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ABSTRACT: Rheumatoid arthritis (RA) is a complex autoimmune disease, with a prevalence of approximately 1% in the population worldwide. RA is a chronic inflammatory disease primarily affecting joints and patients suffer from a plethora of symptoms, including pain, fatigue and stiffness. Joint pain is one of the most egregious symptoms in RA. Animal models of RA are used extensively in research to understand the pathogenesis of inflammatory arthritis and in the assessment of potential disease-modifying agents. There is an increasing need for disease-relevant animal models for pain research and several of the RA animal models that previously were not used in pain research have now been characterized for this purpose. The most commonly used RA model is the collagen-induced arthritis (CIA) model. However, it has certain disadvantages when used for pain research. Here we describe an alternative model, the collagen antibody-induced arthritis (CAIA) model to study RA-induced pain. This model has been used to investigate disease pathology for more than 10 years, but has just recently been characterized as a pain model. In comparison to CIA, more mouse strains are susceptible to CAIA and the degree of joint pathology and systemic disease is less severe, making the assessment of arthritis-associated nociceptive behavior, such as paw withdrawal from mechanical or thermal stimuli, as well as changes in normal behavior such as locomotion more easily investigated. The aim of this chapter is to describe the CAIA model and several techniques used to study inflammatory pain-like behavior.
10/2012: pages 437-455; , ISBN: 978-1-62703-094-6
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ABSTRACT: OBJECTIVES: Chronic inflammation of the peripheral joints is a hallmark of rheumatoid arthritis (RA). Whereas the autoantibody response in RA is directed mainly to ubiquitous antigens the response to cartilage proteins have been less extensively studied. Here we have defined the immune response in pristane-induced arthritis (PIA) in the rat to the cartilage specific proteins collagen type II (CII) and XI (CXI) and genetically fine mapped their underlying MHC associations. METHODS: The genetic control of CII and CXI immunity were mapped using intra-MHC recombinant strains upon immunization with the respective collagens. Reactivity to CII and CXI were tested in acute and chronic PIA and in 356 HLA-typed patients with recently diagnosed RA. RESULTS: Mapping of arthritis susceptibility within the MHC region revealed a 144-223kb locus containing less than 12 genes, including paralogues for HLA-DQ and DR. Susceptibility to CII and CXI were linked to haplotypes RT1(av1) (DA) and RT1(f) (DA.1F), respectively. After injection of pristane, both strains developed weak T cell and IgG responses to CII, but not to CXI. In chronic arthritis, however, collagen reactivity was stronger, specific for CXI and restricted to rats with RT1(f) MHC. Among RA patients, 12% showed specific IgG response to CXI, 6% to CII and 6% to both collagens. CONCLUSION: These findings demonstrate a shift in cartilage recognition in early and chronic arthritis in the rat, suggesting that CXI autoreactivity contributes to the perpetuation of chronic disease and highlights the importance of joint antigens in arthritis development.
Arthritis Rheum. 01/2012;
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Annals of Rheumatic Diseases; 01/2012
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ABSTRACT: 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.
Clinical & Experimental Immunology 07/2011; 165(1):121-9. · 3.36 Impact Factor
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European Journal of Pain; 01/2011
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ABSTRACT: In this study, we sought to determine the effect of the quantitative trait locus Pia7 on arthritis severity. The regulatory locus derived from the arthritis-resistant E3 rat strain was introgressed into the arthritis-susceptibility DA strain through continuous backcrossing. Congenic rats were studied for their susceptibility to experimental arthritis using pristane and adjuvant oil. In addition, cell number and function of various leukocyte populations were analyzed either under naive or stimulated conditions. We found that the minimal congenic fragment of DA.E3-Pia7 rats overlapped with the minimal fragment in DA.PVG-Oia2 congenic rats, which has been positionally cloned to the antigen-presenting lectin-like receptor complex (APLEC) genes. DA.E3-Pia7 congenic rats were protected from both PIA and OIA, but the protection was more pronounced in OIA. In adoptive transfer experiments we observed that the Pia7 locus controlled the priming of arthritogenic T cells and not the effector phase. In addition, Pia7 congenic rats had a significant higher frequency of B cells and granulocytes as well as TNFalpha production after stimulation, indicating a higher activation state of cells of the innate immune system. In conclusion, this study shows that the APLEC locus is a major locus regulating the severity of experimentally induced arthritis in rats.
Genes and immunity 03/2010; 11(3):239-45. · 4.22 Impact Factor
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O Snir,
M Widhe,
C von Spee,
J Lindberg,
L Padyukov,
K Lundberg,
A Engström,
P J Venables,
J Lundeberg, R Holmdahl,
L Klareskog,
V Malmström
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ABSTRACT: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles.
To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles.
Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed.
72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles.
Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.
Annals of the rheumatic diseases 05/2009; 68(5):736-43. · 8.11 Impact Factor
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2nd European congress of Immunology Proceedings, Berlin, Germany; 01/2009
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ABSTRACT: Oestrogen is not only a sex hormone but also an important regulator of the immune system. Expression of the heavy chain of IgM (mu) is essential for B-cell differentiation. However, a small number of IgA-positive B cells can be found in mice lacking the mu chain (muMT-/-). The aim of this study was to investigate the effects of oestrogen on this alternative B-cell pathway in muMT-/- mice. Our results clearly demonstrate that oestrogen increases the frequency of IgA-producing B cells in muMT-/- mice in both bone marrow and spleen cells. We also show that mature IgM-producing B cells are not required for oestrogen-mediated suppression of granulocyte-mediated inflammation or thymic involution. In conclusion, we demonstrate that 17beta-estradiol benzoate increases the frequency of IgA-producing B cells in muMT-/- mice, suggesting that oestrogen can influence the alternative B-cell pathway found in muMT-/- mice.
Scandinavian Journal of Immunology 02/2008; 67(1):12-7. · 2.23 Impact Factor
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ABSTRACT: The expression of genes specifically in B cells is of great interest in both experimental immunology as well as in future clinical gene therapy. We have constructed a novel enhanced B cell-specific promoter (Igk-E) consisting of an immunoglobulin kappa (Igk) minimal promoter combined with an intronic enhancer sequence and a 3' enhancer sequence from Ig genes. The Igk-E promoter was cloned into a lentiviral vector and used to control expression of enhanced green fluorescent protein (eGFP). Transduction of murine B-cell lymphoma cell lines and activated primary splenic B cells, with IgK-E-eGFP lentivirus, resulted in expression of eGFP, as analysed by flow cytometry, whereas expression in non-B cells was absent. The specificity of the promoter was further examined by transducing Lin(-) bone marrow with Igk-E-eGFP lentivirus and reconstituting lethally irradiated mice. After 16 weeks flow cytometry of lymphoid tissues revealed eGFP expression by CD19+ cells, but not by CD3+, CD11b+, CD11c+ or Gr-1+ cells. CD19+ cells were comprised of both marginal zone B cells and recirculating follicular B cells. Activated human peripheral mononuclear cells were also transduced with Igk-E-eGFP lentivirus under conditions of selective B-cell activation. The Igk-E promoter was able to drive expression of eGFP only in CD19+ cells, while eGFP was expressed by both spleen focus-forming virus and cytomegalovirus constitutive promoters in CD19+ and CD3+ lymphocytes. These data demonstrate that in these conditions the Igk-E promoter is cell specific and controls efficient expression of a reporter protein in mouse and human B cells in the context of a lentiviral vector.
Gene Therapy 01/2008; 14(23):1623-31. · 3.71 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a polygenic and multifactorial disease. Many complex immunological and genetic interactions are
involved in the final out come of the clinical disease. To understand the various disease pathways operating during the disease
course, we need many different animal models. Collagen induced arthritis (CIA) is one of the widely used animal models sharing
many pathological and histological similarities with RA and antibodies play an important role in the inflammatory phase of
CIA. This chapter describes, in detail, an animal model for arthritis using CII specific monoclonal antibodies, the so-called
collagen antibody induced arthritis (CAIA), which shares many characteristics of CIA. CAIA model provides an opportunity to
study the inflammatory phase of arthritis without involving the priming phase of the immune response. CAIA can be used for
not only studying inflammatory processes in arthritis and screening drug candidates controlling joint inflammatory phase but
also as a model for studying common mechanisms involved in many antibody mediated diseases.
Key WordsCollagen induced arthritis–collagen antibody induced arthritis–collagen type II–monoclonal antibodies–rheumatoid arthritis
01/2007: pages 215-223; , ISBN: 978-1-58829-918-5
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ABSTRACT: Two monoclonal IgG rheumatoid factors were obtained alter hybridization of spleen cells from DBA/1 mice immunized with immune complexes containing native collagen type II and a monoclonal anti-collagen II antibody. One of these rheumatoid factors reacted not only with purified murine Fc fragments, but also with Fab fragments of the anti-collagen II antibody used for immunization, whereas no reactivity was seen with Fab fragments from normal mouse IgG. The findings demonstrate the ability of immune complexes encompassing native collagen type II to induce production of IgG rheumatoid factors, and suggest that an idiotypic relationship may exist between certain rheumatoid factors and anti-collagen II antibodies.
Scandinavian Journal of Immunology 06/2006; 24(2):197 - 203. · 2.23 Impact Factor
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ABSTRACT: Collagen type II-spedfic long-term cultured T helper cells, derived from the DBA/1 mouse, have been established and characterized. Clones from these T-cell lines could he shown to recognize either species-specific or species-nonspecific determinants on the collagen type II molecule, including determinants on autologous mouse collagen. Induction of arthritis via transfer to both irradiated and normal syngeneic recipient mice was obtained with both collagen type II-specific T-cell lines and an autoreactive and collagen type II-specific T-cell clone. Fewer cells were needed to evoke arthritis in normal than in irradiated recipients. Cells from lines and the clone used for transfer were by immunocytochemistry shown to have T helper phenotype.
Scandinavian Journal of Immunology 06/2006; 22(3):295 - 306. · 2.23 Impact Factor
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ABSTRACT: Immunization of female Lewis rats with bovine type II collagen induces a severe polyarthritis with an incomplete penetration. Castration of the rats increased the incidence to 94% compared with 50% among sham-operated controls. When castrated female rats were implanted with silicon capsules containing β-oestradiol they developed arthritis with a delayed onset and a decreased severity compared with castrated rats implanted with empty Silastic capsules. The levels of anti-type II collagen auto-antibodies were not affected by castration or oestrogen treatment. These findings show that oestrogen suppresses the development of collagen arthritis in rats and that this effect is mediated by mechanisms other than anti-type II collagen autoantibodies.
Scandinavian Journal of Immunology 06/2006; 26(5):579 - 583. · 2.23 Impact Factor
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ABSTRACT: Arthritis was induced in DBA/1 mice by passive transfer of syngeneic anti-type II collagen (CII) scrum concentrate. After transfer of serum containing 0.2 or 0.5 mg anti-CII auto-antibodies the first clinical signs of arthritis appeared 48 h after injection. Severe clinical arthritis was detected 96 h after injection. Immunohistochemical analyses of joints 48 h after serum injection revealed synovial foci in intercarpal and mclacarpophalangeal joints of macrophage-like cells, expressing C3bi-receptors and major hislocompatibility complex class II molecules, and infiltration of few CD4+ lymphocytes. Later (96 h afler injection), the inflamed synovia were dominated by C3bireceptor+ polymorphonuclear cells. In contrast to conventionally induced collagen arthritis (CIA), the inflammatory infiltrates, filling joint spaces and synovial tissue, were extensively dominated by polymorphonuclear cells, whereas macrophage-like cells expressing class II molecules and a few T cells were seen only in the periphery of the developing pannus. The anti-CII serum induced arthritis may be used as a model for studies of humoral mediated mechanisms operating in conventionally induced CIA as well as in rheumatoid arthrilis.
Scandinavian Journal of Immunology 06/2006; 31(2):147 - 157. · 2.23 Impact Factor
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ABSTRACT: Administration or oestrogen to castrated female rats has previously been shown to exert a suppressive effect both on the development of collagen-induced arthritis (CIA) and on the delayed-type hypersensitivity (DTH) reaction to collagen II (CII). The present study is concerned with the mechanisms responsible for this suppression, particularly as to the role of the thymus and the CD8+ T lymphocytes; both the thymic epithelial cells and the CD8+ T cells have earlier been implicated as responsible for oestrogen-mediated immunomodulation on the basis of their expression of oestrogen receptors. Adult thymectomy alone did not affect either the incidence or severity of arthritis. Furthermore, adult thymectomy did not change the observed suppressive effects of oestrogen treatment on arthritis development or auto-anti-CII T-cell immunity. Elimination of CD8+ T cells was subsequently achieved in groups of thymectomized rats by utilizing the fact that efficient depletion of CD8+ T cells occurs after in vivo treatment with OX8 monoclonal antibodies; depletion of peripheral CD8+ T cells failed to influence the suppressive effect of oestrogen on CIA and on the in vitro proliferate response of lymph-node cells to-CII. Depletion of CD8+ T cells did, however, in itself reduce the incidence of CIA in non-oestrogen-treated and thymectomized rats. We conclude that oestrogen may exert its suppressive effect on development of CIA and on T-cell responsiveness via mechanisms independent of both the thymus and the CD8+ T-cell subpopulation, but that CD8+ T cells are nevertheless involved in the regulation and/or effectuation of the immune reactions responsible for development of collagen arthritis in rats.
Scandinavian Journal of Immunology 06/2006; 30(6):741 - 747. · 2.23 Impact Factor
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ABSTRACT: The specificity of the recognition of type II collagen (CII) by T cells in the DBA/1 mouse was analysed using fragments of chick and rat CII obtained by cyanogen bromide (CB) cleavage. Firstly DBA/1 mice were immunized with chick CB fragments 5, 8, 9, 10, 11 and 12. Ten days later the draining lymph node cells were cultured with rat and mouse CII and the proliferative response was determined by incorporation of [3H]thymidine All peptides were capable of triggering T cells recognizing rat CII but only CB9 immunized mice responded well to mouse CII. Secondly, lymph node cells from CBA/1 mice immunized with rat and mouse CII were cultured with the CB fragments including rat CB10 and CB11, and the proliferative response was determined. After immunization with rat CH, the response was strongly dominated by T cells recognizing CB11 with equal responses against chick and rat CB11. After immunization with mouse CH only rat CB10 gave a strong response. It is concluded that several epitopes on the CH molecule can be recognized by T cells in the DBA/1 mouse and that most of these epitopes are shared by rat and chick CH but not mouse CH. These epitopes exhibit strong immunodominance. In mice immunized with intact heterologous CH, the immunodominant response is directed against one or more epitopes on the CB11 fragment present on several heterologous CH but apparently not on mouse CH. In mice immunized with autologous CH the immunodominant response is directed against one or more epitopes on the CBl0 fragment present on rat and mouse CH. They are either absent in chick CH or located in the carboxyterminal end of the CB10 fragment where a cyanogen bromide cleavage site is present in chick CH but not in rat CH. These results suggest that the proposed importance of CBH in collagen-induced arthritis is due to activation of T cells reactive with heterologous CH only. These cells may be important for the induction of the strong auto-antibody-response after immunization with heterologous CH. Structures of importance for direct T cell involvement in the arthritic process and recognized by autoreactive T cells are suggested to be found on CB10.
Scandinavian Journal of Immunology 06/2006; 33(5):505 - 510. · 2.23 Impact Factor
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ABSTRACT: It has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 protein that is involved in production of free oxygen radicals through the NADPH oxidase complex, which opens up a new pathway for therapeutic treatment of inflammatory diseases. In most cases, however, a quantitative trait locus (QTL) is the sum effect of several genes within and outside the QTL, which make positional cloning difficult. Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders.
Current topics in microbiology and immunology 02/2006; 305:259-76. · 4.93 Impact Factor
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R Holmdahl
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ABSTRACT: Inflammation is a physiological response that may go uncontrolled and thereby develop in a chronic way. This seems to happen in many common diseases of autoimmune, degenerative, or allergic character. Rheumatoid arthritis (RA) is by definition a chronic disease with an autoimmune inflammatory attack on diarthrodial cartilaginous joints. The development of new treatment neutralizing cytokines involved in the inflammatory attack has given relief and gives the promise of more effective treatment of already established disease. It is now time to set our eyes on a new vision to develop preventive and curative treatment based on knowledge of the unique and causative pathogenic mechanisms. To do this we believe it is important to identify the natural-selected polymorphisms that are associated with disease. These have proven to be extremely difficult to identify in complex diseases such as RA, but using animal models, this work is closer to reality. Animal models have recently been developed mimicking various aspects of the human disease. We will present an example in which a genetic polymorphism associated with the development of arthritis has been identified. On the basis of this finding, a new pathway involving control of immune tolerance by reactive oxidative species has been identified and a new class of antiinflammatory agents activating the induced oxidative burst protein complex is suggested.
Ernst Schering Foundation symposium proceedings. 02/2006;
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ABSTRACT: One of the major quantitative trait loci (QTLs) associated with arthritis in crosses between B10.RIII and RIIIS/J mice is the Cia5 on chromosome 3. Early in the congenic mapping process it was clear that the locus was complex, consisting of several subloci with small effects. Therefore, we developed two novel strategies to dissect a QTL: the partial advanced inter-cross (PAI) strategy, with which we recently found the Cia5 region to consist of three loci, Cia5, Cia21 and Cia22, and now we introduce the QTL-chip strategy, where we have combined congenic mapping with a QTL-restricted expression profiling using a novel microarray design. The expression of QTL genes was compared between parental and congenic mice in lymph node, spleen and paw samples in five biological replicates and in dye-swapped experiments at three time points during the induction phase of arthritis. The QTL chip approach revealed 4 genes located in Cia21, differently expressed in lymph nodes, and 14 genes in Cia22, located within two clusters. One cluster contains six genes, differently expressed in spleen, and the second cluster contains eight genes, differently expressed in paws. We conclude the QTL-chip strategy to be valuable in the selection of candidate genes to be prioritized for further investigation.
Genes and Immunity 11/2005; 6(7):575-83. · 3.87 Impact Factor
