| 1. |
- 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. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
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| 9. |
- 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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| 10. |
- 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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