Type II Collagen Autoimmunity in Animals and Provocations Leading to Arthritis

Holmdahl, Rikard; Andersson, Mikael; Goldschmidt, Tom; Gustafsson, Kenth; Jansson, Liselotte; Mo, John

doi:10.1111/j.1600-065x.1990.tb00817.x

Cited by 282 publications

(259 citation statements)

References 131 publications

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“…Despite the well-established role of CII as a potentially relevant autoantigen in human RA as well as in experimental arthritis [5][6][7][8]14], so far no structural data have been available to give insight into its recognition by B-or T-cell receptors of autoreactive lymphocytes at a molecular level. In this respect, our studies based on a molecular modeling approach combined with site directed mutagenesis of recombinant CIIC1scFv variants of the arthitogenic mAb CIIC1 provide initial experimental evidence.…”

Section: Discussionmentioning

confidence: 99%

“…In this respect, structurespecific features might provide a clue to the understanding of the recognition of CII as a tissue-specific autoantigen in cartilage by germline-encoded IgG. Thus, the triple helical structure of CII has earlier been demonstrated as crucial for antibody binding since its heat denaturation does not only destroy CII recognition by the CIIC1 mAb [11] but also the potential of CII to induce arthritis in susceptible strains of mice upon immunization [5]. Accordingly, the unique structural feature of the triple helix is a constitutive element of CII as an arthritogenic autoantigen that is kept preserved in the interaction with the CIIC1 mAb according to our MD simulation data.…”

Section: Discussionmentioning

confidence: 99%

“…Although the pathogenic role of these autoantibodies still remains elusive, the recently demonstrated therapeutic efficacy of B-cell depleting treatment strategies in RA might be regarded as circumstantial evidence supporting a potential of autoantibody-mediated mechanisms to contribute to joint pathology [4]. In this respect, collagen type II (CII), as the major component of cartilage, deserves special attention as a relevant autoantigen and the hypothesis of CII-directed autoimmunity as an important pathogenic mechanism in RA is an appealing explanation for the chronicity of the arthritic process as well as for its fatal consequences on joint cartilage integrity [5]. Several lines of evidence further support the concept of a CII-driven autoimmune process in RA.…”

Section: Introductionmentioning

confidence: 99%

“…Sera of RA patients contain CII-specific autoantibodies [6,7] and anti-CII IgG-producing B cells have been detected in rheumatoid synovium and synovial fluid [8,9], suggesting an ongoing intra-articular antigen-driven immune process. Direct evidence for the arthritogenic potential of CII autoimmunity is derived from experimental disease models of collagen-induced arthritis [5]. Moreover, the pathogenic role of certain CII autoantibodies with specificities for a few evolutionarily conserved epitopes was directly demonstrated by arthritistransfer experiments in the mouse [7,10].…”

Section: Introductionmentioning

confidence: 99%

“…collagen type II (CII), as the major component of cartilage, deserves special attention as a relevant autoantigen and the hypothesis of CII-directed autoimmunity as an important pathogenic mechanism in RA is an appealing explanation for the chronicity of the arthritic process as well as for its fatal consequences on joint cartilage integrity [5]. Several lines of evidence further support the concept of a CII-driven autoimmune process in RA.…”

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Collagen type II is recognized by a pathogenic antibody through germline encoded structures

et al. 2008

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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.Key words: Autoantibody . Collagen type II . Comparative modeling . Molecular dynamics simulations . Rheumatoid arthritis IntroductionIncreased titers of circulating autoantibodies are characteristic features of rheumatoid arthritis (RA) reflecting the activation of humoral immune responses during chronic joint inflammation. A variety of those autoantibodies have proven their usefulness as disease makers such as rheumatoid factors recognizing the Fc part of IgG or the so-called anti-citrullinated protein antibodies exhibiting specificity for posttranslational conversions of arginine into citrulline residues in several autoantigens such as fibrin (ogen), vimentin, fibronectin and (pro)filaggrin [1][2][3]. Although the pathogenic role of these autoantibodies still remains elusive, the recently demonstrated therapeutic efficacy of B-cell depleting treatment strategies in RA might be regarded as circumstantial evidence supporting a potential of autoantibody-mediated mechanisms to contribute to joint pathology [4]. In this respect, 2784collagen type II (CII), as the major component of cartilage, deserves special attention as a relevant autoantigen and the hypothesis of CII-directed autoimmunity as an important pathogenic mechanism in RA is an appealing explanation for the chronicity of the arthritic process as well as for its fatal consequences on joint cartilage integrity [5]. Several lines of evidence further support the concept of a CII-driven autoimmune process in RA. Sera of RA patients contain CII-specific autoantibodies [6,7] and anti-CII IgG-producing B cells have been detected in rheumatoid synovium and synovial fluid [8...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Collagen type II is recognized by a pathogenic antibody through germline encoded structures

et al. 2008

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Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis

Corthay¹,

Bäcklund²,

Broddefalk³

et al. 1998

Eur. J. Immunol.

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154

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Immunization of mice with type II collagen (CII) leads to collagen-induced arthritis (CIA), a model for rheumatoid arthritis. T cell recognition of CII is believed to be a critical step in CIA development. We have analyzed the T cell determinants on CII and the TCR used for their recognition, using twenty-nine T cell hybridomas derived from C3H.Q and DBA/1 mice immunized with rat CII. All hybridomas were specific for the CII(256-270) segment. However, posttranslational modifications (hydroxylation and variable O-linked glycosylation) of the lysine at position 264 generated five T cell determinants that were specifically recognized by different T cell hybridoma subsets. TCR sequencing indicated that each of the five T cell epitopes selected its own TCR repertoire. The physiological relevance of this observation was shown by in vivo antibody-driven depletion of TCR Valpha2-positive T cells, which resulted in an inhibition of the T cell proliferative response in vitro towards the non-modified CII(256-270), but not towards the glycosylated epitope. Most hybridomas (20/29) specifically recognized CII(256-270) glycosylated with a monosaccharide (beta-D-galactopyranose). We conclude that this glycopeptide is immunodominant in CIA and that posttranslational modifications of CII create new T cell determinants that generate a diverse TCR repertoire.

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Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma

Ohno

Yoshinaga

Fujita

et al. 2001

Cancer

117

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Five protected analogues of β‐D‐galactosyl‐(5R)‐5‐hydroxy‐L‐lysine were prepared, in which the galactosyl moiety was modified by monodeoxygenation or inversion of stereochemistry at C‐4. The building blocks were used in the solid‐phase synthesis of a set of glycopeptides related to the peptide fragment CII256–273 from type II collagen. Evaluation of the glycopeptides revealed that T‐cell hybridomas obtained in collagen‐induced arthritis (CIA), which is a common mouse model for rheumatoid arthritis, recognized the galactosyl moiety with high specificity for individual hydroxy groups. Moreover, T‐cell hybridomas obtained in a humanized variant of CIA were also found to recognize the glycopeptides in an equally carbohydrate‐specific manner. The results allowed the generation of models of the complexes formed between the appropriate class II major histocompatibility complex (MHC) molecule, glycopeptide, and the T‐cell receptor, that is, of an interaction that is critical for the stimulation of T cells in the arthritis models. In the structural models, peptide side chains anchor the glycopeptide in pockets in the class II MHC molecule, whereas the galactosylated hydroxylysine residue forms the key contacts with the T‐cell receptor. Importantly, the results also suggest that a T‐cell response towards glycopeptide fragments from type II collagen could play an important role in the development of rheumatoid arthritis in humans.

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Type II Collagen Autoimmunity in Animals and Provocations Leading to Arthritis

Cited by 282 publications

References 131 publications

Collagen type II is recognized by a pathogenic antibody through germline encoded structures

Collagen type II is recognized by a pathogenic antibody through germline encoded structures

Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis

Depth of invasion parallels increased cyclooxygenase-2 levels in patients with gastric carcinoma

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