A pH-induced modification of CII increases its arthritogenic properties

Lundberg, Karin; Ottosson, Lars; Westman, E.; Sunnerhagen, Maria; Hultenby, Kjell; Harris, Helena Erlandsson

doi:10.1016/j.jaut.2004.05.002

Cited by 4 publications

(3 citation statements)

References 29 publications

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“…We hypothesize that the requirements for extensive processing of the glycosylated arthritogenic epitope shown herein, the low glycosylation status of collagen at an early age (47), and the inability of some APCs to process CII (21) may result in a paucity of glycosylated peptide/HLA-DR1 complexes in the thymus, the inefficiency of negative selection, and the escape of glycosylated CII-specific T cells into periphery. The accumulation of advanced glycation end products with age (48), as well as the temperature-and pH-dependent changes in the structural integrity of collagen (49,50) or the increased collagen turnover could enhance the availability of CII and/or the accessibility of arthritogenic CII epitopes to antigen processing and lead to the activation of CII-specific T cells and the development or progression of autoimmune arthritis.…”

Section: Discussionmentioning

confidence: 99%

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

Delwig

Altmann

Isaacs

et al. 2006

Arthritis & Rheumatism

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Objective. Type II collagen (CII) is a candidate autoantigen implicated in the pathogenesis of rheumatoid arthritis (RA). Posttranslational glycosylation of CII could alter intracellular antigen processing, leading to the development of autoimmune T cell responses. To address this possibility, we studied the intracellular processing of CII for presentation of the arthritogenic glycosylated epitope CII 259-273 to CD4 T cells in macrophages from HLA-DR1-transgenic mice.Methods. HLA-DR1-transgenic mice were generated on a class II major histocompatibility complexdeficient background, and T cell hybridomas specific for the glycosylated and nonglycosylated epitope CII [259][260][261][262][263][264][265][266][267][268][269][270][271][272][273] were developed. Subcellular fractionation of macrophages was used to localize CII degradation to particular compartments and to identify the catalytic subtype of proteinases involved.Results. We showed that the glycosylated CII 259-273epitope required more extensive processing than did the nonglycosylated form of the same epitope. Dense fractions containing lysosomes were primarily engaged in the processing of CII for antigen presentation, since these compartments contained 1) enzyme activity that generated antigenic CII fragments bearing the arthritogenic glycosylated epitope, 2) the antigenic CII fragments themselves, 3) CII peptide-receptive HLA-DR1 molecules, and 4) peptide/HLA-DR1 complexes that could directly activate T cell hybridomas. Degradation of CII by dense fractions occurred optimally at pH 4.5 and was abrogated by inhibitors of serine and cysteine proteinases. Conclusion. Processing of the arthritogenic glycosylated CII259-273 epitope, which is implicated in the induction of autoimmune arthritis, is more stringently regulated than is processing of the nonglycosylated form of the same epitope. Mechanisms of intracellular processing of the glycosylated epitope may constitute novel therapeutic targets for the treatment of RA.

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Section: Discussionmentioning

confidence: 99%

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

Delwig

Altmann

Isaacs

et al. 2006

Arthritis & Rheumatism

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“…During the development of RA, inflammatory joints show many pathological signals different from those of normal tissues, such as low pH environment, overexpressed MMPs, and hypoxic microenvironment. [13][14][15] Previous intra-articular drug delivery systems provided sustained drug release only, which was independent of the disease state. [16] Designing a responsive drug delivery system that depends on special pathological signals can significantly improve drug release behavior at the inflammatory site, improve drug bioavailability, and result in an excellent curative effect.…”

Section: Discussionmentioning

confidence: 99%

A Metabolic Driven Bio‐Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis

Wang

Yin

et al. 2023

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Overexpressed matrix metalloproteinases, hypoxia microenvironment, and metabolic abnormality are important pathological signs of rheumatoid arthritis (RA). Designing a delivery carrier according to the pathological characteristics of RA that can control drug release in response to disease severity may be a promising treatment strategy. Psoralen is the main active ingredient isolated from Psoralea corylifolia L. and possesses excellent anti‐inflammatory activities as well as improving bone homeostasis. However, the specific underlying mechanisms, particularly the possible relationships between the anti‐RA effects of psoralen and related metabolic network, remain largely unexplored. Furthermore, psoralen shows systemic side effects and has unsatisfactory solubility. Therefore, it is desirable to develop a novel delivery system to maximize psoralen's therapeutic effect. In this study, a self‐assembled degradable hydrogel platform is developed that delivers psoralen and calcium peroxide to arthritic joints and controls the release of psoralen and oxygen according to inflammatory stimulation, to regulate homeostasis and the metabolic disorder of the anoxic arthritic microenvironment. Therefore, the hydrogel drug delivery system based on the responsiveness of the inflammatory microenvironment and regulation of metabolism provides a new therapeutic strategy for RA treatment.

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“…COL2 conformational changes can be induced by decreased pH detected during synovial inflammation [ 173 , 174 ]. It was demonstrated that COL2 is more immunogenic in acidic environment and its pH-induced conformational changes correlate with arthritogenic properties [ 175 ]. These data represent another line in COL2 PTMs that can be involved in RA pathogenesis and remains to be further studied.…”

Section: Collagen Type II (Col2) Posttranslational Modifications In R...mentioning

confidence: 99%

Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis

Batsalova

Dzhambazov

2023

IJMS

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Collagen type II (COL2), the main structural protein of hyaline cartilage, is considerably affected by autoimmune responses associated with the pathogenesis of rheumatoid arthritis (RA). Posttranslational modifications (PTMs) play a significant role in the formation of the COL2 molecule and supramolecular fibril organization, and thus, support COL2 function, which is crucial for normal cartilage structure and physiology. Conversely, the specific PTMs of the protein (carbamylation, glycosylation, citrullination, oxidative modifications and others) have been implicated in RA autoimmunity. The discovery of the anti-citrullinated protein response in RA, which includes anti-citrullinated COL2 reactivity, has led to the development of improved diagnostic assays and classification criteria for the disease. The induction of immunological tolerance using modified COL2 peptides has been highlighted as a potentially effective strategy for RA therapy. Therefore, the aim of this review is to summarize the recent knowledge on COL2 posttranslational modifications with relevance to RA pathophysiology, diagnosis and treatment. The significance of COL2 PTMs as a source of neo-antigens that activate immunity leading to or sustaining RA autoimmunity is discussed.

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A pH-induced modification of CII increases its arthritogenic properties

Cited by 4 publications

References 29 publications

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

The impact of glycosylation on HLA–DR1–restricted T cell recognition of type II collagen in a mouse model

A Metabolic Driven Bio‐Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis

Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis

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