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  • 1.
    Hietala, M. A.
    et al.
    Göteborg University, Göteborg, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Persson, L.
    Göteborg University, Göteborg, Sweden.
    Fahlen, S.
    Göteborg University, Göteborg, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Pekna, M.
    Göteborg University, Göteborg, Sweden.
    Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis2004In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 34, no 4, p. 1208-16Article in journal (Refereed)
    Abstract [en]

    To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3- and factor B (FB)-deficient (C3(-/-) and FB(-/-)) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days 7-10. Although 75% of C3(-/-) mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB(-/-) mice ranked intermediate in comparison with C3(-/-) and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3(-/-) and FB(-/-) mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis.

  • 2.
    Khmaladze, Ia
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Saxena, Amit
    Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production2015In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 45, no 8, p. 2243-2251Article in journal (Refereed)
    Abstract [en]

    Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knock-in mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collagen-induced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.

  • 3.
    Khmaladze, Ia
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Saxena, Amit
    Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    B-cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production2015In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 45, no 8, p. 2243-2251Article in journal (Refereed)
    Abstract [en]

    Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knock-in mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collagen-induced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.

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  • 4.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden.
    Andren, Maria
    Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Martinsson, Pernilla
    Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Bajtner, Estelle
    Lund University, Lund, Sweden.
    Hellstrom, Silvia
    Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Kleinau, Sandra
    Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcgammaRIIB2003In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 33, no 8, p. 2269-2277Article in journal (Refereed)
    Abstract [en]

    IgG anti-collagen type II (CII) antibodies (Ab) can induce arthritis in healthy mice. Here we have investigated if single monoclonal IgG anti-CII Ab can induce arthritis in CIA-susceptible DBA/1 mice and if there is an IgG subclass dependency. The involvement of Fc receptors for IgG (FcgammaR) in anti-CII Ab-mediated arthritis was also investigated by comparing the clinical outcome in DBA/1 mice to those in FcgammaR-deficient mice. We demonstrate for the first time that single mAb to naive DBA/1 mice can induce persistent arthritis. Histology of the inflamed joints revealed massive cellular infiltrate and cartilage and bone destruction. All IgG subclasses tested (IgG1, IgG2a and IgG2b) were arthritogenic, with the IgG1 and IgG2b isotypes as the dominating arthritogenic Ab. Pathogenicity was dependent on engagement of activating FcgammaR, as FcRgamma-deficient mice were completely resistant to Ab-mediated arthritis. The arthritis induced with the IgG1 and IgG2b Ab was also inhibited by FcgammaRIII disruption, whereas arthritis mediated by the IgG2a Ab was not substantially affected. The arthritic response of the IgG1 and IgG2b isotypes, but not of the IgG2a Ab, was further enhanced in mice lacking the inhibitory FcgammaRIIB. These results demonstrate that single IgG anti-CII mAb can induce erosive arthritis and that IgG anti-CII Ab mediate arthritis by engagement of FcgammaR.

  • 5.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden.
    Collin, Mattias
    Lund University, Lund, Sweden.
    Olsen, Arne
    Lund University, Lund, Sweden.
    Nimmerjahn, Falk
    Rockefeller University, New York, NY, United States; University of Erlangen-Nuremberg, Erlangen-Nuremberg, Germany.
    Blom, Anna M.
    Lund University, Lund, Sweden.
    Ravetch, Jeffrey V.
    Rockefeller University, New York, NY, United States.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Endoglycosidase treatment abrogates IgG arthritogenicity: importance of IgG glycosylation in arthritis2007In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 37, no 10, p. 2973-2982Article in journal (Refereed)
    Abstract [en]

    The glycosylation status of IgG has been implicated in the pathology of rheumatoid arthritis. Earlier, we reported the identification of a novel secreted endo-beta-N-acetylglucosaminidase (EndoS), secreted by Streptococcus pyogenes that specifically hydrolyzes the beta-1,4-di-N-acetylchitobiose core of the asparagine-linked glycan of human IgG. Here, we analyzed the arthritogenicity of EndoS-treated collagen type II (CII)-specific mouse mAb in vivo. Endoglycosidase treatment of the antibodies inhibited the induction of arthritis in (BALB/c x B10.Q) F1 mice and induced a milder arthritis in B10.RIII mice as compared with the severe arthritis induced by non-treated antibodies. Furthermore, EndoS treatment did not affect the binding of IgG to CII and their ability to activate complement, but it resulted in reduced IgG binding to FcgammaR and disturbed the formation of stable immune complexes. Hence, the asparagine-linked glycan on IgG plays a crucial role in the development of arthritis. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  • 6.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    A genetic contamination in MHC-congenic mouse strains reveals a locus on chromosome 10 that determines autoimmunity and arthritis susceptibility2005In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 35, no 4, p. 1275-1282Article in journal (Refereed)
    Abstract [en]

    Among the arthritis-susceptible MHC (H-2)-congenic mouse strains, B10.RIII mice are highly susceptible to collagen-induced arthritis. Surprisingly, the B10.RIII strain was also more susceptible to the T cell independent model CAIA (collagen-antibody-induced arthritis). Through genome-wide genotyping, we found that the B10.RIII and B10.Q strains differed not only in chromosome 17 (MHC) but also in a region on chromosome 10, which contained a fragment from the MHC donor RIIIS/J. We isolated the chromosome 10 as well as the chromosome 17 segments on the B10.RIII and B10.Q backgrounds. Congenic mice containing the RIIIS/J-derived chromosome 10 segment showed significantly higher susceptibility and severity of arthritis with an enhanced autoimmune response to type II collagen. Furthermore, this chromosomal segment significantly promoted CAIA. Similarly, the RIIIS/J segment in chromosome 17 also promoted CAIA independently of other gene segments. These data show that other gene regions, apart from MHC class II, may explain effects both at the priming and effector level of arthritis observed in widely used MHC congenic strains. These new congenic fragments, on both chromosome 10 and 17, provide new mouse strains suitable for studies aiming at positional cloning of new genes associated with arthritis.

  • 7.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Arthritis induced with cartilage-specific antibodiesis IL-4-dependent2006In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 36, no 6, p. 1608-1618Article in journal (Refereed)
    Abstract [en]

    It is widely believed that IL-4 exerts its influence by profiling the immune response during priming and expansion of immune cells, and thereby modulates the outcome of chronic inflammation. In the present investigation, collagen antibody-induced arthritis (CAIA) was used to delineate the role of IL-4 in a T cell-independent inflammatory phase. Mice predisposed to Th2 cytokines (BALB/c and STAT4-deficient mice) developed a more severe arthritis than mice biased towards Th1 cytokines (C57BL/6 and STAT6-deficient mice). Reduced incidence of CAIA was observed in IL-4-deficient mice compared to control littermates. Infiltrating cells in the paws of IL-4-sufficient mice had increased osteoclast activity and tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion. Massive infiltration of granulocytes and joint and cartilage damage were present in arthritic paws. Depletion of IL-4 suppressed CAIA, which was abrogated by IFN-gamma neutralization. IL-1R- and IL-1RTNFR-deficient mice were completely resistant to CAIA. Thus, IL-4 promotes an antibody-mediated and TNF-alpha/IL-1beta-dependent inflammation in vivo.

  • 8.
    Svensson, Lars
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Johansson, Åsa
    Lund University, Lund, Sweden.
    Jansson, Liselotte
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    IL-4-deficient mice develop less acute but more chronic relapsing collagen-induced arthritis2002In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 32, no 10, p. 2944-2953Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis as well as collagen-induced arthritis (CIA) is thought to involve T cell autoimmunity of the Th1 type and the Th2 cytokine IL-4 has been proposed to play a suppressive role. To exclude a possible skewing role of the mycobacteria used in the complete Freund's adjuvant (CFA) we induced CIA with type II collagen (CII) in incomplete Freund's adjuvant (IFA). Our results show that IL-4 deficiency leads to a lesser susceptibility to arthritis and lower B and T cell responses if induced with CII/IFA but not if induced with CII/CFA. In addition, IL-4-deficient mice were less susceptible to arthritis induced with monoclonal anti-CII antibodies. However, mice immunized with CII/IFA later developed a chronic relapsing disease, which was promoted by IL-4 deficiency. We conclude that IL-4 plays different roles depending on the type of adjuvant used and the phase (acute or chronic) of the clinical disease.

  • 9.
    Vaartjes, Daniëlle
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Klaczkowska, Dorota
    Karolinska Institute, Stockholm, Sweden.
    Cragg, Mark S.
    University of Southampton Faculty of Medicine, Southampton, United Kingdom.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Bäckdahl, Liselotte
    Karolinska Institute, Stockholm, Sweden.
    Holmdahl, Rikard
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Genetic dissection of a major haplotype associated with arthritis reveal FcγR2b and FcγR3 to act additively2021In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 51, no 3, p. 682-693Article in journal (Refereed)
    Abstract [en]

    A haplotype with tightly linked Fc gamma receptor (FcγR) genes is known as a major locus controlling immune responses and autoimmune diseases, including arthritis. Here, we split a congenic fragment derived from the NOD mouse (Cia9) to study its effect on immune response and arthritis in mice. We found that arthritis susceptibility was indeed controlled by the FcγR gene cluster and a recombination between the FcγR2b and FcγR3 loci gave us the opportunity to separately study their impact. We identified the NOD-derived FcγR2b and FcγR3 alleles as disease-promoting for arthritis development without impact on antibody secretion. We further found that macrophage-mediated phagocytosis was directly correlated to FcγR3 expression in the congenic mice. In conclusion, we positioned FcγR2b and FcγR3 alleles as disease regulatory and showed that their genetic polymorphisms independently and additively control innate immune cell activation and arthritis.

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