Identification of Novel Native Autoantigens in Rheumatoid Arthritis

Poulsen, Thomas B.; Damgaard, Dres; Jørgensen, Maléne Møller; Šenolt, Ladislav; Blackburn, Jonathan M.; Nielsen, Claus Henrik; Stensballe, Allan

doi:10.3390/biomedicines8060141

Cited by 20 publications

(24 citation statements)

References 77 publications

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“…RA antibody systems are remarkably diverse, characterized by the presence of those against native proteins as well as those containing posttranslational modi cations (PTMs) [42,43]. While current models of RA have embraced PTMs as core principles of pathogenesis [42,44], α-native protein antibodies are not adequately explained by the PTM-centric paradigm of autoantigen selection.…”

Section: Discussionmentioning

confidence: 99%

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The CN-index of hnRNP-DL Predicts an Individual “Window of Treatment Success” in RA Patients

Marklein

Jenning

Konthur

et al. 2021

Preprint

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BackgroundThere is a need for biomarker to identify patients ‘at risk’ for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers.MethodsUsing Protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. ResultshnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. This CNDL (Citrullinated-Native-hnRNP-DL)-index identified and the bioinformatic value was explored, as a new value for an “individual window of treatment success” in early RA and for the detection of RF-IgM/α-CCP2 seronegative RA patients (24-46%). Negative CNDL-index was found in SLE patients, risk-RA- and early RA-cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC-analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients.ConclusionCNDL-index defines patients is a possible biomarker for develop RA and the “window of treatment success” thereby potentially closing the sensitivity gap.

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Section: Discussionmentioning

confidence: 99%

“…For α-hnRNP-A2/B1 autoantibodies has already been published that it is also associated with less erosive disease, exclusively in early RA [18,29]. Recently, several more reactivities against native proteins in RA have been published [43].…”

Section: Discussionmentioning

confidence: 99%

The CN-index of hnRNP-DL Predicts an Individual “Window of Treatment Success” in RA Patients

Marklein

Jenning

Konthur

et al. 2021

Preprint

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“…Similarly, Poulsen et al. investigated the global reactivity of autoantibodies in RA patients ( 13 ). Additionally, Horn et al.…”

Section: Proteome Microarraysmentioning

confidence: 99%

“…McAndrew et al applied the IMMUNOME ™ array in autoantibody profiling with SLE serum samples (36, 85). Similarly, Poulsen et al investigated the global reactivity of autoantibodies in RA patients(13).…”

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confidence: 99%

Applications of Protein Microarrays in Biomarker Discovery for Autoimmune Diseases

Song

Bai

et al. 2021

Front. Immunol.

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Dysregulated autoantibodies and cytokines were deemed to provide important cues for potential illnesses, such as various carcinomas and autoimmune diseases. Increasing biotechnological approaches have been applied to screen and identify the specific alterations of these biomolecules as distinctive biomarkers in diseases, especially autoimmune diseases. As a versatile and robust platform, protein microarray technology allows researchers to easily profile dysregulated autoantibodies and cytokines associated with autoimmune diseases using various biological specimens, mainly serum samples. Here, we summarize the applications of protein microarrays in biomarker discovery for autoimmune diseases. In addition, the key issues in the process of using this approach are presented for improving future studies.

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“…However, the development of autoimmune disorders is not always based on oxidized antigens. Instead, some antigens are native [72], citrullinated [73,74] or deaminated [75]. Interestingly, Hultqvist and colleagues have shown that elevating the low oxidative burst capacity led to suppressing an autoimmune response [76,77].…”

Section: Concept and Challenges Of Multi-ros-modified Autologous Tumor Vaccinesmentioning

confidence: 99%

ROS Cocktails as an Adjuvant for Personalized Antitumor Vaccination?

Clemen

Bekeschus

2021

Vaccines

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Cancer is the second leading cause of death worldwide. Today, the critical role of the immune system in tumor control is undisputed. Checkpoint antibody immunotherapy augments existing antitumor T cell activity with durable clinical responses in many tumor entities. Despite the presence of tumor-associated antigens and neoantigens, many patients have an insufficient repertoires of antitumor T cells. Autologous tumor vaccinations aim at alleviating this defect, but clinical success is modest. Loading tumor material into autologous dendritic cells followed by their laboratory expansion and therapeutic vaccination is promising, both conceptually and clinically. However, this process is laborious, time-consuming, costly, and hence less likely to solve the global cancer crisis. Therefore, it is proposed to re-focus on personalized anticancer vaccinations to enhance the immunogenicity of autologous therapeutic tumor vaccines. Recent work re-established the idea of using the alarming agents of the immune system, oxidative modifications, as an intrinsic adjuvant to broaden the antitumor T cell receptor repertoire in cancer patients. The key novelty is the use of gas plasma, a multi-reactive oxygen and nitrogen species-generating technology, for diversifying oxidative protein modifications in a, so far, unparalleled manner. This significant innovation has been successfully used in proof-of-concept studies and awaits broader recognition and implementation to explore its chances and limitations of providing affordable personalized anticancer vaccines in the future. Such multidisciplinary advance is timely, as the current COVID-19 crisis is inexorably reflecting the utmost importance of innovative and effective vaccinations in modern times.

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Identification of Novel Native Autoantigens in Rheumatoid Arthritis

Cited by 20 publications

References 77 publications

The CN-index of hnRNP-DL Predicts an Individual “Window of Treatment Success” in RA Patients

The CN-index of hnRNP-DL Predicts an Individual “Window of Treatment Success” in RA Patients

Applications of Protein Microarrays in Biomarker Discovery for Autoimmune Diseases

ROS Cocktails as an Adjuvant for Personalized Antitumor Vaccination?

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