Epitope-specific antibody response is controlled by immunoglobulin VH polymorphisms

Raposo, Bruno; Dobritzsch, Doreen; Ge, Changrong; Ekman, Diana; Xu, Bingze; Lindh, Ingrid; Förster, Michael; Uysal, Hüseyin; Nandakumar, Kutty Selva; Schneider, Günter; Holmdahl, Rikard

doi:10.1084/jem.20130968

Cited by 36 publications

(33 citation statements)

References 31 publications

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“…We can thus compare how the same linear epitope is bound by ACC4 (C1 CIT360 ) and ACC1 (C1 CIT365 ) but with different modification states. The other two structures comprise the Fab-peptide complexes of the anti-CII antibodies CIIC1 (20) and M2139 (22), which recognize the native, i.e., triple-helical and unmodified, C1 and J1 epitopes of CII, respectively. Comparisons of these structures may allow identification of determinants of the conformational selectivity, i.e., single-chain versus triple-helical epitopes, of these antibodies.…”

Section: Comparison Of CII Epitope Binding By Other Acpas and Anti-cimentioning

confidence: 99%

Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

Ge¹,

Tong²,

Liang³

et al. 2017

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Section: Comparison Of CII Epitope Binding By Other Acpas and Anti-cimentioning

confidence: 99%

Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

Ge¹,

Tong²,

Liang³

et al. 2017

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“…Interestingly, in the mouse the highly pathogenic antibodies to type II collagen (CII) are not negatively selected but rather contain an expanded germline-encoded B cell response, and this phenomenon has been associated with several MHC class II and Ig-V alleles [23][24][25]. Thus, avidity maturation (and pathogenicity) may not necessarily involve germinal center selection and somatic mutations, but might still be promoted by T-cell help.…”

Section: Stage 1 -Autoimmune Priming In Healthy Individualsmentioning

confidence: 99%

“…However, as it is easier to crystallize antibodies with high affinity, these examples might not be representative of the full repertoire of RA associated RFs. In addition, the possible occurrence of somatic mutations needs to be analyzed by sequencing the correct V gene from the same individual that antibody was derived from to ensure that mutations are not due to individual allelic differences.In animal models high titers of ACPAs have so far not been demonstrated, whereas RFs occur in the collagen-induced arthritis (CIA) [20], pristane-induced arthritis (PIA) [21], and the SKG (with a ZAP70 mutation) [22] type II collagen (CII) are not negatively selected but rather contain an expanded germline-encoded B cell response, and this phenomenon has been associated with several MHC class II and Ig-V alleles [23][24][25]. Thus, avidity maturation (and pathogenicity) may not necessarily involve germinal center selection and somatic mutations, but might still be promoted by T-cell help.…”

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confidence: 99%

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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“…We also showed that B-cell hybridomas generated from B10Q.ACB mice lack somatic mutations in the IgH and L chains, which might operate as a protective mechanism to avoid high affinity autoimmune responses. All the investigated CII-specific pathogenic antibodies so far, including the CB20-used for generating the ACB mouse, bind to CII using germ line-encoded binding sites [14,34]. Hence, we suggest that the CII reactivity is encoded in the natural repertoire and may also have a regulatory function in a physiological context [35].…”

Section: Discussionmentioning

confidence: 91%

“…The most striking observation that was associated with the development of arthritis in the ROS deficient mice was the intra-molecular epitope spreading. Although the triple helical CII molecule is partly repetitive in its amino acid sequence, the repetitive glycines in every third position are not on the surface of the molecule and hence do not participate in antibody binding [14,18,34]. Thus, the antibodies bind unique structures and the epitope spreading cannot be explained by cross-reactivity of antibodies.…”

Section: Discussionmentioning

confidence: 99%

B‐cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production

et al. 2015

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Autoantibody-mediated inflammation contributes to the development of rheumatoid arthritis (RA), and anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients. We had previously generated and characterized knockin mice expressing a germline-encoded, CII-specific IgH (B10Q.ACB), which demonstrated positive selection of self-reactive B cells. Here, we show that despite the spontaneous production of CII-specific autoantibodies, B10Q.ACB mice are protected from collageninduced arthritis. Introducing a mutation in the Ncf1 gene, leading to ROS deficiency, breaks this strong arthritis resistance. Disease development in Ncf1-mutated B10Q.ACB mice is associated with an enhanced germinal center formation but without somatic mutations of the auto-reactive B cells, increased T-cell responses and intramolecular epitope-spreading. Thus, ROS-mediated B-cell tolerance to a self-antigen could operate by limiting the expansion of the auto-reactive B-cell repertoire, which has important implications for the understanding of epitope spreading phenomena in rheumatoid arthritis and other autoimmune diseases.Keywords: Auto-reactive B cells r Autoantibodies r Arthritis r Epitope spreading r ROS Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionAutoimmune diseases affect 5% of the worldwide population, and often involve autoantibody-mediated tissue inflammation. The development of rheumatoid arthritis (RA) involves autoantibodies such as rheumatoid factor and antibodies to citrullinated protein antigens. These antibodies appear in the blood of RA patients, many years before the onset of clinical symptoms [1,2], and durCorrespondence: Dr. Rikard Holmdahl e-mail: rikard.holmdahl@ki.se ing the preclinical phase epitope spreading of the antibodies to citrullinated protein antigens occurs [3,4].Anti-type II collagen (CII) antibodies are present in the serum, synovial fluid, and cartilage of RA patients [5,6]. These are directed to both native triple helical (approx. 10% of the patients) and modified citrullinated (approx. 40% of the patients) epitopes [7,8]. The triple helical CII-directed antibodies are detected during the early joint inflammatory phase of RA [9,10]. Interestingly, the identification of the CII epitopes showed that they are highly conserved between mammals [11,12]. Functional analysis of single chain variable fragment antibody [13] Numerous studies identified the prototypes of different pathogenic autoimmune diseases, where the production of hightiter, high affinity autoantibodies to the proposed antigens is generated in germinal centers (GC). GCs in the secondary lymphoid organs are the sites of intense B-cell proliferation and support somatic hyper mutation and the subsequent selection of high affinity B cells. Extra-follicular (non-GC) origin of the autoantibodies was described in many mouse models of autoimmune diseases [19]. We have previously found that Ncf1 polymorphism leads to a lower oxid...

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Epitope-specific antibody response is controlled by immunoglobulin VH polymorphisms

Abstract: Epitope-specific antibody responses recognized by germline-encoded structures are of significant relevance for the development of autoantibody-mediated autoimmune diseases.

Cited by 36 publications

References 31 publications

Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage

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

B‐cell epitope spreading and inflammation in a mouse model of arthritis is associated with a deficiency in reactive oxygen species production

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