| 1. |
- Dzhambazov, Balik, et al.
(författare)
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The major T cell epitope on type II collagen is glycosylated in normal cartilage but modified by arthritis in both rats and humans
- 2005
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 35:2, s. 357-366
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Tidskriftsartikel (refereegranskat)abstract
- Type II collagen (CII) is a target for autoreactive T cells in both rheumatoid arthritis and the murine model collagen-induced arthritis. The determinant core of CII has been identified as CII260-270, and the alteration of this T cell epitope by posttranslational modifications is known to be critical for development of arthritis in mice. Using CII-specific T cell hybridomas we have now shown that the immunodominant T cell epitope in the normal (healthy) human and rat joint cartilage is O-glycosylated at the critical T cell receptor recognition position 264 with a mono- or di-saccharide attached to a hydroxylysine. In contrast, in the arthritic human and rat joint cartilage there are both glycosylated and non-glycosylated CII forms. Glycosylated CII from normal cartilage could not be recognized by T cells reactive to peptides having only lysine or hydroxylysine at position 264, showing that antigen-presenting cells could not degrade the O-linked carbohydrate. Thus, the variable forms of the glycosylated epitope are determined by the structures present in cartilage, and these vary during the disease course. We conclude that the chondrocyte determines the structures presented to the immune system and that these structures are different in normal versus arthritic states.
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| 2. |
- Holmdahl, Meirav, et al.
(författare)
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Cysteine proteases in Langerhans cells limits presentation of cartilage derived type II collagen for autoreactive T cells.
- 2004
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Ingår i: International Immunology. - : Oxford University Press (OUP). - 1460-2377. ; 16:5, s. 717-726
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Tidskriftsartikel (refereegranskat)abstract
- Development of type-II collagen (CII)-induced arthritis (CIA) is dependent on activation of CII-reactive T cells. Dendritic cells (DCs) are believed to play a crucial role in antigen-specific priming of T cells but it is still unclear how the CII-reactive T cells are primed since Langerhans cells (LCs) are poor antigen-presenting cells for CII. In the present study we show that LCs, treated with cysteine protease inhibitors, are able to process and present CII to T-cell hybridomas specific for the immune-dominant glycosylated 259–270 peptide bound to the MHC class II molecule Aq. Interestingly, the self (mouse) CII peptide could also now be efficiently presented. The poor presentation by LCs is a peptide-specific effect, since both bovine CII (bCII) (presenting a different peptide on H-2r) and ovalbumin could be efficiently presented, and blockage of cysteine proteases did not enhance antigen presentation. The enhanced CII-presentation by cysteine protease inhibition is seen mainly in LCs and not in antigen-primed B cells or macrophages. B cell and macrophage presentation of CII occur even without protease inhibition and are only to a minor extent influenced by cysteine protease inhibition. These data suggest that a LC deficiency in processing of the immune-dominant CII epitope in both CIA and RA may limit the exposure of this self-antigen to T cells, but that presentation can be overcome by modulation of the peptide proteolysis during CII processing.
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| 3. |
- Holmdahl, Meirav, et al.
(författare)
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Primed B cells present type-II collagen to T cells.
- 2002
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 55:4, s. 382-389
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Tidskriftsartikel (refereegranskat)abstract
- Development of type-II collagen (CII)-induced arthritis (CIA) is dependent on a T-cell mediated activation of autoreactive B cells. However, it is still unclear if B cells can present CII to T cells. To investigate the role of B cells as antigen-presenting cells (APCs) for CII, we purified B cells from lymph nodes of immunized and nonimmunized mice. These B cells were used as APC for antigen-specific T-cell hybridomas. B cells from naïve mice did present native, triple-helical, CII (nCII) but also ovalbumin (OVA) and denatured CII (dCII) to antigen-specific T-cell hybridomas. In addition, B cells primed with nCII or OVA, but not dCII, activated the antigen-specific T-cell hybridomas two to three times better than naïve B cells. We conclude that antigen-primed B cells have the capacity to process and present CII to primed T cells, and antigen-primed antigen-specific B cells are more efficient as APC than naïve B cells. We further conclude that B cells have the potential to play an important role as APC in the development of CIA.
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| 4. |
- Holmdahl, Meirav, et al.
(författare)
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Structure-Immune Response Relationships of Hapten-Modified Collagen II Peptides in a T-Cell Model of Allergic Contact Dermatitis.
- 2008
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Ingår i: Chemical Research in Toxicology. - : American Chemical Society (ACS). - 1520-5010 .- 0893-228X. ; 21, s. 1514-1523
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Tidskriftsartikel (refereegranskat)abstract
- Allergic contact dermatitis (ACD) is mediated by T cells that specifically recognize hapten-modified peptides. T cells are known to recognize antigens as short processed peptides bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APC). It has previously been demonstrated that T cells can specifically recognize carbohydrates on the lysine at position 264 of the immunodominant (256-273) sequence from type II collagen (CII) and that such recognition is critical for the development of arthritis in mice and may play a role in rheumatoid arthritis in humans. In the present study, we have used this approach in modeling ACD, but instead of the carbohydrate, the strong sensitizer 2,4-dinitrofluorobenzene (DNFB) is bound to the epsilon-amine of the lysine at position 264. Specific T-cell hybridomas of this antigenic peptide, with dinitrophenyl (Dnp) on the epsilon-amine of lysine at position 264 (CIILysDnp 3), were established from mice immunized with CIILysDnp 3. In an immune response assay, these T-cell hybridomas were tested with a series of new synthetic hapten-modified peptides, all chemically identical except for the stereochemimistry ( d, l) and the length of the position-264 amino acid side chain bonding the hapten. The T-cell hybridomas recognized the CIILysDnp 3 peptide used for immunization; interestingly, they also recognized the CII peptide with a one-carbon-longer side chain (homolysine), CIIhLysDnp 6, and CIIAlaPipDnp 11, having a ring structure analogous to that of lysine with the same number of carbons in the bonding chain as in the CIILysDnp 3 peptide used for immunization. Dnp-modified CII peptides with a shorter bonding chain produced no immune response. These data demonstrate that the T-cell recognition of the Dnp-modified peptides is highly specific and moreover dependent on the length of the amino acid side chain that bonds the Dnp.
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| 5. |
- Khmaladze, Ia, et al.
(författare)
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Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:35, s. E3669-E3678
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Tidskriftsartikel (refereegranskat)abstract
- Psoriasis (Ps) and psoriasis arthritis (PsA) are poorly understood common diseases, induced by unknown environmental factors, affecting skin and articular joints. A single i.p. exposure to mannan from Saccharomyces cerevisiae induced an acute inflammation in inbred mouse strains resembling human Ps and PsA-like disease, whereas multiple injections induced a relapsing disease. Exacerbation of disease severity was observed in mice deficient for generation of reactive oxygen species (ROS). Interestingly, restoration of ROS production, specifically in macrophages, ameliorated both skin and joint disease. Neutralization of IL-17A, mainly produced by gammadelta T cells, completely blocked disease symptoms. Furthermore, mice depleted of granulocytes were resistant to disease development. In contrast, certain acute inflammatory mediators (C5, Fcgamma receptor III, mast cells, and histamine) and adaptive immune players (alphabeta T and B cells) were redundant in disease induction. Hence, we propose that mannan-induced activation of macrophages leads to TNF-alpha secretion and stimulation of local gammadelta T cells secreting IL-17A. The combined action of activated macrophages and IL-17A produced in situ drives neutrophil infiltration in the epidermis and dermis of the skin, leading to disease manifestations. Thus, our finding suggests a new mechanism triggered by exposure to exogenous microbial components, such as mannan, that can induce and exacerbate Ps and PsA.
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| 6. |
- 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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| 7. |
- Ahlqvist, Emma, et al.
(författare)
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High-resolution mapping of a complex disease, a model for rheumatoid arthritis, using heterogeneous stock mice
- 2011
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Ingår i: Human Molecular Genetics. - Oxford : Oxford University Press. - 0964-6906 .- 1460-2083. ; 20:15, s. 3031-3041
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Tidskriftsartikel (refereegranskat)abstract
- Resolving the genetic basis of complex diseases like rheumatoid arthritis will require knowledge of the corresponding diseases in experimental animals to enable translational functional studies. Mapping of quantitative trait loci in mouse models of arthritis, such as collagen-induced arthritis (CIA), using F(2) crosses has been successful, but can resolve loci only to large chromosomal regions. Using an inbred-outbred cross design, we identified and fine-mapped CIA loci on a genome-wide scale. Heterogeneous stock mice were first intercrossed with an inbred strain, B10.Q, to introduce an arthritis permitting MHCII haplotype. Homozygous H2(q) mice were then selected to set up an F(3) generation with fixed major histocompatibility complex that was used for arthritis experiments. We identified 26 loci, 18 of which are novel, controlling arthritis traits such as incidence of disease, severity and time of onset and fine-mapped a number of previously mapped loci. © The Author 2011. Published by Oxford University Press. All rights reserved.
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| 8. |
- Ahlqvist, Emma, et al.
(författare)
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The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis.
- 2009
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 11:3
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Forskningsöversikt (refereegranskat)abstract
- ABSTRACT: For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future.
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| 9. |
- Amirahmadi, S. F., et al.
(författare)
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Arthritogenic anti-type II collagen antibodies are pathogenic for cartilage-derived chondrocytes independent of inflammatory cells
- 2005
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 52:6, s. 1897-1906
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Some monoclonal antibodies (mAb) to type II collagen (CII) are arthritogenic upon passive transfer to mice. We undertook this study to investigate whether such mAb are pathogenic in the absence of mediators of inflammation. METHODS: The arthritogenic mAb CIIC1 and M2139, and the nonarthritogenic mAb CIIF4, each reactive with a distinct and well-defined conformational epitope on CII, were compared with control mAb GAD6. Bovine chondrocytes were cultured with one of the mAb, and on days 3, 6, and 9, antibody binding by chondrocytes and newly synthesized extracellular matrix (ECM) was examined by immunofluorescence, morphologic effects were studied by electron microscopy, and synthesis of matrix components was determined by metabolic labeling with (3)H-proline for collagen and (35)S-sulfate for proteoglycans. RESULTS: All 3 mAb to CII bound to the matrix. CIIC1 and M2139 adversely affected the cultures, whereas CIIF4 did not. CIIC1 caused disorganization of CII fibrils in the ECM without affecting chondrocyte morphology, and increased matrix synthesis. M2139 caused thickening and aggregation of CII fibrils in the ECM and abnormal chondrocyte morphology but matrix synthesis was unaffected. CONCLUSION: The unique arthritogenic capacity of particular anti-CII mAb upon passive transfer could be explained by their adverse, albeit differing, effects in primary cultures of chondrocytes. Such effects occur independent of inflammation mediators and are related to the epitope specificity of the mAb. Interference with the structural integrity of CII could precede, and even initiate, the inflammatory expression of disease.
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| 10. |
- Andersson, Ida E, 1982-, et al.
(författare)
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Design of glycopeptides used to investigate class II MHC binding and T-Cell responses associated with autoimmune arthritis
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 6:3, s. e17881-
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Tidskriftsartikel (refereegranskat)abstract
- The glycopeptide fragment CII259–273 from type II collagen (CII) binds to the murine Aq and human DR4 class II Major Histocompatibility Complex (MHC II) proteins, which are associated with development of murine collagen-induced arthritis (CIA) and rheumatoid arthritis (RA), respectively. It has been shown that CII259–273 can be used in therapeutic vaccination of CIA. This glycopeptide also elicits responses from T-cells obtained from RA patients, which indicates that it has an important role in RA as well. We now present a methodology for studies of (glyco)peptide-receptor interactions based on a combination of structure-based virtual screening, ligand-based statistical molecular design and biological evaluations. This methodology included the design of a CII259–273 glycopeptide library in which two anchor positions crucial for binding in pockets of Aq and DR4 were varied. Synthesis and biological evaluation of the designed glycopeptides provided novel structure-activity relationship (SAR) understanding of binding to Aq and DR4. Glycopeptides that retained high affinities for these MHC II proteins and induced strong responses in panels of T-cell hybridomas were also identified. An analysis of all the responses revealed groups of glycopeptides with different response patterns that are of high interest for vaccination studies in CIA. Moreover, the SAR understanding obtained in this study provides a platform for the design of second-generation glycopeptides with tuned MHC affinities and T-cell responses.
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| 11. |
- Andersson, Ida E., 1982-, et al.
(författare)
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(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition
- 2011
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 133:36, s. 14368-14378
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Tidskriftsartikel (refereegranskat)abstract
- The structural basis for antigen presentation by class II major histocompatibility complex (MHC) proteins to CD4(+) T-cells is important for understanding and possibly treating autoimmune diseases. In the work described in this paper, (E)-alkene and ethylene amide-bond isosteres were used to investigate the effect of removing hydrogen-bonding possibilities from the CII259-270 glycopeptide, which is bound by the arthritis-associated murine A(q) class II MHC protein. The isostere-modified glycopeptides showed varying and unexpectedly large losses of A(q) binding that could be linked to the dynamics of the system. Molecular dynamics (MD) simulations revealed that the backbone of CII259-270 and the A(q) protein are able to form up to 11 hydrogen bonds, but fewer than this number are present at any one time. Most of the strong hydrogen-bond interactions were formed by the N-terminal part of the glycopeptide, i.e., in the region where the isosteric replacements were made. The structural dynamics also revealed that hydrogen bonds were strongly coupled to each other; the loss of one hydrogen-bond interaction had a profound effect on the entire hydrogen-bonding network. The A(q) binding data revealed that an ethylene isostere glycopeptide unexpectedly bound more strongly to A(q) than the corresponding (E)-alkene, which is in contrast to the trend observed for the other isosteres. Analysis of the MD trajectories revealed that the complex conformation of this ethylene isostere was structurally different and had an altered molecular interaction pattern compared to the other A(q)/glycopeptide complexes. The introduced amide-bond isosteres also affected the interactions of the glycopeptide/A(q) complexes with T-cell receptors. The dynamic variation of the patterns and strengths of the hydrogen-bond interactions in the class II MHC system is of critical importance for the class II MHC/peptide/TCR signaling system.
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| 12. |
- Andersson, Ida E., 1982-, et al.
(författare)
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Oxazole-modified glycopeptides that target arthritis-associated class II MHC Aq and DR4 proteins
- 2010
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Ingår i: Organic and biomolecular chemistry. - : RSC Publishing. - 1477-0520 .- 1477-0539. ; 8:13, s. 2931-2940
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Tidskriftsartikel (refereegranskat)abstract
- The glycopeptide CII259-273, a fragment from type II collagen (CII), can induce tolerance in mice susceptible to collagen-induced arthritis (CIA), which is a validated disease model for rheumatoid arthritis (RA). Here, we describe the design and synthesis of a small series of modified CII259-273 glycopeptides with oxazole heterocycles replacing three potentially labile peptide bonds. These glycopeptidomimetics were evaluated for binding to murine CIA-associated A(q) and human RA-associated DR4 class II major histocompatibility complex (MHC) proteins. The oxazole modifications drastically reduced or completely abolished binding to A(q). Two of the glycopeptidomimetics were, however, well tolerated in binding to DR4 and they also induced strong responses by one or two DR4-restricted T-cell hybridomas. This work contributes to the development of an altered glycopeptide for inducing immunological tolerance in CIA, with the long-term goal of developing a therapeutic vaccine for treatment of RA.
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| 13. |
- Andersson, Ida E., 1982-, et al.
(författare)
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Probing Molecular Interactions within Class II MHC A(q)/Glycopeptide/T-Cell Receptor Complexes Associated with Collagen-Induced Arthritis.
- 2007
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 50:23, s. 5627-5643
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Tidskriftsartikel (refereegranskat)abstract
- T cells obtained in a mouse model for rheumatoid arthritis are activated by a glycopeptide fragment from rat type II collagen (CII) bound to the class II major histocompatibility complex A(q) molecule. We report a comparative model of A(q) in complex with the glycopeptide CII260-267. This model was used in a structure-based design approach where the amide bond between Ala(261) and Gly(262) in the glycopeptide was selected for replacement with psi[COCH2], psi[CH2NH2+], and psi[(E)-CH=CH] isosteres. Ala-Gly isostere building blocks were then synthesized and introduced in CII260-267 and CII259-273 glycopeptides. The modified glycopeptides were evaluated for binding to the A(q) molecule, and the results were interpreted in view of the A(q)/glycopeptide model. Moreover, recognition by a panel of T-cell hybridomas revealed high sensitivity for the backbone modifications. These studies contribute to the understanding of the interactions in the ternary A(q)/glycopeptide/T-cell receptor complexes that activate T cells in autoimmune arthritis and suggest possibilities for new vaccination approaches.
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| 14. |
- Andersson, Maria L.E., et al.
(författare)
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Autoantibodies to Disease-Related Proteins in Joints as Novel Biomarkers for the Diagnosis of Rheumatoid Arthritis
- 2023
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:7, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- Objective. This study was undertaken to develop and characterize a multiplex immunoassay for detection of autoantibodies against peptides derived from proteins known to play a role in development of arthritis and that are also expressed in joints.Methods. We selected peptides from the human counterpart of proteins expressed in the joints, based on mouse models that showed these to be targeted by pathogenic or regulatory antibodies in vivo. Using bead-based flow immunoassays measuring IgG antibodies, we selected triple helical or cyclic peptides, containing the epitopes, to avoid collinear reactivity. We characterized the analytical performance of the immunoassay and then validated it in 3 independent rheumatoid arthritis (RA) cohorts (n = 2,110), Swedish age- and sex-matched healthy controls, and patients with osteoarthritis (OA), patients with psoriatic arthritis (PsA), and patients with systemic lupus erythematosus (SLE).Results. Screening assays showed 5 peptide antigens that discriminated RA patients from healthy controls with 99% specificity (95% confidence interval [CI] 98-100%). In our validation studies, we reproduced the discriminatory capacity of the autoantibodies in 2 other RA cohorts, showing that the autoantibodies had high discriminatory capacity for RA versus OA, PsA, and SLE. The novel biomarkers identified 22.5% (95% CI 19-26%) of early RA patients seronegative for anti-cyclic citrullinated peptide and rheumatoid factor. The usefulness of the biomarkers in identifying seronegative RA patients was confirmed in validation studies using 2 independent cohorts of RA patients and cohorts of patients with OA, PsA, and SLE.Conclusion. A multiplex immunoassay with peptides from disease-related proteins in joints was found to be useful for detection of specific autoantibodies in RA serum. Of note, this immunoassay had high discriminatory capacity for early seronegative RA.
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| 15. |
- Andersson, Sofia E M, 1979, et al.
(författare)
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Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis
- 2016
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance. Methods: To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used. Results: Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naive mice ameliorated the development of CII-induced arthritis. Conclusion: Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.
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| 16. |
- Andersson, Åsa, et al.
(författare)
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A genetic basis for shared autoimmunity in mouse models.
- 2005
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Ingår i: Autoimmunity. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 38:3, s. 209-217
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Forskningsöversikt (refereegranskat)abstract
- Development of autoimmune disease is the result of activation of the immune system that subsequently leads to tissue destruction. Although the clinical outcome significantly differs between autoimmune diseases, some pathogenic pathways could be shared. During the recent years, intense efforts to find the genetic factors behind development of the complex and polygenic autoimmune diseases have been undertaken. The difficulties in addressing what genetic factors predispose for autoimmunity in humans underline the importance of animal models in the understanding of the general mechanisms behind the initiation of disease. Interestingly, it has been observed in studies of experimental models of autoimmune diseases, that many of the genetic linkages to disease development are located in the same genetic regions and potentially could be controlled by the same gene. Furthermore, comparison of the mouse/rat genetic regions with regions of association to human inflammatory diseases, also demonstrates some homologous loci between species. Some mouse strains can develop disease in more than one model for autoimmunity. This not only argues for some general mechanisms, but it also supports mechanisms related to the specific tissues attacked in the various autoimmune diseases. Here, we will discuss some aspects of shared autoimmunity in mouse models from a genetic point of view.
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| 17. |
- Bajtner, Estelle, et al.
(författare)
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Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen
- 2005
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7, s. R1148-R1157
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 18. |
- Bauer, K, et al.
(författare)
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Perforin deficiency attenuates collagen-induced arthritis
- 2005
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:4, s. 877-884
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Tidskriftsartikel (refereegranskat)abstract
- Collagen-induced arthritis ( CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8(+) T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8(+) T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp(-/-), and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp(+/+), 64%; DBA/1J-pfp(-/-), 54%), a slightly delayed onset ( onset of disease: DBA/1J-pfp(+/+), 53 +/- 3.6; DBA/1J-pfp(-/-), 59 +/- 4.9 ( mean SEM), and milder form of the disease ( maximum disease score: DBA/1J-pfp(+/+), 7.3 +/- 1.1; DBA/1J-pfp(-/-), 3.4 +/- 1.4 ( mean SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp(-/-) mice compared with pfp(+/+) mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA.
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| 19. |
- Becanovic, K, et al.
(författare)
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Advanced intercross line mapping of Eae5 reveals Ncf-1 and CLDN4 as candidate genes for experimental autoimmune encephalomyelitis
- 2006
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 176:10, s. 6055-6064
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Tidskriftsartikel (refereegranskat)abstract
- Eae5 in rats was originally identified in two F-2 intercrosses, (DA x BN) and (E3 X DA), displaying linkage to CNS inflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), respectively. This region overlaps with an arthritis locus, Pia4, which was also identified in the (E3 X DA) cross. Two congenic strains, BN.DA-Eae5 and BN.DA-Eae5.R1, encompassing the previously described Eae5 and Pia4, were established. DA alleles within the chromosome 12 fragment conferred an increase in disease susceptibility as well as increased inflammation and demyelination in the CNS as compared with BN alleles. To enable a more precise fine mapping of EAE regulatory genes, we used a rat advanced intercross line between the EAE-susceptible DA strain and the EAE-resistant PVG.1AV1 strain. Linkage analysis performed in the advanced intercross line considerably narrowed down the myelin oligodendrocyte glycoprotein-EAE regulatory locus (Eae5) to a similar to 1.3-megabase region with a defined number of candidate genes. In this study we demonstrate a regulatory effect of Eae5 on MOG-EAE by using both congenic strains as well as fine mapping these effects to a region containing Ncf-1, a gene associated with arthritis. In addition to structural polymorphisms in Ncf-1, both sequence polymorphisms and expression differences were identified in CLDN4. CLDN4 is a tight junction protein involved in blood-brain barrier integrity. In conclusion, our data strongly suggests Ncf-1 to be a gene shared between two organ-specific inflammatory diseases with a possible contribution by CLDN4 in encephalomyelitis.
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| 20. |
- Becanovic, K, et al.
(författare)
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New loci regulating rat myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis
- 2003
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 1550-6606 .- 0022-1767. ; 170:2, s. 1062-1069
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Tidskriftsartikel (refereegranskat)abstract
- Myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in rats that closely mimics many clinical and histopathological aspects of multiple sclerosis. Non-MHC quantitative trait loci regulating myelin oligodendrocyte glycoprotein-induced EAE have previously been identified in the EAE-permissive strain, DA, on rat chromosomes 4,10,15, and 18. To find any additional gene loci in another well-known EAE-permissive strain and thereby to assess any genetic heterogeneity in the regulation of the disease, we have performed a genome-wide linkage analysis in a reciprocal (LEW.1AV1 x PVG.1AV1) male/female F-2 population (n = 185). We examined reciprocal crosses, but no parent-of-origin effect was detected. The parental rat strains share the RT1(av1) MHC haplotype; thus, non-MHC genes control differences in EAE susceptibility. We identified Eae(16) on chromosome 8 and Eae17 on chromosome 13, significantly linked to EAE phenotypes. Two loci, on chromosomes 1 and 17, respectively showed suggestive linkage to clinical and histopathological EAE phenotypes. Eae16 and Eae17 differ from those found in previously studied strain combinations, thus demonstrating genetic heterogeneity of EAE. Furthermore, we detected a locus-specific parent-of-origin effect with suggestive linkage in Eae17. Further genetic and functional dissection of these loci may disclose critical disease-regulating molecular mechanisms.
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| 21. |
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| 22. |
- Bersellini Farinotti, Alex, et al.
(författare)
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Cartilage-binding antibodies induce pain through immune complex-mediated activation of neurons
- 2019
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 216:8, s. 1904-1924
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis-associated joint pain is frequently observed independent of disease activity, suggesting unidentified pain mechanisms. We demonstrate that antibodies binding to cartilage, specific for collagen type II (CII) or cartilage oligomeric matrix protein (COMP), elicit mechanical hypersensitivity in mice, uncoupled from visual, histological and molecular indications of inflammation. Cartilage antibody-induced pain-like behavior does not depend on complement activation or joint inflammation, but instead on tissue antigen recognition and local immune complex (IC) formation. smFISH and IHC suggest that neuronal Fcgr1 and Fcgr2b mRNA are transported to peripheral ends of primary afferents. CII-ICs directly activate cultured WT but not FcRγ chain-deficient DRG neurons. In line with this observation, CII-IC does not induce mechanical hypersensitivity in FcRγ chain-deficient mice. Furthermore, injection of CII antibodies does not generate pain-like behavior in FcRγ chain-deficient mice or mice lacking activating FcγRs in neurons. In summary, this study defines functional coupling between autoantibodies and pain transmission that may facilitate the development of new disease-relevant pain therapeutics.
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| 23. |
- Blom, Anna, et al.
(författare)
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C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice
- 2009
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 68:1, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 24. |
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| 25. |
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| 26. |
- 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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| 27. |
- Boeiers, Ulrika, et al.
(författare)
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Collagen type II is recognized by a pathogenic antibody through germline encoded structures
- 2008
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Ingår i: European Journal of Immunology. - : Wiley. - 1521-4141 .- 0014-2980. ; 38:10, s. 2784-2795
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Tidskriftsartikel (refereegranskat)abstract
- Collagen type II (CII) is a cartilage-specific target of pathologic humoral autoimmune responses in rheumatoid arthritis as well as in the collagen-induced arthritis model. The aim of the present study is to investigate the critical amino acid residues conferring CII epitope specificity of the prototypic arthritogenic murine mAb CIIC1. A homology model of the CIIC1 single-chain antibody fragment (CIIC1scFv) in complex with its triple helical epitope was established. in silico predictions based on extensive molecular dynamics simulations were experimentally tested by the recombinant expression and functional analysis of CIIC1scFv containing alanine replacements allowing the identification of crucial CII-binding sites in the CDR2 and CDR3 regions of both heavy and light chains. Since the conversion of the CIIC1scFv sequence into the respective germline at all 13 somatically mutated positions did not affect its CII binding, our data indicate that potentially harmful cartilage-specific humoral autoimmunity could be germline encoded. The molecular modeling further demonstrates that the rigid collagen triple helix restricts the likelihood of molecular interactions with the CDR regions of the antibody considerably compared with globular antigens. These sterical constraints provide an explanation as to why somatic mutations in the arthritogenic autoantibody have no obvious impact on CII recognition.
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| 28. |
- Boman, Antonia, et al.
(författare)
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Antibodies against citrullinated peptides are associated with clinical and radiological outcomes in patients with early rheumatoid arthritis : a prospective longitudinal inception cohort study
- 2019
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 5:2
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Anticitrullinated peptide antibody (ACPA) responses for 22 citrullinated peptides in patients with early rheumatoid arthritis (RA) were analysed and related to radiological and clinical outcome during the first 2 years in a prospective inception cohort.Methods: The ACPA reactivities were assessed in 1022 patients with early RA (symptoms <12 months) using the custom-made microarray chip (Thermo Fisher Scientific, Uppsala, Sweden) in a prospective longitudinal study of observational assessments of Disease Activity Score (DAS28 and its components) and radiology during the first 24 months, accounting for the treatment.Results: Frequency of ACPA reactivities varied between 13.3% and 63.1%. Of the anticyclic citrullinated peptide-2 (anti-CCP2) antibody-negative patients, ACPA reactivities were positive in 32.6%. Smoking, human leucocyte antigen-shared epitope (HLA-SE), anti-CCP2/rheumatoid factor, protein tyrosine phosphatase non-receptor type 22 (1858C/T) and DAS28 were significantly associated with number of ACPA reactivities. The ACPA reactivities modified differently the development of DAS28 over 24 months (identified using trajectories). Anti-Filaggrin307-324, anti-hnRNP (Peptide)-Z1 and anti-F4-CIT-R antibodies anticipated lower DAS28 values (p<0.01–0.05), while positivity for anti-Fibrinogen(Fib)β62-78(74), and anti-Fibα563-583 predicted higher DAS28 (p<0.01 both). Interaction between anti-Fibß36-52, anti-Pept-5 and anti-Bla-26 antibodies, respectively, and DAS28 during 24 months decreased significantly the DAS28 values (p<0.01–0.05). Corticosteroids and biologicals were related to DAS28-area under the curve and Larsen score 24 months. Anti-vimentin2-17 antibodies remained significantly associated with Larsen score at baseline and 24 months, respectively, and radiological progression, besides biologicals at 24 months adjusted for sex and age.Conclusions: Several ACPA reactivities modified significantly the DAS28 development during the first 24 months and were significantly associated with Larsen score at baseline, 24 months and radiological progression.
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| 29. |
- Bonner, Michael Y., et al.
(författare)
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Formyl peptide receptor (FPR) agonists promote immune evasion independent of functional Ncf1 derived ROS
- 2020
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 204:1_Supplement, s. 242.46-242.46
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that in both the absence of the Ncf1 gene or in the presence of a loss-of-function SNP, mice have a lower tumor burden when compared to wildtype animals. Here, we investigate a formyl peptide receptor (FPR) agonist in this setting and demonstrate that it promotes tumor immune evasion through an immune-Ncf1/ROS-dependent mechanism. We observed an increased colonization of B16F10 tumor cells in the lungs of FPR-agonist-treated wildtype C57BL6N mice compared to vehicle-control-treated mice. A significant reduction in tumor burden was expectedly seen in the Ncf1*/* mutant strain compared to the wildtype. However, FPR-agonist treatment did not promote tumor growth in Ncf1*/* treated mice when compared to vehicle-control-treated Ncf1*/* mice. These results suggest that FPR agonists can promote tumor evasion by acting through FPRs on immune cells in a NOX2/ROS-independent fashion and in a fashion independent of FPRs on the tumor.
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| 30. |
- Brink, Mikael, et al.
(författare)
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Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage
- 2015
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- The presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2. Methods: A total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia). Results: The concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P < 0.001) and also increased significantly after disease onset (P < 0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P < 0.05, all). Conclusions: The results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.
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| 31. |
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| 32. |
- Brink, Mikael, et al.
(författare)
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Multiplex Analyses of Antibodies Against Citrullinated Peptides in Individuals Prior to Development of Rheumatoid Arthritis
- 2013
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 65:4, s. 899-910
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Tidskriftsartikel (refereegranskat)abstract
- Objective The presence of antibodies against cyclic citrullinated peptides has been demonstrated to precede the onset of symptoms of rheumatoid arthritis (RA) by several years. The aim of this study was to analyze antibodies against 10 citrullinated autoantigen-derived peptides for reactivity before the onset of RA symptoms. Methods A casecontrol study was conducted within the Medical Biobank of Northern Sweden. The study was performed in 409 individuals, 386 of whom donated 717 blood samples before the onset of symptoms of RA (pre-patients). The median period of time predating the onset of RA was 7.4 years. A total of 1,305 population-based control subjects were also studied. Antibodies to 10 citrullinated peptides, fibrinogen 573 (Fib573), Fib591, Fib3652, Fib72, Fib74, -enolase (citrullinated -enolase peptide 1 [CEP-1]), triple-helical type II collagen peptide C1 (citC1III), filaggrin, vimentin 217 (Vim217), and Vim6075, were analyzed using a microarray system. Results The fluorescence intensity of antibodies against Fib3652, Fib74, CEP-1, citC1III, and filaggrin was significantly increased in pre-patients compared with controls (P < 0.001). The levels of the earliest-detectable antibodies (Fib591 and Vim6075) fluctuated over time, with only a slight increase after the onset of disease. The frequency of antibodies against Fib3652, CEP-1, and filaggrin increased gradually, reaching the highest levels before symptom onset. The frequency of a cluster of antibodies, citC1III, Fib573, and Fib74, increased only slightly before the onset of symptoms but increased prominently after disease onset. The odds ratio for the development of RA in individuals expressing both CEP-1 and Fib3652 antibodies (using data from samples obtained <3.35 years predating symptom onset) was 40.4 (95% confidence interval 19.882.3) compared with having either antibody alone. Conclusion Development of an immune response toward citrullinated peptides is initially restricted but expands with time to induce a more specific response, with levels, particularly those of antibodies against CEP-1, Fib3652, and filaggrin, increasing during the predating time period closer to the onset of symptoms.
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| 33. |
- Brink, Mikael, et al.
(författare)
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Rheumatoid factor isotypes in relation to antibodies against citrullinated peptides and carbamylated proteins before the onset of rheumatoid arthritis
- 2016
-
Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362. ; 18
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The presence of rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and antibodies against citrullinated protein and peptides (ACPA) precedes the onset of symptoms of rheumatoid arthritis (RA) by several years. Relationships between the development of these antibodies are not obvious. Methods: Three isotypes [immunoglobulin A (IgA), IgG and IgM) of RF were analysed in 321 pre-symptomatic individuals who provided 598 samples collected a median of 6.2 (interquartile range 7.2) years before the onset of symptoms, and in 492 population control subjects. All samples were donated to the Biobank of Northern Sweden. RF isotypes were analysed using the EliA system (Phadia GmbH, Freiburg, Germany) with 96 % specificity according to receiver operating characteristic curves. Ten ACPA specificities were analysed using the ImmunoCAP ISAC system, and anti-CCP2 and anti-CarP antibodies were evaluated using enzyme-linked immunosorbent assays. Results: The frequencies of RF isotypes in pre-symptomatic individuals were significantly increased compared with control subjects (p < 0.0001). In samples collected >= 15 years before the onset of symptoms, the IgA-RF isotype was significantly more prevalent than the most frequent ACPAs. Combinations of IgM- and IgA-RF isotypes with ACPA specificities [a-enolase (CEP-1/Eno(5-21))], fibrinogen (Fib)beta(36-52), Fiba(580-600), filaggrin (CCP-1/Fil(307-324)) and anti-CCP2 antibodies were associated with a significantly shorter time to onset of symptoms (p < 0.001-0.05). Using conditional inference tree analysis, anti-CCP2 in combination with anti-filaggrin antibodies gave the highest probability, 97.5 %, for disease development. Conclusions: RF isotypes predicted the development of RA, particularly in combination with ACPA, anti-CCP2 or anti-CarP antibodies. The highest probability for disease development was the presence of anti-CCP2 and anti-filaggrin antibodies.
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| 34. |
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| 35. |
- Burkhardt, H., et al.
(författare)
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Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse
- 2002
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 46:9, s. 2339-2348
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To analyze the fine specificity of IgG autoantibodies in sera from rheumatoid arthritis (RA) patients for type II collagen (CII) epitopes that are arthritogenic in collagen-induced arthritis (CIA), a relevant murine model of RA. METHODS: For enzyme-linked immunosorbent assay (ELISA) analysis of conformation-dependent autoantibody binding, recombinant chimeric collagens that harbor the respective CII epitopes as an insertion within the frame of a constant type X collagen triple helix were constructed. In addition, synthetic peptides mimicking the native collagen structures were applied for the first time in the ELISA assessment of humoral CII autoimmunity. RESULTS: The pathogenicity of IgG responses to certain CII determinants in CIA was demonstrated by arthritis development in BALB/c mice upon the combined transfer of 2 mouse monoclonal antibodies specific for precisely mapped conformational CII epitopes (amino acid residues 359-369 [C1(III)] and 551-564 [J1]), whereas antibodies to another epitope (F4) were not arthritogenic. To test whether human autoimmune responses are similarly directed to these conserved CII determinants, serum IgG was analyzed. The prevalence of sera with increased IgG binding to the C1(III) epitope was significantly higher in RA compared with sera from healthy donors or from patients with other rheumatic conditions, e.g., osteoarthritis (OA), systemic lupus erythematosus (SLE), or relapsing polychondritis (RP), whereas levels of antibodies specific for the nonarthritogenic F4 epitope were associated with OA rather than RA. CONCLUSION: Autoimmunity to CII, although detectable in different rheumatic conditions, differs in fine specificity between distinct disease entities. In RA, in contrast to degenerative joint disease, RP, and SLE, autoantibody responses are directed to an evolutionary conserved CII structure that is also targeted by pathogenic autoimmune responses in murine models of arthritis.
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| 36. |
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| 37. |
- 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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| 38. |
- 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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| 39. |
- Bäcklund, Johan, et al.
(författare)
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Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis.
- 2002
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 99:15, s. 9960-9965
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is associated with certain MHC class II alleles and is characterized by a chronic autoimmune response in the joints. Using transgenic mice expressing human DR4 (DRB1*0401) and human CD4, but lacking endogenous MHC class II, we show that posttranslational glycosylation of type II collagen (CII) influences the level of T cell tolerance to this candidate cartilage-specific autoantigen. In such mice, the expression of human CII resulted in a tolerized murine T cell response to human CII. However, tolerance induction remained incomplete, preferentially deleting responses to the nonmodified CII 263-270 epitope, whereas T cell recognition of a glycosylated variant of this epitope was affected to a lesser degree. A similar dominance of T cell responses to CII-glycopeptides was recorded in a cohort of severely affected RA-patients (n = 14). Thus, RA T cells predominantly recognize the immunodominant CII peptide in its glycosylated form and may explain why previously it has been difficult to detect T cell responses to CII in RA patients.
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| 40. |
- Bäcklund, Johan, et al.
(författare)
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Reversal of tolerance induced by transplantation of skin expressing the immunodominant T cell epitope of rat type II collagen entitles development of collagen-induced arthritis but not graft rejection.
- 2002
-
Ingår i: European Journal of Immunology. - 1521-4141. ; 32:6, s. 1773-1783
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Tidskriftsartikel (refereegranskat)abstract
- Collagen-induced arthritis (CIA) is induced in H-2(q) mice after immunization with rat type II collagen (CII). The immunodominant T cell epitope on heterologous CII has been located to CII256-270. We have previously shown that TSC transgenic mice, which express the heterologous epitope in type I collagen (CI), e.g. in skin, are tolerized against rat CII and resistant to CIA. In this study we transplanted skin from TSC transgenic mice onto non-transgenic CIA-susceptible littermates to investigate whether introduction of this epitope to a naïve immune system would lead to T cell priming and graft rejection or instead to tolerance and arthritis protection. Interestingly, TSC grafts were accepted and not even immunization of recipient mice with CII in adjuvant induced graft rejection. Instead, TSC skin recipients displayed a reduced T and B cell response to CII and were also protected from arthritis. However, additional priming could break arthritis protection and was accompanied by an increased T cell response to the grafted epitope. Strikingly, despite the regained T cell response, development of arthritis was not accompanied by graft rejection, showing that these immune-mediated inflammatory responses involve different mechanisms.
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| 41. |
- Carlsén, Stefan, et al.
(författare)
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Cartilage oligomeric matrix protein induction of chronic arthritis in mice
- 2008
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 58:7, s. 2000-2011
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP-induced arthritis (COMPIA). METHODS: Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q x DBA/1)F1, (BALB/c x B10.Q)F1, Ncf1 mutated, H-2Aq, H-2Ap, and human DR4+-transgenic mice were used. Anti-COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested. RESULTS: Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H-2q and H-2p MHC haplotypes allowed the initiation of COMPIA. Using H-2Aq-transgenic and H-2Ap-transgenic mice, we demonstrated a role of both the Aq and Ep class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA-resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti-COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)-associated DR4 molecule were found to be highly susceptible to COMPIA. CONCLUSION: Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.
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| 42. |
- Carlsén, Stefan, et al.
(författare)
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Type IX collagen deficiency enhances the binding of cartilage-specific antibodies and arthritis severity
- 2006
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 8:4
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 43. |
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| 44. |
- Chemin, Karine, et al.
(författare)
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A Novel HLA-DRB1*10:01-Restricted T Cell Epitope From Citrullinated Type II Collagen Relevant to Rheumatoid Arthritis
- 2016
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 68:5, s. 1124-1135
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Antibodies against citrullinated type II collagen (Cit-CII) are common in the sera and synovial fluid of patients with rheumatoid arthritis (RA); however, the known T cell epitope of CII is not dependent on citrullination. The aim of this study was to identify and functionally characterize the Cit-CII-restricted T cell epitopes that are relevant to RA. Methods. Peripheral blood mononuclear cells (PBMCs) from HLA-DRB1*10:01-positive patients with RA and healthy donors were stimulated in vitro with candidate CII peptides. CD154 up-regulation was measured as a marker of antigen-specific activation, and anti-HLA-DR-blocking experiments confirmed HLA restriction. Cytokine production was measured using a Luminex technique. Direct peptide-binding assays using HLA-DRB1*10:01 and HLA-DRB1*04:01 monomeric proteins were performed. The T cell receptor (TCR) beta-chain of CD154-enriched antigen-specific T cells was analyzed using high-throughput sequencing. Results. A novel Cit-CII peptide was identified based on its ability to activate CD4+ T cells from HLA-DRB1*10:01-positive individuals. When stimulated in vitro, Cit-CII autoreactive T cells produced proinflammatory cytokines. Cit-CII311-325 bound (with low affinity) to HLA-DRB1*10:01 but not to HLA-DRB1*04:01, while the native form was unable to bind either protein. In addition, highly expanded clones were identified in the TCR beta repertoire of Cit-CII311-325-stimulated PBMCs. Conclusion. These results illustrate the ability of the citrullination process to create T cell epitopes from CII, a cartilage-restricted protein that is relevant to RA pathogenesis. The exclusive binding of Cit-CII311-325 to HLA-DRB1*10:01 suggests that recognition of citrullinated epitopes might vary between individuals carrying different RA-associated HLA-DR molecules.
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| 45. |
- Corthay, Alexandre, et al.
(författare)
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Collagen-induced arthritis development requires alpha beta T cells but not gamma delta T cells: studies with T cell-deficient (TCR mutant) mice
- 1999
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Ingår i: International Immunology. - 1460-2377. ; 11:7, s. 1065-1073
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Tidskriftsartikel (refereegranskat)abstract
- Collagen type II (CII)-induced arthritis (CIA) in mice is a model for rheumatoid arthritis (RA) in which the role of T lymphocytes remains controversial. To clarify this, we have bred a targeted gene deletion of TCR beta or delta loci into two mouse strains susceptible to CIA, the B10.Q and DBA/1 strains. The TCRbeta-/- mice lacked alphabeta T cells, which was compensated by an expansion of B cells, gammadelta T cells and NK cells. The beta-/- mice, but not control beta+/- littermates, were completely resistant to CIA. The production of anti-CII IgG antibodies was also abolished in beta-/- mice, revealing a strict alphabeta T cell dependency. In contrast, beta-/- mice produced reduced, but significant, anti-CII IgM titers after immunization with either CII or ovalbumin, indicating a multispecificity for these alphabeta T cell-independent IgM antibodies. The TCRdelta-/- mice lacked gammadelta T cells but had no other significant changes in lymphocyte or monocyte subsets. The cytokine response (IL-2, IL-4, IL-10 and IFN-gamma) in delta-/- mice, quantified by flow cytometry staining of mitogen-stimulated lymphocytes, was indistinguishable from normal mice. Likewise, no statistically significant differences were observed in CIA between mice lacking gammadelta T cells and control littermates, considering arthritis incidence, day of disease onset, maximum arthritic score, anti-CII IgG titers and disease course. We conclude that alphabeta T cells are necessary for CIA development and for an IgG response towards CII, whereas gammadelta T cells are neither necessary nor sufficient for development of CIA.
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| 46. |
- Corthay, Alexandre, et al.
(författare)
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Evaluation of the percentage of peripheral T cells with two different T cell receptor alpha-chains and of their potential role in autoimmunity
- 2001
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Ingår i: Journal of Autoimmunity. - Rockville, MD : American Association of Immunologists. - 0896-8411 .- 1095-9157. ; 16:4, s. 423-429
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 47. |
- Corthay, Alexandre, et al.
(författare)
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Role of glycopeptide-specific T cells in collagen-induced arthritis: an example how post-translational modification of proteins may be involved in autoimmune disease
- 2001
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 33:7, s. 456-465
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Tidskriftsartikel (refereegranskat)abstract
- Immunization of mice with type II collagen (CII), a cartilage-restricted protein, leads to collagen-induced arthritis (CIA), a model for rheumatoid arthritis (RA). CIA symptoms consist of an erosive joint inflammation caused by an autoimmune attack, mediated by both T and B lymphocytes. CD4+ alphabeta T cells play a central role in CIA, both by helping B cells to produce anti-CII antibodies, and by interacting with other cells in the joints, eg macrophages. In H-2q mice, most CII-specific CD4+ T cells recognize the CII(256-270) peptide presented on the major histocompatibility complex (MHC) class II Aq molecule. Post-translational modifications (hydroxylation and variable glycosylation) of the lysine residue at position 264 of CII generate at least four different T-cell determinants that are specifically recognized by distinct T-cell subsets. Most T cells recognize CII(256-270) glycosylated with the monosaccharide galactose, which is consequently immunodominant in CIA. Recent studies indicate that the arthritogenic T cells in CIA are glycopeptide-specific, suggesting that induction of self-tolerance may be rendered more difficult by glycosylation of CII. These data open the possibility that outoimmune disease may be caused by the creation of new epitopes by posttranslational modification of proteins under circumstances such as trauma, inflammation or ageing.
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| 48. |
- Crandall, H, et al.
(författare)
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Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase
- 2005
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Ingår i: American Journal of Pathology. - 1525-2191. ; 167:3, s. 775-785
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Tidskriftsartikel (refereegranskat)abstract
- Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candidate gene for regulation of Lyme arthritis and reveal Lyme arthritis to be independent of NADPH oxidase activity, distinguishing it from other models of rheumatoid arthritis.
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| 49. |
- Crombie, D. E., et al.
(författare)
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Destructive effects of murine arthritogenic antibodies to type II collagen on cartilage explants in vitro
- 2005
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Certain monoclonal antibodies (mAbs) to type II collagen (CII) induce arthritis in vivo after passive transfer and have adverse effects on chondrocyte cultures and inhibit self assembly of collagen fibrils in vitro. We have examined whether such mAbs have detrimental effects on pre-existing cartilage. Bovine cartilage explants were cultured over 21 days in the presence of two arthritogenic mAbs to CII (CIIC1 or M2139), a non-arthritogenic mAb to CII (CIIF4) or a control mAb (GAD6). Penetration of cartilage by mAb was determined by immunofluorescence on frozen sections and correlated with changes to the extracellular matrix and chondrocytes by morphometric analysis of sections stained with toluidine blue. The effects of mAbs on matrix components were examined by Fourier transform infrared microspectroscopy (FTIRM). A possible role of Fc-binding was investigated using F(ab)2 from CIIC1. All three mAbs to CII penetrated the cartilage explants and CIIC1 and M2139, but not CIIF4, had adverse effects that included proteoglycan loss correlating with mAb penetration, the later development in cultures of an abnormal superficial cellular layer, and an increased proportion of empty chondrons. FTIRM showed depletion and denaturation of CII at the explant surface in the presence of CIIC1 or M2139, which paralleled proteoglycan loss. The effects of F(ab)2 were greater than those of intact CIIC1. Our results indicate that mAbs to CII can adversely affect preformed cartilage, and that the specific epitope on CII recognised by the mAb determines both arthritogenicity in vivo and adverse effects in vitro. We conclude that antibodies to CII can have pathogenic effects that are independent of inflammatory mediators or Fc-binding.
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| 50. |
- Croxford, Allyson M., et al.
(författare)
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Chemical changes demonstrated in cartilage by synchrotron infrared microspectroscopy in an antibody-induced murine model of rheumatoid arthritis
- 2011
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Ingår i: Journal of Biomedical Optics. - Bellingham, WA : SPIE - International Society for Optical Engineering. - 1083-3668 .- 1560-2281. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- Collagen antibody-induced arthritis develops in mice following passive transfer of monoclonal antibodies (mAbs) to type II collagen (CII) and is attributed to effects of proinflammatory immune complexes, but transferred mAbs may react directly and damagingly with CII. To determine whether such mAbs cause cartilage damage in vivo in the absence of inflammation, mice lacking complement factor 5 that do not develop joint inflammation were injected intravenously with two arthritogenic mAbs to CII, M2139 and CIIC1. Paws were collected at day 3, decalcified, paraffin embedded, and 5-mum sections were examined using standard histology and synchrotron Fourier-transform infrared microspectroscopy (FTIRM). None of the mice injected with mAb showed visual or histological evidence of inflammation but there were histological changes in the articular cartilage including loss of proteoglycan and altered chondrocyte morphology. Findings using FTIRM at high lateral resolution revealed loss of collagen and the appearance of a new peak at 1635 cm(-1) at the surface of the cartilage interpreted as cellular activation. Thus, we demonstrate the utility of synchrotron FTIRM for examining chemical changes in diseased cartilage at the microscopic level and establish that arthritogenic mAbs to CII do cause cartilage damage in vivo in the absence of inflammation. © 2011 Society of Photo-Optical Instrumentation Engineers (SPIE).
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