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- Ahlqvist, Emma, et al.
(författare)
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Fragmentation of two quantitative trait loci controlling collagen-induced arthritis reveals a new set of interacting subloci
- 2007
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Ingår i: Journal of Immunology. - 1550-6606. ; 178:5, s. 3084-3090
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Tidskriftsartikel (refereegranskat)abstract
- Linkage analysis of F-2 crosses has led to identification of large numbers of quantitative trait loci (QTL) for complex diseases, but identification of the underlying genes has been more difficult. Reasons for this could be complications that arise from separation of interacting or neighboring loci. We made a partial advanced intercross (PAI) to characterize and fine-map linkage to collagen-induced arthritis in two chromosomal regions derived from the DBA/1 strain and crossed into the B10.Q strain: Cia7 on chromosome 7 and a locus on chromosome 15. Only Cia7 was detected by a previous F-2 cross. Linkage analysis of the PAI revealed a different linkage pattern than the F-2 cross, adding multiple loci and strong linkage to the previously unlinked chromosome 15 region. Subcongenic strains derived from animals in the PAI confirmed the loci and revealed additional subloci. In total, no less than seven new loci were identified. Several loci interacted and three loci were protective, thus partly balancing the effect of the disease-promoting loci. Our results indicate that F-2 crosses do not reveal the full complexity of identified QTLs, and that detection is more dependent on the genetic context of a QTL than the potential effect of the underlying gene.
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2. |
- Bockermann, Robert, et al.
(författare)
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Imlifidase-generated Single-cleaved IgG : Implications for Transplantation
- 2022
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 106:7, s. 1485-1496
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Tidskriftsartikel (refereegranskat)abstract
- Background. Imlifidase is an immunoglobulin G (IgG)-specific protease conditionally approved in the EU for desensitization in highly sensitized crossmatch positive kidney transplant patients. Imlifidase efficiently cleaves both heavy chains of IgG in a 2-step process. However, low levels of the intermediate cleavage product, single-cleaved IgG (scIgG), may persist in the circulation. The study objective was to investigate Fc-mediated effector functions of scIgG and its potential impact on common clinical immunologic assays used to assess transplant eligibility.Methods. Imlifidase-generated scIgG, obtained by in vitro cleavage of HLA-sensitized patient serum or selected antibodies, was investigated in different complement- and Fc gamma R-dependent assays and models, including clinical tests used to evaluate HLA-specific antibodies.Results. ScIgG had significantly reduced Fc-mediated effector function compared with intact IgG, although some degree of activity in complement- and Fc gamma R-dependent models was still detectable. A preparation of concentrated scIgG generated from a highly HLA-sensitized individual gave rise to a positive signal in the anti-HLA IgG LABScreen, which uses anti-Fc detection, but was entirely negative in the C1qScreen. The same high-concentration HLA-binding scIgG preparation also generated positive complement-dependent cytotoxicity responses against 80%-100% of donor T and B cells, although follow-up titrations demonstrated a much lower intrinsic activity than for intact anti-HLA IgG.Conclusions. ScIgG has a significantly reduced capacity to mediate Fc-dependent effector functions. However, remaining HLA-reactive scIgG in plasma after imlifidase treatment can cause positive assay results equivalent to intact IgG in clinical assays. Therefore, complete IgG cleavage after imlifidase treatment is essential to allow correct decision-making in relation to transplant eligibility.
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4. |
- Bockermann, Robert, et al.
(författare)
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Type II collagen without adjuvant induces eosinophilic arthritis.
- 2007
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 37:2, s. 540-548
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilia is a characteristic feature of many inflammatory diseases including inflammatory bowel disease and asthma. It also occurs in a subtype of rheumatoid arthritis but the role of eosinophils has been unclear and animal models have been lacking. Here, we introduce a new mouse model to study the role of eosinophilia in arthritis. Intraperitoneal injection of type II collagen alone, without any adjuvant, was sufficient to induce chronic arthritis in a mouse with transgenic T cells specific for type II collagen. The arthritis was accompanied by infiltration of eosinophils into the synovial tissue and the disease could be blocked with neutralizing anti-IL-5 antibodies. To our knowledge, this is the first description of an eosinophilic disease form of destructive arthritis.
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6. |
- Bäcklund, Johan, et al.
(författare)
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Genetic control of tolerance to type II collagen and development of arthritis in an autologous collagen-induced arthritis model
- 2003
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 171:7, s. 3493-3499
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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7. |
- Bäcklund, Johan, et al.
(författare)
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Glycosylation of type II collagen is of major importance for T cell tolerance and pathology in collagen-induced arthritis.
- 2002
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Ingår i: European Journal of Immunology. - 1521-4141. ; 32:12, s. 3776-3784
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Tidskriftsartikel (refereegranskat)abstract
- Type II collagen (CII) is a candidate cartilage-specific autoantigen, which can become post-translationally modified by hydroxylation and glycosylation. T cell recognition of CII is essential for the development of murine collagen-induced arthritis (CIA) and also occurs in rheumatoid arthritis (RA). The common denominator of murine CIA and human RA is the presentation of an immunodominant CII-derived glycosylated peptide on murine Aq and human DR4 molecules, respectively. To investigate the importance of T cell recognition of glycosylated CII in CIA development after immunization with heterologous CII, we treated neonatal mice with different heterologous CII-peptides (non-modified, hydroxylated and galactosylated). Treatment with the galactosylated peptide (galactoseat position 264) was superior in protecting mice from CIA. Protection was accompanied by a reduced antibody response to CII and by an impaired T cell response to the glycopeptide. To investigate the importance of glycopeptide recognition in an autologous CIA model, we treated MMC-transgenic mice, which express the heterologous CII epitope with a glutamic acid in position 266 in cartilage, with CII-peptides. Again, a strong vaccination potential of the glycopeptide was seen. Hence CII-glycopeptides may be the optimal choice of vaccination target in RA, since humans share the same epitope as the MMC mouse
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8. |
- Holm, Lotta, et al.
(författare)
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Side-chain and backbone amide bond requirements for glycopeptide stimulation of T-cells obtained in a mouse model for rheumatoid arthritis
- 2006
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Ingår i: Bioorganic & Medicinal Chemistry. - Oxford : Elsevier BV. - 0968-0896 .- 1464-3391. ; 14:17, s. 5921-5932
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Tidskriftsartikel (refereegranskat)abstract
- Collagen induced arthritis (CIA) is the most studied animal model for rheumatoid arthritis and is associated with the MHC class II molecule A(q). T-cell recognition of a peptide from type II collagen, C11256-270, bound to A(q) is a requirement for development of CIA. Lysine 264 is the major T-cell recognition site of C11256-270 and CIA is in particular associated with recognition of lysine 264 after posttranslational hydroxylation and subsequent attachment of a beta-D-galactopyranosyl moiety. In this paper we have studied the structural requirements of collagenous glycopeptides required for T-cell stimulation, as an extension of earlier studies of the recognition of the galactose moiety. Synthesis and evaluation of alanine substituted glycopeptides revealed that there are T-cells that only recognise the galactosylated hydroxylysine 264, and no other amino acid side chains in the peptide. Other T-cells also require glutamic acid 266 as a T-cell contact point. Introduction of a methylene ether isostere instead of the amide bond between residues 260 and 261 allowed weaker recognition by some, but not all, of the T-cells. Altogether, these results allowed us to propose a model for glycopeptide recognition by the T-cells, where recognition from one or the other side of the galactose moiety could explain the different binding patterns of the T-cells. (c) 2006 Elsevier Ltd. All rights reserved.
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- Holmdahl, Rikard, et al.
(författare)
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The molecular pathogenesis of collagen-induced arthritis in mice--a model for rheumatoid arthritis.
- 2002
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Ingår i: Ageing Research Reviews. - 1872-9649. ; 1:1, s. 135-147
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Forskningsöversikt (refereegranskat)abstract
- The most widely used model for rheumatoid arthritis is the collagen-induced arthritis (CIA) in mice. This model has gained acceptance since it is reproducible, well defined and has proven useful for development of new therapies for rheumatoid arthritis, as exemplified by the most recent advancement using TNFalpha neutralization treatment. The collagen-induced arthritis model, however, represents only certain pathways leading to arthritis and there is no consensus on how they operate. Nevertheless, we are beginning to understand the immune recognition structures, such as MHC molecules, lymphocyte receptors and type II collagen epitopes, which are of crucial importance for the development of this disease. These provide useful tools for further investigations of the pathogenesis of CIA as well as for understanding the pathogenesis of rheumatoid arthritis.
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