Therapeutic Vaccination of Active Arthritis with a Glycosylated Collagen Type II Peptide in Complex with MHC Class II Molecules

Dzhambazov, Balik; Nandakumar, Kutty Selva; Kihlberg, Jan; Fugger, Lars; Holmdahl, Rikard; Vestberg, Mikael

doi:10.4049/jimmunol.176.3.1525

Cited by 58 publications

(75 citation statements)

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“…This study also demonstrated that the CII 261-273 peptide requires internalization by APC, regardless of DM expression, and that it is presented via class II molecules accessing the recycling pathway. Studies suggest that differential processing of glycosylated versus non-glycosylated CII may reflect crucial differences between RA patients and normal individuals [6,38,39]. It has been shown that CII exists largely in the glycosylated form in healthy cartilage, whereas RA cartilage is characterized by the presence of both glycosylated and non-glycosylated forms of CII [6,7,39].…”

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“…It has been shown that CII exists largely in the glycosylated form in healthy cartilage, whereas RA cartilage is characterized by the presence of both glycosylated and non-glycosylated forms of CII [6,7,39]. While the posttranslational modification of CII may play a role in the balance between tolerance and autoimmunity in mice and in humans [6,7,38,39], the specific role of T cells against the glycosylated and non-glycosylated CII epitope(s) still remains unclear. APC may also vary in their ability to process and generate distinct pools of glycosylated and non-glycosylated CII, altering antigen processing and T cell responses to the dominant epitope.…”

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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Rheumatoid arthritis, an autoimmune disease, is significantly associated with the HLA class II allele HLA-DR4. While the etiology of rheumatoid arthritis remains unknown, type II collagen (CII) is a candidate autoantigen. An immunodominant pathogenic epitope from this autoantigen, CII [261][262][263][264][265][266][267][268][269][270][271][272][273] , which binds to HLA-DR4 and activates CD4 + T cells, has been identified. The non-classical class II antigen, HLA-DM, is also a key component of class II antigen presentation pathways influencing peptide presentation by HLA-DR molecules expressed on professional antigen-presenting cells (APC). Here, we investigated whether the HLA-DR4-restricted presentation of the pathogenic CII 261-273 epitope was regulated by HLA-DM expression in APC. We show that APC lacking HLA-DM efficiently display the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope to activate CD4 + T cells, and that presentation of this peptide is modulated dependent on the level of HLA-DM expression in APC. Mechanistic studies demonstrated that the CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide is internalized by APC and edited by HLA-DM molecules in the recycling pathway, inhibiting peptide presentation and T cell recognition. These findings suggest that HLA-DM expression in APC controls class IImediated CII [261][262][263][264][265][266][267][268][269][270][271][272][273] peptide/epitope presentation and regulates CD4 + T cell responses to this self epitope, thus potentially influencing CII-dependent autoimmunity.Key words: CD4 + T cells Á HLA-DM Á HLA-DR Á Peptide presentation Á Type II collagen IntroductionType II collagen (CII) is the major protein component of articular cartilage [1]. It is thought that T and B cell responses to this autoantigen are associated with the development and pathogenesis of rheumatoid arthritis (RA) [2,3]. It is also widely believed that RA is genetically linked to HLA class II molecules, including some HLA-DR4 alleles, and that T cell responses in collagendependent RA are directed towards the immunodominant pathogenic epitope CII [261][262][263][264][265][266][267][268][269][270][271][272][273] [4,5]. Studies also suggest that T cells from patients with RA predominantly recognize the glycosylated form of the immunodominant CII peptide [6,7]. Professional antigen-presenting cells (APC) such as B cells, macrophages and dendritic cells abundantly express HLA class II proteins and play critical roles in the pathogenesis of autoimmune arthritis by presenting autoantigens to T cells [4,5,8].In RA, cartilage proteins including CII undergo degradation by proteases, leading to the generation of peptides that can bind to HLA class II proteins and trigger CD4 + T cell activation [9]. Studies suggest that the peptides are loaded onto class II proteins Eur. J. Immunol. 2008. 38: 1961-1970 Immunomodulation in the endosomal and lysosomal compartments of APC prior to transit to the cell surface for T cell recognition [5...

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HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

et al. 2008

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“…We have previously shown the importance of galactosylation at position K 264 of CII259-273 for the immune recognition [12][13][14][15][16][17] and that CII in the healthy individuals is completely glycosylated at this position [16]. In line with these findings, an additional modification at position Q 267 by deamidation makes the study of the immune response more complex.…”

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confidence: 54%

“…It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthritis has been previously described [12][13][14][15][16][17].…”

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Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

Dzhambazov

Lindh

Engström³

et al. 2009

Eur J Immunol

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The calcium-dependent enzyme tissue transglutaminase (tTG) is associated with diverse biological functions, such as induction of apoptosis, modeling of the extracellular matrix, receptor-mediated endocytosis, cell growth and differentiation, cell adhesion and signal transduction. Also, it may deamidate glutamine residues to glutamic acid and catalyze cross-linking of proteins. In this study, we have investigated the impact of tTG for posttranslational modifications and cross-linking of the immunodominant T-cell epitope CII260-270 and their effects on the collagen-induced arthritis, an animal model for rheumatoid arthritis. By using mass spectrometry analysis and hybridoma assays, we have demonstrated that tTG could perform both types of modifications (deamidation and cross-link formation) on the immunodominant T-cell epitope CII259-273. Replacement of the glutamine at position 267 with glutamic acid leads to a decreased binding affinity to MHC II. T cells recognized both non-modfied (Q 267 ) and modified (E 267 ) CII259-273-peptides. We also show that administration of tTG leads to increased incidence, severity and histopathological manifestations of collagen-induced arthritis in mice. Moreover, we conclude that both processes, deamidation and cross-linking, are involved in the tTG-catalyzed reactions, and in vivo administration of tTG enhances arthritis severity and joint destruction in mice.Key words: Collagen-induced arthritis . CII-peptide . Posttranslational modifications .T cells . Tissue transglutaminase IntroductionPosttranslational modifications of proteins are being recognized as increasingly important for the initiation and pathogenesis of autoimmune diseases. Such modifications could lead to breaking of the immunological tolerance to self proteins by creation of new epitopes within the target antigen. Rheumatoid arthritis (RA) is an autoimmune disease involving an inflammatory attack on peripheral cartilaginous joints characterized by leukocyte infiltration, secretion of inflammatory cytokines and auto-Ab, and subsequent cartilage destruction, irreversible bone erosion and joint deformation. Major candidate autoantigens in RA that are locally expressed in the joint are type II collagen (CII), fibrin, and proteoglycans. CII is of particular interest, since T-and B-cell autoimmune responses to this protein leads to collagen-induced arthritis (CIA) in mice [1], rats [2] and primates [3,4], which shares many phenotypic features with RA. The shared immunodominant T-cell epitope in CIA and RA has been identified as . Amino acids of this immunodominant core can be posttranslationally modified either by enzymatic processes or spontaneously. It is well established that during aging, inflammation, trauma or other pathologic processes, the frequency of posttranslational modifications, such as glycosylation, glycation, citrullination, oxidation, deamidation/transamidation or 2412phosphorylation, is increased [10,11]. The role of glycosylated immunodominant CII260-270-peptide for development of autoimmune arthri...

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Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

2014

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Extensive genome-wide association studies have recently shed some light on the causes of chronic autoimmune diseases and have confirmed a central role of the adaptive immune system. Moreover, better diagnostics using disease-associated autoantibodies have been developed, and treatment has improved through the development of biologicals with precise molecular targets. Here, we use rheumatoid arthritis (RA) as a prototype for chronic autoimmune disease to propose that the pathogenesis of autoimmune diseases could be divided into three discrete stages. First, yet unknown environmental challenges seem to activate innate immunity thereby providing an adjuvant signal for the induction of adaptive immune responses that lead to the production of autoantibodies and determine the subsequent disease development. Second, a joint-specific inflammatory reaction occurs. This inflammatory reaction might be clinically diagnosed as the earliest signs of the disease. Third, inflammation is converted to a chronic process leading to tissue destruction and remodeling. In this review, we discuss the stages involved in RA pathogenesis and the experimental approaches, mainly involving animal models that can be used to investigate each disease stage. Although we focus on RA, it is possible that a similar stepwise development of disease also occurs in other chronic autoimmune settings such as multiple sclerosis (MS), type 1 diabetes, and systemic lupus erythematosus.Keywords: Animal models r Autoimmunity r Rheumatology Revisiting past efforts of RA researchEven though much detail has been recently revealed on the genetics and epidemiology of autoimmune diseases, several concepts on autoimmunity have been around for a long time. Early rheumatology studies were already deeply engaged in analyzing rheumatoid factors (RFs), that is, autoantibodies to Ig, and the Correspondence: Dr. Rikard Holmdahl e-mail: Rikard.Holmdahl@ki.se strong genetic association of RA with the HLA-DR alloantigens. However, many of the underlying causes of RA and the different stages in the disease process are still unclear even with the most recent information and therefore many of the old conceptual questions remain.The main result of recent genome-wide association studies (GWAS) is the confirmation of the strong association between "classical" (RF-positive) RA and the "shared epitope" MHC class II alleles [1][2][3]. The shared epitope is a specific peptide-binding pocket, originally defined as a structure in the polymorphic DRB1 chain shared by many alleles with basic amino acids at positionwww.eji-journal.eu 1594 Rikard Holmdahl et al. Eur. J. Immunol. 2014. 44: 1593-1599 70 and 74 [2], to which one now also may add positions 11 and 13 that are also strongly associated with RA [3]. In addition, the identity of around hundred genetic loci, with minor contribution to RA susceptibility, strengthen the dogma that RA is caused by aberrant autoreactive T cells [4,5]. Even though the influence of MHC and CD4 + T cells are more validated than ever, we still search for th...

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Therapeutic Vaccination of Active Arthritis with a Glycosylated Collagen Type II Peptide in Complex with MHC Class II Molecules

Cited by 58 publications

References 49 publications

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

HLA‐DM negatively regulates HLA‐DR4‐restricted collagen pathogenic peptide presentation and T cell recognition

Tissue transglutaminase enhances collagen type II‐induced arthritis and modifies the immunodominant T‐cell epitope CII260‐270

Autoimmune priming, tissue attack and chronic inflammation — The three stages of rheumatoid arthritis

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