genetic inactivation of CCR2 did not affect the numbers of DCs nor improve the arthritis phenotype. Conclusion-CD8α + DCs were tolerogenic to the development of arthritis. CD8α + DCs deficiency heightened the sensitivity to arthritis in Ccr2 −/− mice. Ccr2 deficiency did not alter the arthritic phenotype in SKG mice suggesting the arthritis in Ccr2 −/− mice was T cell-independent.
International Immunology, 1999
which the role of T lymphocytes remains controversial. To clarify this, we have bred a targeted gene deletion of TCR β or δ loci into two mouse strains susceptible to CIA, the B10.Q and DBA/1 strains. The TCRβ -/mice lacked αβ T cells, which was compensated by an expansion of B cells, γδ T cells and NK cells. The β -/mice, but not control β ⍣/littermates, were completely resistant to CIA. The production of anti-CII IgG antibodies was also abolished in β -/mice, revealing a strict αβ T cell dependency. In contrast, β -/mice produced reduced, but significant, anti-CII IgM titers after immunization with either CII or ovalbumin, indicating a multispecificity for these αβ T cellindependent IgM antibodies. The TCRδ -/mice lacked γδ T cells but had no other significant changes in lymphocyte or monocyte subsets. The cytokine response (IL-2, IL-4, IL-10 and IFN-γ) in δ -/mice, quantified by flow cytometry staining of mitogen-stimulated lymphocytes, was indistinguishable from normal mice. Likewise, no statistically significant differences were observed in CIA between mice lacking γδ T cells and control littermates, considering arthritis incidence, day of disease onset, maximum arthritic score, anti-CII IgG titers and disease course. We conclude that αβ T cells are necessary for CIA development and for an IgG response towards CII, whereas γδ T cells are neither necessary nor sufficient for development of CIA.
Deletion of either CD55 or CD97 ameliorates arthritis in mouse models
Arthritis & …, 2010
Objective. CD55 (decay-accelerating factor) is best known for its role in the negative regulation of the complement system. Indeed, lack of this molecule leads to disease aggravation in many autoimmune disease models. However, CD55 is abundantly present on fibroblast-like synoviocytes and is also a ligand of the adhesion-class heptahelical receptor CD97, which is expressed by infiltrating macrophages. Treatment with antibodies to CD97 ameliorates the collagen-induced model of rheumatoid arthritis (RA) in DBA/1 mice, but the net contribution of CD55 is unknown. This study was undertaken to investigate the role of CD55 in experimental RA.
Development of a new humanized mouse model to study acute inflammatory arthritis
Journal of Translational Medicine, 2012
Background: Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis. Methods: One to two-day old irradiated NOD-scid IL2rγ null (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund's adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically.