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  • 1.
    Aksel Jacobsen, Freja
    et al.
    Novo Nordisk A/S, Bagsværd, Denmark.
    Andersson, Åsa
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS).
    Inhibitors of intracellular enzymes for treatment of multiple sclerosis2019In: Atlas of ScienceArticle, review/survey (Other (popular science, discussion, etc.))
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  • 2.
    Aksel Jacobsen, Freja
    et al.
    University of Copenhagen, Copenhagen, Denmark & Novo Nordisk A/S, Bagsværd, Denmark.
    Scherer, Alexander N.
    Yale University School of Medicine, New Haven, CT, USA.
    Mouritsen, Jeppe
    University of Copenhagen, Copenhagen, Denmark & Novozymes A/S, Bagsværd, Denmark.
    Bragadóttir, Hera
    University of Copenhagen, Copenhagen, Denmark & Xelia Pharmaceuticals A/S, Copenhagen, Denmark.
    Bäckström, B. Thomas
    Novo Nordisk A/S, Måløv, Denmark & BTB Pharma, Malmö, Sweden.
    Sardar, Samra
    University of Copenhagen, Copenhagen, Denmark.
    Holmberg, Dan
    Lund University, Malmö, Sweden.
    Koleske, Anthony J.
    Yale University School of Medicine, New Haven, CT, USA.
    Andersson, Åsa
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). University of Copenhagen, Copenhagen, Denmark.
    A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation2018In: Journal of Neuroimmune Pharmacology, ISSN 1557-1890, E-ISSN 1557-1904, Vol. 13, no 2, p. 265-276Article in journal (Refereed)
    Abstract [en]

    Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis. © 2018 The Author(s)

  • 3.
    Andersson, Åsa
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). Köpenhamns universitet, Köpenhamn, Danmark.
    Abl-tyrosinkinaser och multipel skleros2018In: BestPractice, Vol. 6, no 24, p. 14-16Article, review/survey (Other academic)
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  • 4.
    Andersson, Åsa
    et al.
    Halmstad University, School of Business, Innovation and Sustainability, The Rydberg Laboratory for Applied Sciences (RLAS). University of Copenhagen, Copenhagen, Denmark.
    Aksel Jacobsen, Freja
    Copenhagen University, Copenhagen, Denmark.
    B-cells and Inflammation in the Absence of the Abelson Related Gene (Arg)2016In: Journal of Clinical & Cellular Immunology, E-ISSN 2155-9899, Vol. 7, no 6, article id 1000470Article in journal (Refereed)
    Abstract [en]

    The Abelson non-receptor tyrosine kinases, c-Abl and Arg, are important regulators of cellular processes in cancer, inflammation, infection, and neuronal dynamics. Recent research on the role for these kinases in processes involving interactions with the cytoskeleton or signaling molecules, may lead to further insight into the pathogenesis of a variety of disorders, including chronic inflammatory diseases. In a mouse model for multiple sclerosis, we recently reported that Arg deficient mice develop T-cell mediated autoimmune neuro-inflammation with the same severity as littermate controls, but display a different B-cell phenotype upon immunization. Here we comment on these results and discuss the role for Arg in B-cell activation and homeostasis.

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  • 5.
    Andersson, Åsa
    et al.
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). Department of Drug Design and Pharmacology, Copenhagen University, Copenhagen, Denmark.
    Sardar, Samra
    Nordic Bioscience, Copenhagen, Denmark.
    A transcriptional regulator controlling severity in experimental arthritis2019In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 78, no Suppl. 2, p. 667-667, article id FRI0011Article in journal (Refereed)
    Abstract [en]

    Background: Susceptibility to Rheumatoid Arthritis (RA) is dependent on complex interactions among genetic and environmental factors. Protein candidates and their role in pathways leading to chronic inflammation of the joints, in addition to their potential as drug targets, can be revealed with the help of experimental models for disease (1). From the results of functional genetic studies, we have recently shown that the T-box gene, TBX3, is a candidate gene in Collagen Induced Arthritis (CIA), an experimental model for RA (2). TBX3 encodes a transcriptional regulator involved in differentiation of several organs, including bone, during embryonic development. It has, in addition, been demonstrated important in oncogenesis (3). Our studies suggest that TBX3 has a role in B-cell activation and is important for the severity of disease in the CIA model (2). Objectives: The objective of this project is to understand the role for the transcriptional regulator TBX3 in development of RA. Methods: Bioinformatics based comparative studies of mouse and human alleles in the regulatory region of TBX3. CRISPR/Cas9-introduced deletions and base modifications in human B-cell lines. Activation of genetically modified B-cells in vitro, followed by analyses of proliferative response and antibody production. Results: Studies of CIA development in mice with single nucleotide polymorphisms (SNPs) in the regulatory region of Tbx3 revealed a significant difference in severity of arthritis. In line with this, the anti-collagen type II antibody titers were shown substantially higher in mice with more severe arthritis, even before onset of disease. In addition, preliminary data shows that the proliferative response to Type II collagen upon re-challenge of lymph node cells in vitro is higher in these mice, suggesting a more active response to the disease-inducing antigen. Because the TBX3 gene is conserved between mouse and human, we are investigating whether similar genetic variations are found in the regulatory region of the human TBX3 gene and whether the putative genetic variation would lead to a distinct B-cell phenotype upon activation in vitro. Conclusion: We suggest that the oncoprotein TBX3 is a novel candidate contributing to disease severity in experimental arthritis. Investigations of genetic variation in the TBX3 gene and its role in the activation of human B-cells will reveal whether this protein is a candidate for influencing also development of RA.

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  • 6.
    Backlund, J.
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Bockermann, R.
    Lund University, Lund, Sweden.
    Mori, L.
    University Hospital, Basel, Switzerland.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Genetic control of tolerance to type II collagen and development of arthritis in an autologous collagen-induced arthritis model2003In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 171, no 7, p. 3493-3499Article in journal (Refereed)
    Abstract [en]

    T cell recognition of the type II collagen (CII) 260-270 peptide is a bottleneck for the development of collagen-induced arthritis (CIA), an animal model of rheumatoid arthritis. We have earlier made C3H.Q mice expressing CII with glutamic acid instead of aspartic acid at position 266 (the MMC-C3H.Q mouse), similar to the rat and human CII epitope, which increases binding to MHC class II and leads to effective presentation of the peptide in vivo. These mice show T cell tolerance to CII, but also develop severe arthritis. The present investigation shows that non-MHC genes play a decisive role in determining tolerance and arthritis susceptibility. We bred MMC into B10.Q mice, which display similar susceptibility to CIA induced with rat CII as the C3H.Q mice. In contrast to MMC-C3H.Q mice, MMC-B10.Q mice were completely resistant to arthritis. Nontransgenic (B10.Q x C3H.Q)F(1) mice were more susceptible to CIA than either of the parental strains, but introduction of the MMC transgene leads to CIA resistance, showing that the protection is dominantly inherited from B10.Q. In an attempt to break the B10-mediated CIA protection in MMC-transgenic mice, we introduced a transgenic, CII-specific, TCR beta-chain specific for the CII(260-270) glycopeptide, in the highly CIA-susceptible (B10.Q x DBA/1)F(1) mice. The magnification of the autoreactive CII-specific T cell repertoire led to increased CIA susceptibility, but the disease was less severe than in mice lacking the MMC transgene. This finding is important for understanding CIA and perhaps also rheumatoid arthritis, as in both diseases MHC class II-restricted T cell recognition of the glycosylated CII peptide occurs.

  • 7.
    Bajtner, E.
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Engström, Å.
    Uppsala Biomedical Center, IMBIM, Uppsala, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen2005In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 7, p. R1148-R1157Article in journal (Refereed)
    Abstract [en]

    Antibodies against type II collagen (CII) are important in the development of collagen-induced arthritis (CIA) and possibly also in rheumatoid arthritis. We have determined the fine specificity and arthritogenicity of the antibody response to CII in chronic relapsing variants of CIA. Immunization with rat CII in B10.Q or B10.Q(BALB/cxB10.Q)F2 mice induces a chronic relapsing CIA. The antibody response to CII was determined by using triple-helical peptides of the major B cell epitopes. Each individual mouse had a unique epitope-specific response and this epitope predominance shifted distinctly during the course of the disease. In the B10.Q mice the antibodies specific for C1 and U1, and in the B10.Q(BALB/cxB10.Q)F2 mice the antibodies specific for C1, U1 and J1, correlated with the development of chronic arthritis. Injection of monoclonal antibodies against these epitopes induced relapses in chronic arthritic mice. The development of chronic relapsing arthritis, initially induced by CII immunization, is associated with an arthritogenic antibody response to certain CII epitopes.

  • 8.
    Blom, A. M.
    et al.
    Malmö University Hospital, Malmö, Sweden; Lund University, University Hospital, Malmö, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden; Karolinska Institutet, Stockholm, Sweden.
    C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice2009In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 68, no 1, p. 136-142Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis. METHODS: We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody-induced arthritis (CAIA), an acute antibody-induced disease and the collagen-induced arthritis (CIA), which carries the full complexity of arthritis. RESULTS: Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement. CONCLUSIONS: Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA.

  • 9.
    Cao, D.
    et al.
    Lund University, Lund, Sweden.
    Khmaladze, Ia
    Karolinska Institute, Stockholm, Sweden.
    Jia, H.
    Lund University, Lund, Sweden.
    Bajtner, E.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden; Karolinska Institute, Stockholm, Sweden.
    Blom, T.
    Lund University, Lund, Sweden.
    Mo, J. A.
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden; Karolinska Institute, Stockholm, Sweden.
    Pathogenic autoreactive B cells are not negatively selected toward matrix protein collagen II2011In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 187, no 9, p. 4451-4458Article in journal (Refereed)
    Abstract [en]

    We have addressed the importance of B cell tolerance to collagen type II, a matrix protein, which is a target in rheumatoid arthritis (RA) and its mouse models. We generated a germline-encoded anti-collagen type II (CII) IgH replacement anti-C1 B cell mouse strain (ACB) to investigate how B cell tolerance to CII, a matrix protein, is subverted and to further understand pathogenesis of RA. Phenotypic analysis revealed that CII-specific B cells were surprisingly neither deleted nor anergized. Instead, they were readily detected in all lymphoid organs. Spontaneously produced autoantibodies could bind directly to cartilage surface without detectable pathology. However, exaggerated arthritis was seen after injection of anti-CII Abs specific for other epitopes. In addition, Abs from CII-specific hybridomas generated from ACB mice induced arthritis. Interestingly, IgH/L chain sequence data in B cell hybridomas revealed a lack of somatic mutations in autoreactive B cells. The ACB model provides the first possibility, to our knowledge, to study B cell tolerance to a matrix protein, and the observations made in the study could not be predicted from previous models. B cell-reactive epitopes on CII are largely shared between human RA and rodent CII-induced arthritis; this study, therefore, has important implications for further understanding of pathological processes in autoimmune diseases like RA.

  • 10.
    Carlsen, S.
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden.
    Type IX collagen deficiency enhances the binding of cartilage-specific antibodies and arthritis severity2006In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 8, no 4, article id R102Article in journal (Refereed)
    Abstract [en]

    Joint cartilage is attacked in both autoimmune inflammatory and osteoarthritic processes. Type IX collagen (CIX) is a protein of importance for cartilage integrity and stability. In this study we have backcrossed a transgenic disruption of the col9a1 gene, which leads to an absence of CIX, into two different inbred mouse strains, DBA/1 and B10.Q. None of the CIX-deficient mice developed observable clinical or microscopic osteoarthritis, but DBA/1 male mice had more pronounced enthesopathic arthritis, the so-called stress-induced arthritis. Both DBA/1 and B10.Q strains are susceptible to the induction of collagen-induced arthritis, and CIX deficiency in both strains led to the development of a more severe arthritis than in the controls. Induction of arthritis with monoclonal antibodies against type II collagen (CII) led to an earlier arthritis in the paws that also involved the knee joints. The antibodies used, which were specific for the J1 and the C1I epitopes of CII, initiate their arthritogenic attack by binding to cartilage. The C1I-specific antibodies bound to cartilage better in CIX-deficient mice than in wild-type animals, demonstrating that the lack of CIX in cartilage leads to an increased accessibility of structures for antibody binding and thus making the joints more vulnerable to inflammatory attack. These findings accentuate the importance of cartilage stability; cartilage disrupted as a result of genetic disorders could be more accessible and vulnerable to an autoimmune attack by pathogenic antibodies.

  • 11.
    Cen, Xiaohong
    et al.
    Southern Medical University, Guangzhou, China.
    Nandakumar, Kutty Selva
    Southern Medical University, Guangzhou, China.
    Small molecule SMU-CX24 targeting toll-like receptor 3 counteracts inflammation: A novel approach to atherosclerosis therapy2022In: Acta Pharmaceutica Sinica B, ISSN 2211-3835, E-ISSN 2211-3843, Vol. 12, no 9, p. 3667-3681Article in journal (Refereed)
    Abstract [en]

    Toll-like receptor 3 (TLR3), as an important pattern recognition receptor (PRR), dominates the innate and adaptive immunity regulating many acute and chronic inflammatory diseases. Atherosclerosis is proved as an inflammatory disease, and inflammatory events involved in the entire process of initiation and deterioration. However, the contribution of TLR3 to atherosclerosis remains unclear. Herein, we identified the clinical relevance of TLR3 upregulation and disease processes in human atherosclerosis. Besides, activation of TLR3 also directly led to significant expression of atherogenic chemokines and adhesion molecules. Conversely, silencing TLR3 inhibited the uptake of oxLDL by macrophages and significantly reduced foam cell formation. Given the aberrance in TLR3 functions on atherosclerosis progression, we hypothesized that TLR3 could serve as novel target for clinical atherosclerosis therapy. Therefore, we developed the novel ellipticine derivative SMU-CX24, which specifically inhibited TLR3 (IC50 = 18.87 ± 2.21 nmol/L). In vivo, atherosclerotic burden was alleviated in Western diet fed ApoE-/- mice in response to SMU-CX24 treatment, accompanying notable reductions in TLR3 expression and inflammation infiltration within atherosclerotic lesion. Thus, for the first time, we revealed that pharmacological downregulation of TLR3 with specific inhibitor regenerated inflammatory environment to counteract atherosclerosis progression, thereby proposing a new strategy and probe for atherosclerosis therapy.

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  • 12.
    Chen, Yong
    et al.
    The Second Clinical Medical College, Jinan University (Shenzhen People’s Hospital), Shenzhen, Guangdong, People’s Republic of China.
    Nandakumar, Kutty Selva
    Southern Medical University-Karolinska Institute United Medical Inflammation Center, Southern Medical University, Guangzhou, Guangdong, People’s Republic of China.
    Albumin/Globulin Ratio as Yin-Yang in Rheumatoid Arthritis and Its Correlation to Inflamm-Aging Cytokines2021In: Journal of Inflammation Research, E-ISSN 1178-7031, Vol. 14, p. 5501-5511Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Inflamm-aging is a novel-concept in rheumatoid arthritis (RA) with accelerating aging process. We try to find a correlation between serum albumin/globulin (A/G) ratio and clinical biochemical parameters, incidence of aging-related diseases (ARDs) as well as inflammaging-related molecules.

    PATIENTS AND METHODS: Healthy controls (HC) and RA patients were compared with their clinical biochemical parameters including albumin and globulin levels, A/G ratio, and levels of serum lipids. Incidence of ARDs in RA was compared with A/G ratio, having a cut off value of 1.2. Expression levels of leptin and Trf2 genes in PBMCs, and inflammatory factors like IL-1β, IL-6, IL-8 and TNF-ɑ between HC and RA patients were compared, and correlated with the A/G ratio.

    RESULTS: Compared to HC, RA patients had decreased levels of albumin, while globulin levels were found to be increased, which led to a significantly lower A/G ratio in RA patients. A/G ratio rather than ESR and CRP had significant correlation with dyslipidemia in RA patients. Patients with A/G <1.2 had a higher risk of ARDs than patients with A/G >1.2. The RR was 2.48 (95% CI: 1.79 to 3.64, p <0.0001). In addition, A/G ratio has positively correlated to leptin and Trf2 expression, while an inverse correlation was observed with the levels of inflamm-aging related cytokines like IL-6, IL-8 and TNF-ɑ.

    CONCLUSION: A decreased A/G ratio in RA patients has significantly correlated with dyslipidemia and ARDs, as well as inflammaging- related adipokine and pro-inflammatory cytokines. Thus, A/G ratio could be a reliable marker for evaluating the inflammaging process during clinical management in ARDs.

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  • 13.
    Chen, Yong
    et al.
    Jinan University (Shenzhen People’s Hospital), Shenzhen, China.
    Wang, Baojiang
    Southern Medical University, Shenzhen, China.
    Chen, Yanjuan
    3School of Basic Medicine, Jinan University, Guangzhou, China.
    Wu, Qunyan
    Southern Medical University, Shenzhen, China.
    Lai, Wing-Fu
    Zhejiang Provincial People’s Hospital, Hangzhou Medical College, Zhejiang, China; Hong Kong Polytechnic University, Wanchai, Hong Kong SAR, China.
    Wei, Laiyou
    Jinan University (Shenzhen People’s Hospital), Shenzhen, China.
    Nandakumar, Kutty Selva
    Southern Medical University - Karolinska Institute (SMU-KI) United Medical Inflammation Center, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
    Liu, Dongzhou
    Jinan University (Shenzhen People’s Hospital), Shenzhen, China.
    HAPLN1 Affects Cell Viability and Promotes the Pro-Inflammatory Phenotype of Fibroblast-Like Synoviocytes2022In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 888612Article in journal (Refereed)
    Abstract [en]

    HAPLN1 maintains aggregation and the binding activity of extracellular matrix (ECM) molecules (such as hyaluronic acid and proteoglycan) to stabilize the macromolecular structure of the ECM. An increase in HAPLN1 expression is observed in a few types of musculoskeletal diseases including rheumatoid arthritis (RA); however, its functions are obscure. This study examined the role of HAPLN1 in determining the viability, proliferation, mobility, and pro-inflammatory phenotype of RA- fibroblast-like synoviocytes (RA-FLSs) by using small interfering RNA (siHAPLN1), over-expression vector (HAPLN1OE), and a recombinant HAPLN1 (rHAPLN1) protein. HAPLN1 was found to promote proliferation but inhibit RA-FLS migration. Metformin, an AMPK activator, was previously found by us to be able to inhibit FLS activation but promote HAPLN1 secretion. In this study, we confirmed the up-regulation of HAPLN1 in RA patients, and found the positive relationship between HAPLN1 expression and the AMPK level. Treatment with either si-HAPLN1 or HAPLN1OE down-regulated the expression of AMPK-ɑ gene, although up-regulation of the level of p-AMPK-ɑ was observed in RA-FLSs. si-HAPLN1 down-regulated the expression of proinflammatory factors like TNF-ɑ, MMPs, and IL-6, while HAPLN1OE up-regulated their levels. qPCR assay indicated that the levels of TGF-β, ACAN, fibronectin, collagen II, and Ki-67 were down-regulated upon si-HAPLN1 treatment, while HAPLN1OE treatment led to up-regulation of ACAN and Ki-67 and down-regulation of cyclin-D1. Proteomics of si-HAPLN1, rHAPLN1, and mRNA-Seq analysis of rHAPLN1 confirmed the functions of HAPLN1 in the activation of inflammation, proliferation, cell adhesion, and strengthening of ECM functions. Our results for the first time demonstrate the function of HAPLN1 in promoting the proliferation and pro-inflammatory phenotype of RA-FLSs, thereby contributing to RA pathogenesis. Future in-depth studies are required for better understanding the role of HAPLN1 in RA.

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  • 14.
    Corthay, Alexandre
    et al.
    University of Oslo, National Hospital, Oslo, Norway; Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Evaluation of the percentage of peripheral T cells with two different T cell receptor alpha-chains and of their potential role in autoimmunity2001In: Journal of Autoimmunity, ISSN 0896-8411, E-ISSN 1095-9157, Vol. 16, no 4, p. 423-429Article in journal (Refereed)
    Abstract [en]

    Approximately 25% of mature T cells possess two distinct cytoplasmic T cell receptor (TCR) alpha-chains, due to productive gene rearrangements of both alleles. Expression of two different alpha-chains at the cell surface is a potential risk factor for development of autoimmunity. However, it has been difficult to determine the frequency of peripheral T cells with two different alpha-chains at the surface. Our new approach is based on comparing by flow cytometry the percentage of cells that express a given Valpha-chain between wild-type mice and mice that are hemizygous for a disrupted Tcra locus (Tcra+/-) and consequently unable to express two rearranged Tcra genes. We consistently found that approximately 8% of total peripheral T cells express two surface alpha-chains. The importance of dual alpha-T cells in autoimmunity was examined in a mouse model for rheumatoid arthritis, namely collagen-induced arthritis (CIA). No significant difference was observed between Tcra+/- mice and wild-type littermates, considering arthritis incidence, day of disease onset, and maximum arthritic score. We therefore conclude that there is incomplete phenotypic allelic exclusion in TCRalpha, and that the presence of a significant number of potentially multireactive T cells does not increase the susceptibility to develop autoimmune arthritis. © 2001 Academic Press.

  • 15.
    Du, Ningchao
    et al.
    Southern Medical University, Guangzhou, China.
    Song, Li
    College of Jinan University, Shenzhen, China.
    Li, Yang
    Southern Medical University, Guangzhou, China.
    Wang, Tingting
    Southern Medical University, Guangzhou, China.
    Fang, Qinghua
    Southern Medical University, Guangzhou, China.
    Ou, Jiaxin
    Southern Medical University, Guangzhou, China.
    Nandakumar, Kutty Selva
    Southern Medical University, Guangzhou, China.
    Phytoestrogens protect joints in collagen induced arthritis by increasing IgG glycosylation and reducing osteoclast activation2020In: International Immunopharmacology, ISSN 1567-5769, E-ISSN 1878-1705, Vol. 83, article id 106387Article in journal (Refereed)
    Abstract [en]

    Based on previous studies, we know that estrogen can protect the joints from arthritis development by increasing IgG glycosylation and inhibiting osteoclast activation. Phytoestrogens, especially genistein and daidzein, are structurally similar to estradiol that can bind to estrogen receptors (ERs). However, how phytoestrogens affect IgG glycosylation and osteoclast activation in vivo are not investigated so far. In this study, we used 20 mg/kg genistein or daidzein to gavage the female DBA1/J mice in collagen induced arthritis (CIA). We assessed arthritis and bone erosion by clinical scores, histopathology, and micro-CT analysis. Inflammatory cells such as neutrophils, B cells, macrophages and T cells in the peripheral blood were analyzed by flow cytometry. Phagocytic function of peritoneal macrophages was assessed by using FITC-labeled Escherichia coli. New monoclonal antibodies against CII were produced, purified and analyzed. Glycosylation levels of polyclonal and monoclonal IgG were detected by lectin-ELISA. Quantitative PCR was used to analyze the genes related to IgG glycosylation (B4galt1, St6gal1) and osteoclasts (TRAP, NFATC1, c-Fos). Expression of NF-κB and Akt signaling pathways as well as downstream transcription factors NFATc1 and c-Fos was studied by Western blot. Our results show that phytoestrogens protect mice from CIA by increasing IgG glycosylation leading to amelioration of inflammation and inhibiting the NF-κB pathway and NFATc1/c-Fos to decrease the activity of osteoclasts. In conclusion, phytoestrogens can protect bone and joints in CIA mice by increasing IgG glycosylation and inhibiting osteoclast activity. © 2020 Elsevier B.V.

  • 16.
    Dzhambazov, Balik
    et al.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Kihlberg, Jan
    Umeå University, Umeå, Sweden.
    Fugger, Lars
    University of Oxford, Oxford, United Kingdom.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Vestberg, Mikael
    Lund University, Lund, Sweden.
    Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 176, no 3, p. 1525-1533Article in journal (Refereed)
    Abstract [en]

    In both collagen-induced arthritis (CIA) and rheumatoid arthritis, T cells recognize a galactosylated peptide from type II collagen (CII). In this study, we demonstrate that the CII259-273 peptide, galactosylated at lysine 264, in complex with Aq molecules prevented development of CIA in mice and ameliorated chronic relapsing disease. In contrast, nonglycosylated CII259-273/Aq complexes had no such effect. CIA dependent on other MHC class II molecules (Ar/Er) was also down-regulated, indicating a bystander vaccination effect. T cells could transfer the amelioration of CIA, showing that the protection is an active process. Thus, a complex between MHC class II molecules and a posttranslationally modified peptide offers a new possibility for treatment of chronically active autoimmune inflammation such as rheumatoid arthritis. © 2006 by The American Association of Immunologists, Inc.

  • 17.
    Fang, Qinghua
    et al.
    Southern Medical University, Guangzhou, China.
    Li, Tingyue
    Erasmus Medical Center, Rotterdam, Netherlands.
    Chen, Peiya
    First Affiliated Hospital of Jinan University, Guangzhou, China.
    Wu, Yuzhe
    Southern Medical University, Guangzhou, China.
    Wang, Tingting
    Southern Medical University, Guangzhou, China.
    Mo, Lixia
    Southern Medical University, Guangzhou, China.
    Ou, Jiaxin
    Southern Medical University, Guangzhou, China.
    Nandakumar, Kutty Selva
    Southern Medical University, Guangzhou, China.
    Comparative Analysis on Abnormal Methylome of Differentially Expressed Genes and Disease Pathways in the Immune Cells of RA and SLE2021In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, article id 668007Article in journal (Refereed)
    Abstract [en]

    We identified abnormally methylated, differentially expressed genes (DEGs) and pathogenic mechanisms in different immune cells of RA and SLE by comprehensive bioinformatics analysis. Six microarray data sets of each immune cell (CD19+ B cells, CD4+ T cells and CD14+ monocytes) were integrated to screen DEGs and differentially methylated genes by using R package "limma." Gene ontology annotations and KEGG analysis of aberrant methylome of DEGs were done using DAVID online database. Protein-protein interaction (PPI) network was generated to detect the hub genes and their methylation levels were compared using DiseaseMeth 2.0 database. Aberrantly methylated DEGs in CD19+ B cells (173 and 180), CD4+ T cells (184 and 417) and CD14+ monocytes (193 and 392) of RA and SLE patients were identified. We detected 30 hub genes in different immune cells of RA and SLE and confirmed their expression using FACS sorted immune cells by qPCR. Among them, 12 genes (BPTF, PHC2, JUN, KRAS, PTEN, FGFR2, ALB, SERB-1, SKP2, TUBA1A, IMP3, and SMAD4) of RA and 12 genes (OAS1, RSAD2, OASL, IFIT3, OAS2, IFIH1, CENPE, TOP2A, PBK, KIF11, IFIT1, and ISG15) of SLE are proposed as potential biomarker genes based on receiver operating curve analysis. Our study suggests that MAPK signaling pathway could potentially differentiate the mechanisms affecting T- and B- cells in RA, whereas PI3K pathway may be used for exploring common disease pathways between RA and SLE. Compared to individual data analyses, more dependable and precise filtering of results can be achieved by integrating several relevant data sets.

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  • 18.
    Fang, Qinghua
    et al.
    Southern Medical University, Guangzhou, China.
    Ou, Jiaxin
    Southern Medical University, Guangzhou, China.
    Nandakumar, Kutty Selva
    Southern Medical University, Guangzhou, China.
    Autoantibodies as Diagnostic Markers and Mediator of Joint Inflammation in Arthritis.2019In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, Vol. 2019, article id 6363086Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis is a systemic, polygenic, and multifactorial syndrome characterized by erosive polyarthritis, damage to joint architecture, and presence of autoantibodies against several self-structures in the serum and synovial fluid. These autoantibodies (anticitrullinated protein/peptide antibodies (ACPAs), rheumatoid factors (RF), anticollagen type II antibodies, antiglucose-6 phosphate isomerase antibodies, anticarbamylated protein antibodies, and antiacetylated protein antibodies) have different characteristics, diagnostic/prognostic value, and pathological significance in RA patients. Some of these antibodies are present in the patients' serum several years before the onset of clinical disease. Various genetic and environmental factors are associated with autoantibody production against different autoantigenic targets. Both the activating and inhibitory FcγRs and the activation of different complement cascades contribute to the downstream effector functions in the antibody-mediated disease pathology. Interplay between several molecules (cytokines, chemokines, proteases, and inflammatory mediators) culminates in causing damage to the articular cartilage and bones. In addition, autoantibodies are proven to be useful disease markers for RA, and different diagnostic tools are being developed for early diagnosis of the clinical disease. Recently, a direct link was proposed between the presence of autoantibodies and bone erosion as well as in the induction of pain. In this review, the diagnostic value of autoantibodies, their synthesis and function as a mediator of joint inflammation, and the significance of IgG-Fc glycosylation are discussed.

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  • 19.
    Fang, Qinghua
    et al.
    Southern Medical University, Guangzhou, China.
    Zhou, Chun
    Southern Medical University, Guangzhou, China.
    Nandakumar, Kutty Selva
    Southern Medical University, Guangzhou, China.
    Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis2020In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, Vol. 2020, article id 3830212Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis is a chronic autoimmune syndrome associated with several genetic, epigenetic, and environmental factors affecting the articular joints contributing to cartilage and bone damage. Although etiology of this disease is not clear, several immune pathways, involving immune (T cells, B cells, dendritic cells, macrophages, and neutrophils) and nonimmune (fibroblasts and chondrocytes) cells, participate in the secretion of many proinflammatory cytokines, chemokines, proteases (MMPs, ADAMTS), and other matrix lysing enzymes that could disturb the immune balance leading to cartilage and bone damage. The presence of autoantibodies preceding the clinical onset of arthritis and the induction of bone erosion early in the disease course clearly suggest that initiation events damaging the cartilage and bone start very early during the autoimmune phase of the arthritis development. During this process, several signaling molecules (RANKL-RANK, NF-κB, MAPK, NFATc1, and Src kinase) are activated in the osteoclasts, cells responsible for bone resorption. Hence, comprehensive knowledge on pathogenesis is a prerequisite for prevention and development of targeted clinical treatment for RA patients that can restore the immune balance improving clinical therapy.

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  • 20.
    Fernandez Lahore, Gonzalo
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden; Southern Medical University–Karolinska Institute United Medical Inflammation Centre, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
    Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases2020In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 117, no 40, p. 24986-24997Article in journal (Refereed)
    Abstract [en]

    It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.

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  • 21.
    Fransen, M. F.
    et al.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Benonisson, H.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van Maren, W. W.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Sow, H. S.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Breukel, C.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Linssen, M. M.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Claassens, J. W. C.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Brouwers, C.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van der Kaa, J.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Camps, M.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Kleinovink, J. W.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Vonk, K. K.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van Heiningen, S.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Klar, N.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van Beek, L.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van Harmelen, V.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Daxinger, L.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden.
    Coward, C.
    University of Cambridge, Cambridge, United Kingdom.
    Lin, Q.
    Juntendo University School of Medicine, Tokyo, Japan.
    Hirose, S.
    Toin University of Yokohama, Yokohama, Japan.
    Salvatori, D.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van Hall, T.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    van Kooten, C.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Mastroeni, P.
    University of Cambridge, Cambridge, United Kingdom.
    Ossendorp, F.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    Verbeek, J. S.
    Leiden University Medical Center, ZA Leiden, the Netherlands.
    A Restricted Role for FcgammaR in the Regulation of Adaptive Immunity2018In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 200, no 8, p. 2615-2626Article in journal (Refereed)
    Abstract [en]

    By their interaction with IgG immune complexes, FcgammaR and complement link innate and adaptive immunity, showing functional redundancy. In complement-deficient mice, IgG downstream effector functions are often impaired, as well as adaptive immunity. Based on a variety of model systems using FcgammaR-knockout mice, it has been concluded that FcgammaRs are also key regulators of innate and adaptive immunity; however, several of the model systems underpinning these conclusions suffer from flawed experimental design. To address this issue, we generated a novel mouse model deficient for all FcgammaRs (FcgammaRI/II/III/IV(-/-) mice). These mice displayed normal development and lymphoid and myeloid ontogeny. Although IgG effector pathways were impaired, adaptive immune responses to a variety of challenges, including bacterial infection and IgG immune complexes, were not. Like FcgammaRIIb-deficient mice, FcgammaRI/II/III/IV(-/-) mice developed higher Ab titers but no autoantibodies. These observations indicate a redundant role for activating FcgammaRs in the modulation of the adaptive immune response in vivo. We conclude that FcgammaRs are downstream IgG effector molecules with a restricted role in the ontogeny and maintenance of the immune system, as well as the regulation of adaptive immunity.

  • 22.
    Gelderman, K. A.
    et al.
    Lund University, Lund, Sweden.
    Hultqvist, M.
    Lund University, Lund, Sweden.
    Pizzolla, A.
    Lund University, Lund, Sweden.
    Zhao, M.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Mattsson, R.
    Lund University, Lund, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden; Turku University, Turku, Finland.
    Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species2007In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 117, no 10, p. 3020-3028Article in journal (Refereed)
    Abstract [en]

    Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.

  • 23.
    Hagert, C.
    et al.
    University of Turku, Turku, Finland.
    Sareila, O.
    University of Turku, Turku, Finland; Karolinska Institute, Stockholm, Sweden.
    Kelkka, T.
    The National Doctoral Programme in Informational and Structural Biology, Turku, Finland; University of Turku, Turku, Finland.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Collin, M.
    Lund University, Lund, Sweden.
    Xu, B.
    Karolinska Institute, Stockholm, Sweden.
    Guerard, S.
    Karolinska Institute, Stockholm, Sweden.
    Bäcklund, J.
    Karolinska Institute, Stockholm, Sweden.
    Jalkanen, S.
    University of Turku, Turku, Finland.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden; Southern Medical University, Guangzhou, China; Lund University, Lund, Sweden; University of Turku, Turku, Finland.
    Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells: A Novel Experimental Model of Rheumatoid Arthritis2018In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 70, no 8, p. 1343-1353Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. METHODS: Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. RESULTS: A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcgamma receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. CONCLUSION: Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system.

  • 24.
    Hansson, Ann-Sofie
    et al.
    Göteborg University, Göteborg, Sweden.
    Johannesson, Martina
    Lund University, Lund, Sweden.
    Svensson, Lars
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Heinegard, Dick
    Göteborg University, Göteborg, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Relapsing polychondritis, induced in mice with matrilin 1, is an antibody- and complement-dependent disease2004In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 164, no 3, p. 959-966Article in journal (Refereed)
    Abstract [en]

    Relapsing polychondritis is an autoimmune disease that affects cartilage in the ear, nose, and respiratory tract. A pathogenic immune response has been proposed and antibodies to several cartilage proteins are detected in sera from these patients. To investigate the role of the humoral immune response in relapsing polychondritis, we used the matrilin-1-induced relapsing polychondritis model. Mice deficient of B cells (muMT) and mice congenic at the complement factor 5, were immunized with matrilin-1, a cartilage-specific protein mainly detected in the tracheal cartilage. To investigate the binding properties and tissue selection of matrilin-1-specific antibodies we produced matrilin-1-specific B-cell hybridomas. Although 83% of the micro MT heterozygous mice developed respiratory distress and erosive chondritis in the respiratory tract, none of the B-cell-deficient mice were susceptible to disease. In addition, we show that complement factor 5 is important for the induction of matrilin-1-induced relapsing polychondritis. Monoclonal matrilin-1-specific antibodies injected into neonatal mice bound specifically to cartilage of the respiratory tract and adult B-cell-deficient mice injected with the same antibodies developed erosive chondritis in the respiratory tract. We conclude that relapsing polychondritis can be mediated by a pathway involving tissue-specific antibodies and complement activation.

  • 25.
    Hayer, Silvia
    et al.
    Medical University of Vienna, Vienna, Wien, Austria.
    Nandakumar, Kutty Selva
    'SMASH' recommendations for standardised microscopic arthritis scoring of histological sections from inflammatory arthritis animal models2021In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 80, no 6, p. 714-726Article in journal (Refereed)
    Abstract [en]

    Animal models for inflammatory arthritides such as rheumatoid arthritis (RA) and psoriatic arthritis are widely accepted and frequently used to identify pathological mechanisms and validate novel therapeutic strategies. Unfortunately, many publications reporting on these animal studies lack detailed description and appropriate assessment of the distinct histopathological features of arthritis: joint inflammation, cartilage damage and bone erosion. Therefore, the European consortium BeTheCure, consisting of 38 academic and industrial partners from 15 countries, set as goal to standardise the histological evaluation of joint sections from animal models of inflammatory arthritis. The consensual approach of a task force including 16 academic and industrial scientists as well as laboratory technicians has resulted in the development of the Standardised Microscopic Arthritis Scoring of Histological sections ('SMASH') recommendations for a standardised processing and microscopic scoring of the characteristic histopathological features of arthritis, exemplified by four different rodent models for arthritis: murine collagen-induced arthritis, collagen-antibody-induced arthritis, human tumour necrosis factor transgenic Tg197 mice and rat pristane-induced arthritis, applicable to any other inflammatory arthritis model. Through standardisation, the SMASH recommendations are designed to improve and maximise the information derived from in vivo arthritis experiments and to promote reproducibility and transparent reporting on such studies. In this manuscript, we will discuss and provide recommendations for analysis of histological joint sections: identification of the regions of interest, sample preparation, staining procedures and quantitative scoring methods. In conclusion, awareness of the different features of the arthritis pathology in animal models of inflammatory arthritis is of utmost importance for reliable research outcome, and the standardised histological processing and scoring methods in these SMASH recommendations will help increase uniformity and reproducibility in preclinical research on inflammatory arthritis.

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  • 26.
    Jacobsen, Freja A.
    et al.
    Dept. of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark & Novo Nordisk A/S, Gentofte, Denmark.
    Hulst, Camilla
    Dept. of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark & Novo Nordisk A/S, Gentofte, Denmark.
    Bäckström, Thomas
    Novo Nordisk A/S, Måløv, Denmark & BTB Pharma, Malmö, Sweden.
    Koleske, Anthony J.
    Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, USA.
    Andersson, Åsa
    Dept. of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
    Arg Deficiency Does not Influence the Course of Myelin Oligodendrocyte Glycoprotein (MOG35-55)-induced Experimental Autoimmune Encephalomyelitis2016In: Journal of Clinical & Cellular Immunology, E-ISSN 2155-9899, Vol. 7, no 3, article id 1000420Article in journal (Refereed)
    Abstract [en]

    Background: Inhibition of Abl kinases has an ameliorating effect on the rodent model for multiple sclerosis, experimental autoimmune encephalomyelitis, and arrests lymphocyte activation. The family of Abl kinases consists of the Abl1/Abl and Abl2/Arg tyrosine kinases. While the Abl kinase has been extensively studied in immune activation, roles for Arg are incompletely characterized. To investigate the role for Arg in experimental autoimmune encephalomyelitis, we studied disease development in Arg-/- mice.

    Methods: Arg-/- and Arg+/+ mice were generated from breeding of Arg+/- mice on the C57BL/6 background. Mice were immunized with the myelin oligodendrocyte glycoprotein (MOG)35-55 peptide and disease development recorded. Lymphocyte phenotypes of wild type Arg+/+ and Arg-/- mice were studied by in vitro stimulation assays and flow cytometry.

    Results: The breeding of Arg+/+ and Arg-/- mice showed skewing in the frequency of born Arg-/- mice. Loss of Arg function did not affect development of experimental autoimmune encephalomyelitis, but reduced the number of splenic B-cells in Arg-/- mice following immunization with MOG peptide.

    Conclusions: Development of MOG-induced experimental autoimmune encephalomyelitis is not dependent on Arg, but Arg plays a role for the number of B cells in immunized mice. This might suggest a novel role for the Arg kinase in B-cell trafficking or regulation. Furthermore, the results suggest that Arg is important for normal embryonic development. © 2016 Jacobsen FA, et al.

  • 27.
    Jochems, C.
    et al.
    The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Islander, U.
    The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Erlandsson, M.
    The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Engdahl, C.
    The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Lagerquist, M.
    The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden; Center for Bone Research at the Sahlgrenska Academy (CBS), Göteborg, Sweden.
    Ohlsson, C.
    Center for Bone Research at the Sahlgrenska Academy (CBS), Göteborg, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden; Karolinska Institute, Stockholm, Sweden.
    Holmdahl, R.
    Lund University, Lund, Sweden; Karolinska Institute, Stockholm, Sweden.
    Carlsten, H.
    The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
    Effects of oestradiol and raloxifene on the induction and effector phases of experimental postmenopausal arthritis and secondary osteoporosis2011In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 165, no 1, p. 121-129Article in journal (Refereed)
    Abstract [en]

    Oestradiol and the selective oestrogen receptor modulator (SERM) raloxifene have been shown to ameliorate collagen-induced arthritis (CIA) in rats and in mice. One aim was to investigate if raloxifene exerts its anti-arthritic and anti-osteoporotic effects during the induction or effector phase of arthritis. A second aim was to analyse if raloxifene activates the oestrogen response element (ERE) to produce its immune-modulator effects. CIA or collagen-antibody-induced arthritis (CAIA) was induced in ovariectomized DBA/1-mice. CIA was used for evaluation of treatment during the induction, and CAIA for the effector phase of arthritis and osteoporosis development. Raloxifene, oestradiol or vehicle was administered 5 days/week. The clinical disease was evaluated continuously. Bone marrow density (BMD) was analysed with peripheral quantitative computer tomography, paws were collected for histological examination, and sera were analysed for markers of bone and cartilage turnover and proinflammatory cytokines. Transgenic luciferase (Luc)-ERE mice were immunized with collagen (CII), and after 10 days injected once with raloxifene, oestradiol or vehicle before termination. Spleens were analysed for luciferase activity to measure ERE activation. Treatment with oestradiol or raloxifene during the induction phase of CIA failed to affect arthritis. Raloxifene did not hamper disease activity in CAIA, whereas oestradiol delayed the onset and ameliorated the severity. Both raloxifene and oestradiol preserved BMD in CAIA. CII-immunization increased the oestradiol-induced ERE activation in spleen, and raloxifene activated the ERE at about 25% the intensity of oestradiol. Further experiments are needed to elucidate the exact mechanisms behind this finding. © 2011 British Society for Immunology.

  • 28.
    Johansson, A. C.
    et al.
    University of Lund, Lund, Sweden.
    Hansson, A. S.
    University of Lund, Lund, Sweden.
    Nandakumar, Kutty Selva
    University of Lund, Lund, Sweden.
    Bäcklund, J.
    University of Lund, Lund, Sweden.
    Holmdahl, R.
    University of Lund, Lund, Sweden.
    IL-10-deficient B10.Q mice develop more severe collagen-induced arthritis, but are protected from arthritis induced with anti-type II collagen antibodies2001In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 167, no 6, p. 3505-3512Article in journal (Refereed)
    Abstract [en]

    IL-10 is a pleiotropic cytokine with stimulatory and inhibitory properties, and is thought to have a protective role in rheumatoid arthritis and collagen-induced arthritis (CIA). In this study, we investigated how IL-10 deficiency affects CIA and anti-collagen type II (CII) Ab-transferred arthritis in C57BL/10.Q (B10.Q) mice. The B10.Q.IL-10(-/-) mice had an 8-cM 129/Ola fragment around the IL-10 gene. The mice were treated with antibiotics, appeared healthy, and had no colitis. T cells from IL-10(-/-) mice expressed similar levels of IFN-gamma, IL-2, and IL-4 after mitogen stimulation; however, macrophages showed a reduced TNF-alpha production compared with IL-10(+/-) littermates. IL-10(-/-) mice had an increased incidence, and a more severe CIA disease than the IL-10(+/-) littermates. To study the role of IL-10 in T cell tolerance, IL-10(-/-) were crossed into mice carrying the immunodominant epitope, CII(256-270), in cartilage (MMC) or in skin (TSC). Both IL-10(-/-) and IL-10(+/-) MMC and TSC mice were completely tolerized against CIA, indicating that lack of IL-10 in this context did not break tolerance. To investigate whether IL-10 was important in the effector phase of CIA, arthritis was induced with anti-CII Abs. Surprisingly, IL-10(-/-) were less susceptible to Ab-transferred arthritis, as only 30% showed signs of disease compared with 90% of the littermates. Therefore, IL-10 seemed to have a protective role in CIA, but seemed to exacerbate the arthritogenicity of anti-CII Abs. These data emphasize the importance of studying IL-10 in a defined genetic context in vivo, to understand its role in a complex disease like arthritis.

  • 29.
    Kessel, C.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institute, Stockholm, Sweden.
    Peters, F. B.
    Scripps Research Institute, La Jolla, CA, USA.
    Gauba, V.
    Scripps Research Institute, La Jolla, CA, USA.
    Schultz, P. G.
    Scripps Research Institute, La Jolla, CA, USA.
    Holmdahl, R.
    Karolinska Institute, Stockholm, Sweden.
    A single functional group substitution in c5a breaks B cell and T cell tolerance and protects against experimental arthritis2014In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 66, no 3, p. 610-621Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A deficiency in C5 protects against arthritis development. However, there is currently no approach successfully translating these findings into arthritis therapy, as by targeting the key component, C5a. The aim of this study was to develop a vaccination strategy targeting C5a as therapy for patients with rheumatoid arthritis. METHODS: An anti-C5a vaccine was generated by incorporating the unnatural amino acid p-nitrophenylalanine (4NPA) into selected sites in the murine C5a molecule. C5a-4NPA variants were screened for their immunogenicity in mice on different arthritis-susceptible class II major histocompatibility complex (MHC) backgrounds. A candidate vaccine was tested for its impact on disease in a murine model of collagen-induced arthritis (CIA). Immunity toward endogenous C5a as well as type II collagen was monitored and characterized. RESULTS: Replacing a single tyrosine residue in position 35 (Y(35) ) with 4NPA allowed the generation of an anti-C5a vaccine, which partly protected mice against the development of CIA while strongly ameliorating the severity of clinical disease. Although differing in just 3 atoms from wild-type C5a (wtC5a), C5aY(35) 4NPA induced loss of T cell and B cell tolerance toward the endogenous protein in mice expressing class II MHC H-2(q) molecules. Despite differential B cell epitope recognition, antibodies induced by both wtC5a and C5aY(35) 4NPA neutralized C5a. Thus, anti-wtC5a IgG titers during arthritis priming were potentially of critical importance for disease protection, because high titers of C5a-neutralizing antibodies after disease onset were unable to reverse the course of arthritis. CONCLUSION: The results of this study suggest that the most effective anti-C5a treatment in arthritis can be accomplished using a preventive vaccination strategy, and that treatment using conventional biologic or small molecule strategies targeting the C5a/C5aR axis may miss the optimal window for therapeutic intervention during the subclinical priming phase of the disease.

  • 30.
    Li, Jinan
    et al.
    Umeå University, Umeå, Sweden.
    Ny, Annelii
    Umeå University, Umeå, Sweden; Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.
    Leonardsson, Göran
    Umeå University, Umeå, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Ny, Tor
    Umeå University, Umeå, Sweden.
    The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis2005In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 166, no 3, p. 783-792Article in journal (Refereed)
    Abstract [en]

    The plasminogen activator (PA) system has been proposed to have important roles in rheumatoid arthritis. Here we have used the autoimmune collagen type II (CII)-induced arthritis (CIA) model and mice deficient for urokinase-type PA (uPA) or plasminogen to investigate the role of the PA system for development of arthritis. Our data revealed that uPA-deficient mice have a lower severity and incidence of CIA than wild-type mice. Furthermore, although >80% of wild-type control mice developed CIA, we found that none of the 50 plasminogen-deficient littermates that were tested developed CIA within a 40-day period. Antibody generation after CII immunization as well as the binding of labeled anti-CII antibodies to the surface of cartilage were similar in wild-type and plasminogen-deficient mice. No sign of inflammation was seen when plasminogen-deficient mice were injected with a mixture of monoclonal antibodies against CII. However, after daily injections of human plasminogen, these mice developed arthritis within 5 days. Our finding that infiltration of inflammatory cells into the synovial joints was impaired in plasminogen-deficient mice suggests that uPA and plasminogen are important mediators of joint inflammation. Active plasmin is therefore essential for the induction of pathological inflammatory joint destruction in CIA. © American Society for Investigative Pathology.

  • 31.
    Li, Yanpeng
    et al.
    Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Li, Zhilei
    Southern University of Science And Technology, Shenzhen, China.
    Nandakumar, Kutty Selva
    Halmstad University, School of Business, Innovation and Sustainability. Southern Medical University, Guangzhou, China.
    Holmdahl, Rikard
    Karolinska Institutet, Stockholm, Sweden; Southern Medical University, Guangzhou, China.
    Human NCF190H Variant Promotes IL-23/IL-17—Dependent Mannan-Induced Psoriasis and Psoriatic Arthritis2023In: Antioxidants, ISSN 2076-3921, Vol. 12, no 7, article id 1348Article in journal (Refereed)
    Abstract [en]

    Recently, a major single nucleotide variant on the NCF1 gene, leading to an amino acid replacement from arginine to histidine at position 90 (NCF1R90H), associated with low production of reactive oxygen species (ROS), was found to be causative for several autoimmune diseases. Psoriasis in the skin (PsO) and psoriatic arthritis (PsA) were induced with mannan by intraperitoneal injection or epicutaneous application, evaluated by visual and histology scoring. Immunostaining was used to identify macrophages, NCF1, and keratinocytes. The population of immune cells was quantified by flow cytometry, gene expression was analyzed by RT-qPCR, and the JAK/STAT signaling pathway was investigated by immunohistochemical staining and western blot. We found that the low ROS responder NCF190H variant promotes PsO and PsA (the MIP model). The NCF190H-expressing mice had hyperactivated macrophages, expanded keratinocytes, and dramatically increased numbers of γδT17 cells with upregulated IL-17A, IL-23, and TNF-α. In addition, the JAK1/STAT3 signaling pathway was also upregulated in cells in the psoriatic skin tissues of Ncf190H mice. To summarize, a defined SNP (NCF1-339, also named NCF190H) was found to activate the IL-23/IL-17 axis and JAK-STAT signaling pathways, leading to hyperactivation of macrophages and keratinocytes and causing mouse psoriasis and psoriatic arthritis. © 2023 by the authors.

  • 32.
    Li, Yanpeng
    et al.
    Southern Medical University, Guangzhou, China.
    Tong, Dongmei
    Karolinska Institute, Stockholm, Sweden.
    Liang, Peibin
    Southern Medical University, Guangzhou, China.
    Lönnblom, Erik
    Karolinska Institute, Stockholm, Sweden.
    Viljanen, Johan
    Uppsala University, Uppsala, Sweden.
    Xu, Bingze
    Karolinska Institute, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Halmstad University, School of Business, Innovation and Sustainability. Southern Medical University, Guangzhou, China.
    Holmdahl, Rikard
    Southern Medical University, Guangzhou, China; Karolinska Institute, Stockholm, Sweden.
    Cartilage-binding antibodies initiate joint inflammation and promote chronic erosive arthritis2020In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 22, no 1, article id 120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Antibodies binding to cartilage proteins are present in the blood and synovial fluid of early rheumatoid arthritis patients. In order to develop animal models mimicking the human disease, we have characterized the arthritogenic capacity of monoclonal antibodies directed towards different joint proteins in the cartilage.

    METHODS: Purified antibodies specific to unmodified or citrullinated collagen type II (CII), collagen type XI (CXI), and cartilage oligomeric matrix protein (COMP) were produced as culture supernatant, affinity purified, pooled as antibody cocktails (Cab3 and Cab4), and injected intravenously into mice to induce arthritis. An adjuvant (lipopolysaccharide or mannan) was subsequently injected intraperitoneally on either day 5 or day 60 to enhance arthritis. Antibody binding and complement activation on the cartilage surface were analyzed by immunohistochemical methods. Bone erosions and joint deformations were analyzed by histological assessments, enzyme-linked immunosorbent assays, and micro-CT. Luminex was used to detect CII-triple helical epitope-specific antibody responses.

    RESULTS: The new cartilage antibody cocktails induced an earlier and more severe disease than anti-CII antibody cocktail. Many of the mouse strains used developed severe arthritis with 3 antibodies, binding to collagen II, collagen XI, and cartilage oligomeric matrix protein (the Cab3 cocktail). Two new models of arthritis including Cab3-induced LPS-enhanced arthritis (lpsCAIA) and Cab3-induced mannan-enhanced arthritis (mCAIA) were established, causing severe bone erosions and bone loss, as well as epitope spreading of the B cell response. Cab4, with addition of an antibody to citrullinated collagen II, induced arthritis more efficiently in moderately susceptible C57BL/6 J mice.

    CONCLUSIONS: The new mouse model for RA induced with cartilage antibodies allows studies of chronic development of arthritis and epitope spreading of the autoimmune response and bone erosion.

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  • 33.
    Liang, Peibin
    et al.
    Southern Medical University, Guangzhou, China.
    Li, Yanpeng
    Southern Medical University, Guangzhou, China.
    Xu, Rui
    Southern Medical University, Guangzhou, China.
    Nandakumar, Kutty Selva
    Southern Medical University, Guangzhou, China.
    Stawikowska, Roma
    Florida Atlantic University, Jupiter, FL, USA.
    Fields, Gregg B.
    Florida Atlantic University, Jupiter, FL, USA.
    Holmdahl, Rikard
    Southern Medical University, Guangzhou, China; Karolinska Institute, Stockholm, Sweden.
    Characterization of chronic relapsing antibody mediated arthritis in mice with a mutation in Ncf1 causing reduced oxidative burst2022In: Molecular Biomedicine, E-ISSN 2662-8651, Vol. 3, no 1, article id 14Article in journal (Refereed)
    Abstract [en]

    Rheumatoid arthritis (RA) is a chronic autoimmune disorder affecting joints with a hallmark of autoantibody production. Mannan-enhanced collagen type II (COL2) antibody induced arthritis (mCAIA) in neutrophil cytosolic factor 1(Ncf1) mutation mouse is a chronic disease model imitating RA in mice. In this study, we characterize the chronic phase of mCAIA in Ncf1 mutated (BQ.Ncf1m1j/m1j) mice. Arthritis was induced by an intravenous injection of anti-COL2 monoclonal antibodies on day 0 followed by intra-peritoneal injections of mannan (from Saccharomyces cerevisiae) on days 3 and 65 in BQ.Ncf1 m1j/m1j and BQ mice. Bone erosion was analysed by computed tomography (CT) and blood cell phenotypes by flow cytometry. Cytokines and anti-COL2 antibodies were analyzed with multiplex bead-based assays. The arthritis in the Ncf1m1j/m1j mice developed with a chronic and relapsing disease course, which was followed for 200 days and bone erosions of articular joints were evaluated. An increased number of circulating CD11b+ Ly6G+ neutrophils were observed during the chronic phase, together with a higher level of G-CSF (granulocyte colony-stimulating factor) and TNF-α. In conclusion, the chronic relapsing arthritis of mCAIA in the Ncf1m1j/m1j mice develop bone erosions associated with a sustained neutrophil type of inflammatory responses.

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  • 34.
    Lindqvist, Anna-Karin B.
    et al.
    Lund University, Lund, Sweden; Cartela AB, Lund 22007, Sweden.
    Johannesson, Martina
    Lund University, Lund, Sweden.
    Johansson, Åsa C. M.
    Lund University, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Blom, Anna M.
    Lund University, Malmö University Hospital, Malmö, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Backcross and partial advanced intercross analysis of nonobese diabetic gene-mediated effects on collagen-induced arthritis reveals an interactive effect by two major loci2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 177, no 6, p. 3952-3959Article in journal (Refereed)
    Abstract [en]

    Genetic segregation analysis between NOD and C57BL strains have been used to identify loci associated with autoimmune disease. Only two loci (Cia2 and Cia9) had earlier been found to control development of arthritis, whereas none of the previously identified diabetes loci was of significance for arthritis. We have now made a high-powered analysis of a backcross of NOD genes on to the B10.Q strain for association with collagen-induced arthritis. We could confirm relevance of both Cia2 and Cia9 as well as the interaction between them, but we did not identify any other significant arthritis loci. Immune cellular subtyping revealed that Cia2 was also associated with the number of blood macrophages. Congenic strains of the Cia2 and Cia9 loci on the B10.Q background were made and used to establish a partial advanced intercross (PAI). Testing the PAI mice for development of collagen-induced arthritis confirmed the loci and the interactions and also indicated that at least two genes contribute to the Cia9 locus. Furthermore, it clearly showed that Cia2 is dominant protective but that the protection is not complete. Because these results may indicate that the Cia2 effect on arthritis is not only due to the deficiency of the complement C5, we analyzed complement functions in the Cia2 congenics as well as the PAI mice. These data show that not only arthritis but also C5-dependent complement activity is dominantly suppressed, confirming that C5 is one of the major genes explaining the Cia2 effect. © 2006 by The American Association of Immunologists, Inc.

  • 35.
    Löfström, Emma
    et al.
    Department of Clinical Microbiology, Halland's hospital Halmstad, Halmstad, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
    Eringfält, Anna
    Department of Clinical Microbiology, Halland's hospital Halmstad, Halmstad, Sweden.
    Kötz, Arne
    Department of Clinical Microbiology, Halland's hospital Halmstad, Halmstad, Sweden.
    Wickbom, Fredrik
    Department of Operation and Intensive care, Halland's hospital Halmstad, Halmstad, Sweden.
    Tham, Johan
    Department of Translational Medicine, Clinical Infection Medicine, Lund University, Skåne University Hospital, Malmö, Sweden.
    Lingman, Markus
    Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, Göteborg, Sweden; Halland's Hospital, Halland county, Halmstad, Sweden.
    Nygren, Jens M.
    Halmstad University, School of Health and Welfare, Centre of Research on Welfare, Health and Sport (CVHI), Health and Nursing.
    Undén, Johan
    Department of Clinical Sciences, Lund University, Lund, Sweden; Department of Operation and Intensive care, Halland's hospital Halmstad, Halmstad, Sweden.
    Dynamics of IgG-avidity and antibody levels after Covid-192021In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 144, article id 104986Article in journal (Refereed)
    Abstract [en]

    Background: A potentially important aspect of the humoral immune response to Covid-19 is avidity, the overall binding strength between antibody and antigen. As low avidity is associated with a risk of re- infection in several viral infections, avidity might be of value to predict risk for reinfection with covid-19. Objectives: The purpose of this study was to describe the maturation of IgG avidity and the antibody-levels over time in patients with PCR-confirmed non-severe covid-19. Study design: Prospective longitudinal cohort study including patients with RT-PCR confirmed covid-19. Blood samples were drawn 1, 3 and 6 months after infection. Antibody levels and IgG-avidity were analysed. Results: The majority had detectable s- and n-antibodies (88,1%, 89,1%, N = 75). The level of total n-antibodies significantly increased from 1 to 3 months (median value 28,3 vs 39,3 s/co, p<0.001) and significantly decreased from 3 to 6 months (median value 39,3 vs 17,1 s/co, p<0.001). A significant decrease in the IgG anti-spike levels (median value 37,6, 24,1 and 18,2 RU/ml, p<0.001) as well as a significant increase in the IgG-avidity index (median values 51,6, 66,0 and 71,0%, p<0.001) were seen from 1 to 3 to 6 months. Conclusion: We found a significant ongoing increase in avidity maturation after Covid-19 whilst the levels of antibodies were declining, suggesting a possible aspect of long-term immunity. © 2021 The Authors. Published by Elsevier B.V.

  • 36.
    Nandakumar, Kutty Selva
    Halmstad University, School of Business, Innovation and Sustainability.
    Vaccines and Vaccine Adjuvants for Infectious Diseases and Autoimmune Diseases2023In: Vaccines, E-ISSN 2076-393X, Vol. 11, no 2, article id 202Article in journal (Refereed)
  • 37.
    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.

  • 38.
    Nandakumar, Kutty Selva
    et al.
    Southern Medical University, Guangzhou, China; Karolinska Institute, Stockholm, Sweden.
    Collin, Mattias
    Lund University, Lund, Sweden.
    Happonen, Kaisa E.
    Lund University, Lund, Sweden; Salk Institute for Biological Studies, La Jolla, CA, United States.
    Lundström, Susanna L.
    Karolinska Institute, Stockholm, Sweden.
    Croxford, Allyson M.
    Monash University, Clayton, VIC, Australia.
    Xu, Bingze
    Karolinska Institute, Stockholm, Sweden.
    Zubarev, Roman A.
    Karolinska Institute, Stockholm, Sweden.
    Rowley, Merrill J.
    Monash University, Clayton, VIC, Australia.
    Blom, Anna M.
    Lund University, Lund, Sweden.
    Kjellman, Christian
    Hansa Medical AB, Lund, Sweden.
    Holmdahl, Rikard
    Southern Medical University, Guangzhou, China; Karolinska Institute, Stockholm, Sweden.
    Streptococcal Endo-β-N-Acetylglucosaminidase Suppresses Antibody-Mediated Inflammation In Vivo2018In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 9, article id 1623Article in journal (Refereed)
    Abstract [en]

    Endo-β-N-acetylglucosaminidase (EndoS) is a family 18 glycosyl hydrolase secreted by Streptococcus pyogenes. Recombinant EndoS hydrolyzes the β-1,4-di-N-acetylchitobiose  core of the N-linked complex type glycan on the asparagine 297 of the γ-chains of IgG. Here, we report that EndoS and IgG hydrolyzed by EndoS induced suppression of local immune complex (IC)-mediated arthritis. A small amount (1 µg given i.v. to a mouse) of EndoS was sufficient to inhibit IgG-mediated arthritis in mice. The presence of EndoS disturbed larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen-antibody binding per se were affected. Thus, EndoS could potentially be used for treating patients with IC-mediated pathology.

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  • 39.
    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.

  • 40.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Therapeutic cleavage of IgG: new avenues for treating inflammation2008In: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 29, no 4, p. 173-178Article in journal (Refereed)
    Abstract [en]

    Autoantibodies developing in humans contribute to the pathogenesis of several diseases, and injected therapeutic antibodies can also trigger adverse side effects. An efficient and rapid elimination of these antibodies are therefore critically needed. Antibody removal by plasmapheresis and immunoadsorption are commonly used methods but have their own limitations. Bacterial enzymes that can cleave IgG molecules or remove carbohydrate moieties to ameliorate their immunogenicity or effector functions in vivo offer new avenues for drug development. Recent discoveries highlight the possibility of cleaving or modifying IgG in vivo by injection of enzymes. Such an approach opens up new therapeutic possibilities not only for the control of pathogenic antibody-mediated inflammatory diseases but also allograft rejection or the treatment of side-effects of 'biologicals' such as monoclonal antibodies. © 2008 Elsevier Ltd. All rights reserved.

  • 41.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden; Karolinska Institutet, Stockholm, Sweden.
    Jansson, Åsa
    Resistentia Pharmaceuticals AB, Uppsala, Sweden.
    Xu, Bingze
    Resistentia Pharmaceuticals AB, Uppsala, Sweden.
    Rydell, Niclas
    Resistentia Pharmaceuticals AB, Uppsala, Sweden; Phadia AB, Uppsala, Sweden.
    Blom, Anna M.
    Department of Laboratory Medicine, Lund University, Skane University Hospital, Malmö, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden; Karolinska Institutet, Stockholm, Sweden.
    A recombinant vaccine effectively induces c5a-specific neutralizing antibodies and prevents arthritis2010In: PLOS ONE, E-ISSN 1932-6203, Vol. 5, no 10, article id e13511Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To develop and validate a recombinant vaccine to attenuate inflammation in arthritis by sustained neutralization of the anaphylatoxin C5a. METHODS: We constructed and expressed fusion protein of C5a and maltose binding protein. Efficacy of specific C5a neutralization was tested using the fusion protein as vaccine in three different arthritis mouse models: collagen induced arthritis (CIA), chronic relapsing CIA and collagen antibody induced arthritis (CAIA). Levels of anti-C5a antibodies and anti-collagen type II were measured by ELISA. C5a neutralization assay was done using a rat basophilic leukemia cell-line transfected with the human C5aR. Complement activity was determined using a hemolytic assay and joint morphology was assessed by histology. RESULTS: Vaccination of mice with MBP-C5a led to significant reduction of arthritis incidence and severity but not anti-collagen antibody synthesis. Histology of the MBP-C5a and control (MBP or PBS) vaccinated mice paws confirmed the vaccination effect. Sera from the vaccinated mice developed C5a-specific neutralizing antibodies, however C5 activation and formation of the membrane attack complex by C5b were not significantly altered. CONCLUSIONS: Exploitation of host immune response to generate sustained C5a neutralizing antibodies without significantly compromising C5/C5b activity is a useful strategy for developing an effective vaccine for antibody mediated and C5a dependent inflammatory diseases. Further developing of such a therapeutic vaccine would be more optimal and cost effective to attenuate inflammation without affecting host immunity. © 2010 Nandakumar et al.

  • 42.
    Nandakumar, Kutty Selva
    et al.
    Lund University, Lund, Sweden.
    Johansson, Björn P.
    Lund University, Lund, Sweden.
    Björck, Lars
    Lund University, Lund, Sweden.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Blocking of experimental arthritis by cleavage of IgG antibodies in vivo2007In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 10, p. 3253-3260Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether IgG-degrading enzyme of Streptococcus pyogenes (IdeS), a bacterial cysteine endopeptidase that cleaves human IgG in the hinge region, can be used for blocking the development of arthritis. METHODS: Recombinant IdeS was purified and tested for specificity against mouse IgG. IdeS was injected intravenously into mice with collagen antibody-induced arthritis (CAIA), collagen-induced arthritis (CIA), or relapsing CIA, and its effects on arthritis development and severity were assessed. RESULTS: IdeS efficiently cleaved mouse IgG2a/c and IgG3 in vitro. Even at low dosage (10 microg), IdeS specifically cleaved IgG2a in vivo without any apparent side effects. IdeS treatment efficiently blocked CAIA induced by IgG2a antibodies. No effect was observed when arthritis was induced with IgG2b anti-type II collagen antibodies; since IdeS does not cleave IgG2b, this indicated that IgG cleavage was the mechanism of action. IdeS treatment reduced the severity of arthritis if administered within 24 hours after the onset of clinical arthritis, but did not block ongoing severe arthritis. IdeS treatment also significantly prevented an antibody-induced relapse in mice that had chronic arthritis, and delayed the onset and reduced the severity of arthritis in classic CIA. CONCLUSION: IdeS has therapeutic potential in IgG antibody-mediated autoimmune arthritis, representing a new and unique means of blocking pathogenic antibodies. © 2007, American College of Rheumatology.

  • 43.
    Nilsang, Suthasinee
    et al.
    Lund University, Lund, Sweden; School of Environmental, Resources and Development, Asian Institute of Technology, Pathumtani, Thailand; Valaya Alongkorn Rajabhat University, Pathumtani, Thailand.
    Nehru, Vishal
    Lund University, Lund, Sweden; Indian Institute of Technology Kanpur, Kanpur, India.
    Plieva, Fatima M.
    Lund University, Lund, Sweden; Protista Biotechnology AB, IDEON, Lund, Sweden.
    Nandakumar, Kutty Selva
    Lund University, Lund, Sweden.
    Rakshit, Sudip Kumar
    School of Environmental, Resources and Development, Asian Institute of Technology, Pathumtani, Thailand.
    Holmdahl, Rikard
    Lund University, Lund, Sweden.
    Mattiasson, Bo
    Lund University, Lund, Sweden.
    Kumar, Ashok
    Indian Institute of Technology Kanpur, Kanpur, India.
    Three-dimensional culture for monoclonal antibody production by hybridoma cells immobilized in macroporous gel particles2008In: Biotechnology progress (Print), ISSN 8756-7938, E-ISSN 1520-6033, Vol. 24, no 5, p. 1122-1131Article in journal (Refereed)
    Abstract [en]

    Cell proliferation and long-term production of monoclonal antibody IgG(2b) by M2139 hybridoma cells immobilized in macroporous gel particles (MGPs) in packed-bed reactor were studied for a period of 60 days. The MGPs were made of supermacroporous gels produced in frozen conditions from crosslinked polyacrylamide and modified with gelatin which were housed in special plastic carriers (7 x 9 mm(2)). Cells were trapped in the interior part of MGPs by attaching to the void space of the gel matrix as three-dimensional (3D) cultivation using gelatin as a substrate layer. Optimizing productivity by hybridoma cell relies on understanding regulation of antibody production. In this study, the behavior of M2139 cells in two-dimensional cultures on multiwell plate surfaces was also investigated. The effect of three different medium such as basal medium Dulbecco's modified Eagle's medium (D-MEM) containing L-glutamine or L-glutamine + 2 mM alpha-ketoglutarate or L-alanyl-glutamine (GlutaMAXtrade mark) was studied prior to its use in 3D cultivation. The kinetics of cell growth in basal medium containing L-glutamine + alpha-ketoglutarate was similar to cells grown on GlutaMAX containing medium, whereas D-MEM containing L-glutamine showed lower productivity. With the maximal viable cell density (6.85 x 10(6) cells mL(-1)) and highest specific mAb production rate (3.9 mug mL(-1) 10(-4) viable cell day(-1)), D-MEM-GlutaMAX was further selected for 3D cultivation. Cells in MGPs were able to grow and secrete antibody for 30 days in packed-bed batch reactor, before a fresh medium reservoir was replaced. After being supplied with fresh medium, cells again showed continuous growth for another 30 days with mAb production efficiency of 50%. These results demonstrate that MGPs can be used efficiently as supporting carrier for long-term monoclonal antibody production. © 2008 American Institute of Chemical Engineers.

  • 44.
    Nygren, Jens Martin
    et al.
    Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Bryder, David
    Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Jacobsen, Sten Eirik W
    Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Prolonged cell cycle transit is a defining and developmentally conserved hemopoietic stem cell property2006In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 177, no 1, p. 201-208Article in journal (Refereed)
    Abstract [en]

    Adult mouse hemopoietic stem cells (HSCs) are typically quiescent and enter and progress through the cell cycle rarely in steady-state bone marrow, but their rate of proliferation can be dramatically enhanced on demand. We have studied the cell cycle kinetics of HSCs in the developing fetal liver at a stage when they expand extensively. Despite that 100% of fetal liver HSCs divide within a 48-h period, their average cell cycle transit time (10.6 h) is twice that of their downstream progenitors, translating into a prolonged G(1) transit and a period of relative quiescence (G(0)). In agreement with their prolonged G(1) transit when compared with hemopoietic progenitors, competitive transplantation experiments demonstrate that fetal HSCs are highly enriched in G(1) but also functional in S-G(2)-M. This observation combined with experimental data demonstrating that adult HSCs forced to expand ex vivo also sustain a uniquely prolonged cell cycle and G(1) transit, demonstrate at least in part why purified HSCs at any state of development or condition are highly enriched in the G(0)-G(1) phases of the cell cycle. We propose that a uniquely prolonged cell cycle transit is a defining stem cell property, likely to be critical for their maintenance and self-renewal throughout development.

  • 45.
    Pfeifle, R.
    et al.
    University Hospital Erlangen, Erlangen, Germany; Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden.
    Krönke, G.
    University Hospital Erlangen, Erlangen, Germany; Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
    Regulation of autoantibody activity by the IL-23-T(H)17 axis determines the onset of autoimmune disease2017In: Nature Immunology, ISSN 1529-2908, E-ISSN 1529-2916, Vol. 18, no 1, p. 104-113Article in journal (Refereed)
    Abstract [en]

    The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the T(H)17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, T(H)17 cells regulated the expression of beta-galactoside alpha2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-T(H)17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance.

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  • 46.
    Raposo, B.
    et al.
    Karolinska Institutet, Stockholm, Sweden.
    Dobritzsch, D.
    Karolinska Institutet, Stockholm, Sweden; Uppsala University, Uppsala, Sweden.
    Ge, C.
    Karolinska Institutet, Stockholm, Sweden.
    Ekman, D.
    Karolinska Institutet, Stockholm, Sweden.
    Xu, B.
    Karolinska Institutet, Stockholm, Sweden.
    Lindh, I.
    Karolinska Institutet, Stockholm, Sweden.
    Förster, M.
    Karolinska Institutet, Stockholm, Sweden.
    Uysal, H.
    Karolinska Institutet, Stockholm, Sweden.
    Nandakumar, Kutty Selva
    Karolinska Institutet, Stockholm, Sweden.
    Schneider, G.
    Karolinska Institutet, Stockholm, Sweden.
    Holmdahl, R.
    Karolinska Institutet, Stockholm, Sweden.
    Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms2014In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 211, no 3, p. 405-411Article in journal (Refereed)
    Abstract [en]

    Autoantibody formation is essential for the development of certain autoimmune diseases like rheumatoid arthritis (RA). Anti-type II collagen (CII) antibodies are found in RA patients; they interact with cartilage in vivo and are often highly pathogenic in the mouse. Autoreactivity to CII is directed to multiple epitopes and conserved between mice and humans. We have previously mapped the antibody response to CII in a heterogeneous stock cohort of mice, with a strong association with the IgH locus. We positioned the genetic polymorphisms and determined the structural requirements controlling antibody recognition of one of the major CII epitopes. Polymorphisms at positions S31R and W33T of the associated variable heavy chain (VH) allele were identified and confirmed by gene sequencing. The Fab fragment binding the J1 epitope was crystallized, and site-directed mutagenesis confirmed the importance of those two variants for antigen recognition. Back mutation to germline sequence provided evidence for a preexisting recognition of the J1 epitope. These data demonstrate a genetic association of epitope-specific antibody responses with specific VH alleles, and it highlights the importance of germline-encoded antibodies in the pathogenesis of antibody-mediated autoimmune diseases.

  • 47.
    Sardar, Samra
    et al.
    University of Copenhagen, Copenhagen, Denmark.
    Alish, Kerr
    University of Copenhagen, Copenhagen, Denmark & Pfizer Pharmaceuticals, Dublin, Ireland.
    Vaartjes, Daniëlle
    University of Copenhagen, Copenhagen, Denmark & Karolinska Institute, Stockholm, Sweden.
    Voetmann, Mathilde Emilie
    University of Copenhagen, Copenhagen, Denmark & Biogen Denmark A/S, Hillerød, Denmark.
    Moltved, Emilie Riis
    University of Copenhagen, Copenhagen, Denmark & QuintilesIMS, North Carolina, USA.
    Andersson, Åsa
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). University of Copenhagen, Copenhagen, Denmark.
    A novel candidate for genetic control of Collagen Induced Arthritis is involved in transcriptional regulation of B-cell proliferation2017Conference paper (Other academic)
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    Abstract IFRA
  • 48.
    Sardar, Samra
    et al.
    University of Copenhagen, Copenhagen, Denmark & Nordic Bioscience A/S, Copenhagen, Denmark.
    Kanne, Katrine
    University of Copenhagen, Copenhagen, Denmark & Novartis International AG, Copenhagen, Denmark.
    Andersson, Åsa
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS). University of Copenhagen, Copenhagen, Denmark.
    Analysis of polymorphisms in the mediator complex subunit 13-like (Med13L) gene in the context of immune function and development of experimental arthritis2018In: Archivum Immunologiae et Therapiae Experimentalis, ISSN 0004-069X, E-ISSN 1661-4917, Vol. 66, no 5, p. 365-377Article in journal (Refereed)
    Abstract [en]

    The Mediator complex subunit 13-like (MED13L) protein is part of the multi-protein mediator complex and plays an important role in gene transcription. Polymorphisms in the MED13L gene have been linked to congenital heart anomalies and intellectual disabilities. Despite recent evidence of indirect links of MED13L to cytokine release and inflammation, impact of genetic variations in MED13L on immune cells remains unexplored. The B10.RIII and RIIIS/J mouse strains vary in susceptibility to induced experimental autoimmune disease models. From sequencing data of the two mouse strains, we identified six polymorphisms in the coding regions of Med13l. By using congenic mice, we studied the effect of these polymorphisms on immune cell development and function along with susceptibility to collagen-induced arthritis, an animal model for Rheumatoid Arthritis (RA). Combining in vivo disease data, in vitro functional data, and computational analysis of the reported non-synonymous polymorphisms, we report that genetic polymorphisms in Med13l do not affect the immune phenotype in these mice and are predicted to be non-disease associated. © The Author(s) 2018

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  • 49.
    Sardar, Samra
    et al.
    Nordic Bioscience A/S, Copenhagen, Denmark.
    Kerr, Alish
    Nuritas, Dublin, Ireland.
    Vaartjes, Daniëlle
    Karolinska Institutet, Stockholm, Sweden.
    Moltved, Emilie Riis
    IQVIA Denmark, Copenhagen, Denmark.
    Karosiene, Edita
    Novo Nordisk A/S, Copenhagen, Denmark.
    Gupta, Ramneek
    Technical University of Denmark, Lyngby, Denmark.
    Andersson, Åsa
    Halmstad University, School of Business, Engineering and Science, The Rydberg Laboratory for Applied Sciences (RLAS).
    The oncoprotein TBX3 is controlling severity in experimental arthritis2019In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 21, no 1, article id 16Article in journal (Refereed)
    Abstract [en]

    Background: Development of autoimmune diseases is the result of a complex interplay between hereditary and environmental factors, with multiple genes contributing to the pathogenesis in human disease as well as in experimental models for disease. The T-box protein 3 is a transcriptional repressor essential during early embryonic development, in the formation of bone and additional organ systems, and in tumorigenesis.

    Methods: With the aim to find novel genes important for autoimmune inflammation, we have performed genetic studies of collagen-induced arthritis, a mouse experimental model for Rheumatoid Arthritis.

    Results: We show that a small genetic fragment on mouse chromosome 5, including Tbx3 and three additional protein-coding genes, is linked to severe arthritis and high titers of anti-collagen antibodies. Gene expression studies have revealed differential expression of Tbx3 in B-cells, where low expression was accompanied by a higher B-cell response upon B-cell receptor stimulation in vitro. Furthermore, we show that serum TBX3 levels rise concomitantly with increasing severity of CIA.

    Conclusions: From these results, we suggest that TBX3 is a novel factor important for the regulation of gene transcription in the immune system and that genetic polymorphisms, resulting in lower expression of Tbx3, are contributing to a more severe form of collagen-induced arthritis and high titers of autoantibodies. We also propose TBX3 as a putative diagnostic biomarker for rheumatoid arthritis.

  • 50.
    Sardar, Samra
    et al.
    University of Copenhagen, Copenhagen, Denmark.
    Vartjes, Daniëlle
    Karolinska Institute, Stockholm, Sweden.
    Voetmann, Mathilde
    University of Copenhagen.
    Andersson, Åsa
    University of Copenhagen, Copenhagen, Denmark.
    Novel candidates for genetic control of Collagen INduced Arthritis are involved in transcriptional regulation of B-cell proliferation2017Conference paper (Refereed)
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    Publ abstract FOCIS 2017
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