Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis

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Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis. / Gronwall, Caroline ; Amara, Khaled; Hardt, Uta ; Krishnamurthy, Akilan ; Steen, Johanna ; Engström, Marianne; Meng, Sun; Zubarev, Roman A. ; Ytterberg, A. Jimmy ; Scheel-Toellner, Dagmar; Greenberg, Jeffrey D. ; Klareskog, Lars ; Catrina , Anca I. ; Malmstrom, vivianne; Silverman, Gregg J. .

In: Journal of Autoimmunity, 21.06.2017.

Research output: Contribution to journalAbstractpeer-review

Harvard

Gronwall, C, Amara, K, Hardt, U, Krishnamurthy, A, Steen, J, Engström, M, Meng, S, Zubarev, RA, Ytterberg, AJ, Scheel-Toellner, D, Greenberg, JD, Klareskog, L, Catrina , AI, Malmstrom, V & Silverman, GJ 2017, 'Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis', Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2017.06.004

APA

Gronwall, C., Amara, K., Hardt, U., Krishnamurthy, A., Steen, J., Engström, M., Meng, S., Zubarev, R. A., Ytterberg, A. J., Scheel-Toellner, D., Greenberg, J. D., Klareskog, L., Catrina , A. I., Malmstrom, V., & Silverman, G. J. (2017). Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis. Journal of Autoimmunity. https://doi.org/10.1016/j.jaut.2017.06.004

Vancouver

Author

Gronwall, Caroline ; Amara, Khaled ; Hardt, Uta ; Krishnamurthy, Akilan ; Steen, Johanna ; Engström, Marianne ; Meng, Sun ; Zubarev, Roman A. ; Ytterberg, A. Jimmy ; Scheel-Toellner, Dagmar ; Greenberg, Jeffrey D. ; Klareskog, Lars ; Catrina , Anca I. ; Malmstrom, vivianne ; Silverman, Gregg J. . / Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis. In: Journal of Autoimmunity. 2017.

Bibtex

@article{65f8f9d04bed40418d25f30a09d3d874,
title = "Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis",
abstract = "Oxidation-associated malondialdehyde (MDA) modification of proteins can generate immunogenic neo-epitopes that are recognized by autoantibodies. In health, IgM antibodies to MDA-adducts are part of the natural antibody pool, while elevated levels of IgG anti-MDA antibodies are associated with inflammatory and autoimmune conditions. Yet, in human autoimmune disease IgG anti-MDA responses have not been well characterized and their potential contribution to disease pathogenesis is not known. Here, we investigate MDA-modifications and anti-MDA-modified protein autoreactivity in rheumatoid arthritis (RA). While RA is primarily associated with autoreactivity to citrullinated antigens, we also observed increases in serum IgG anti-MDA in RA patients compared to controls. IgG anti-MDA levels significantly correlated with disease activity by DAS28-ESR and serum TNF-alpha, IL-6, and CRP. Mass spectrometry analysis of RA synovial tissue identified MDA-modified proteins and revealed shared peptides between MDA-modified and citrullinated actin and vimentin. Furthermore, anti-MDA autoreactivity among synovial B cells was discovered when investigating recombinant monoclonal antibodies (mAbs) cloned from single B cells, and 3.5% of memory B cells and 2.3% of plasma cells were found to be anti-MDA positive. Several clones were highly specific for MDA-modification with no cross-reactivity to other antigen modifications such as citrullination, carbamylation or 4-HNE-carbonylation. The mAbs recognized MDA-adducts in a variety of proteins including albumin, histone 2B, fibrinogen and vimentin. Interestingly, the most reactive clone, originated from an IgG1-bearing memory B cell, was encoded by near germline variable genes, and showed similarity to previously reported natural IgM. Other anti-MDA clones display somatic hypermutations and lower reactivity. Importantly, these anti-MDA antibodies had significant in vitro functional properties and induced enhanced osteoclastogenesis, while the natural antibody related high-reactivity clone did not. We postulate that these may represent distinctly different facets of anti-MDA autoreactive responses.",
keywords = "autoimmunity , oxidation , malondialdehyde acetaldehyde modification , natural autoantibodies , rheumatoid arthritis",
author = "Caroline Gronwall and Khaled Amara and Uta Hardt and Akilan Krishnamurthy and Johanna Steen and Marianne Engstr{\"o}m and Sun Meng and Zubarev, {Roman A.} and Ytterberg, {A. Jimmy} and Dagmar Scheel-Toellner and Greenberg, {Jeffrey D.} and Lars Klareskog and Catrina, {Anca I.} and vivianne Malmstrom and Silverman, {Gregg J.}",
year = "2017",
month = jun,
day = "21",
doi = "10.1016/j.jaut.2017.06.004",
language = "English",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Autoreactivity to malondialdehyde-modifications in rheumatoid arthritis is linked to disease activity and synovial pathogenesis

AU - Gronwall, Caroline

AU - Amara, Khaled

AU - Hardt, Uta

AU - Krishnamurthy, Akilan

AU - Steen, Johanna

AU - Engström, Marianne

AU - Meng, Sun

AU - Zubarev, Roman A.

AU - Ytterberg, A. Jimmy

AU - Scheel-Toellner, Dagmar

AU - Greenberg, Jeffrey D.

AU - Klareskog, Lars

AU - Catrina , Anca I.

AU - Malmstrom, vivianne

AU - Silverman, Gregg J.

PY - 2017/6/21

Y1 - 2017/6/21

N2 - Oxidation-associated malondialdehyde (MDA) modification of proteins can generate immunogenic neo-epitopes that are recognized by autoantibodies. In health, IgM antibodies to MDA-adducts are part of the natural antibody pool, while elevated levels of IgG anti-MDA antibodies are associated with inflammatory and autoimmune conditions. Yet, in human autoimmune disease IgG anti-MDA responses have not been well characterized and their potential contribution to disease pathogenesis is not known. Here, we investigate MDA-modifications and anti-MDA-modified protein autoreactivity in rheumatoid arthritis (RA). While RA is primarily associated with autoreactivity to citrullinated antigens, we also observed increases in serum IgG anti-MDA in RA patients compared to controls. IgG anti-MDA levels significantly correlated with disease activity by DAS28-ESR and serum TNF-alpha, IL-6, and CRP. Mass spectrometry analysis of RA synovial tissue identified MDA-modified proteins and revealed shared peptides between MDA-modified and citrullinated actin and vimentin. Furthermore, anti-MDA autoreactivity among synovial B cells was discovered when investigating recombinant monoclonal antibodies (mAbs) cloned from single B cells, and 3.5% of memory B cells and 2.3% of plasma cells were found to be anti-MDA positive. Several clones were highly specific for MDA-modification with no cross-reactivity to other antigen modifications such as citrullination, carbamylation or 4-HNE-carbonylation. The mAbs recognized MDA-adducts in a variety of proteins including albumin, histone 2B, fibrinogen and vimentin. Interestingly, the most reactive clone, originated from an IgG1-bearing memory B cell, was encoded by near germline variable genes, and showed similarity to previously reported natural IgM. Other anti-MDA clones display somatic hypermutations and lower reactivity. Importantly, these anti-MDA antibodies had significant in vitro functional properties and induced enhanced osteoclastogenesis, while the natural antibody related high-reactivity clone did not. We postulate that these may represent distinctly different facets of anti-MDA autoreactive responses.

AB - Oxidation-associated malondialdehyde (MDA) modification of proteins can generate immunogenic neo-epitopes that are recognized by autoantibodies. In health, IgM antibodies to MDA-adducts are part of the natural antibody pool, while elevated levels of IgG anti-MDA antibodies are associated with inflammatory and autoimmune conditions. Yet, in human autoimmune disease IgG anti-MDA responses have not been well characterized and their potential contribution to disease pathogenesis is not known. Here, we investigate MDA-modifications and anti-MDA-modified protein autoreactivity in rheumatoid arthritis (RA). While RA is primarily associated with autoreactivity to citrullinated antigens, we also observed increases in serum IgG anti-MDA in RA patients compared to controls. IgG anti-MDA levels significantly correlated with disease activity by DAS28-ESR and serum TNF-alpha, IL-6, and CRP. Mass spectrometry analysis of RA synovial tissue identified MDA-modified proteins and revealed shared peptides between MDA-modified and citrullinated actin and vimentin. Furthermore, anti-MDA autoreactivity among synovial B cells was discovered when investigating recombinant monoclonal antibodies (mAbs) cloned from single B cells, and 3.5% of memory B cells and 2.3% of plasma cells were found to be anti-MDA positive. Several clones were highly specific for MDA-modification with no cross-reactivity to other antigen modifications such as citrullination, carbamylation or 4-HNE-carbonylation. The mAbs recognized MDA-adducts in a variety of proteins including albumin, histone 2B, fibrinogen and vimentin. Interestingly, the most reactive clone, originated from an IgG1-bearing memory B cell, was encoded by near germline variable genes, and showed similarity to previously reported natural IgM. Other anti-MDA clones display somatic hypermutations and lower reactivity. Importantly, these anti-MDA antibodies had significant in vitro functional properties and induced enhanced osteoclastogenesis, while the natural antibody related high-reactivity clone did not. We postulate that these may represent distinctly different facets of anti-MDA autoreactive responses.

KW - autoimmunity

KW - oxidation

KW - malondialdehyde acetaldehyde modification

KW - natural autoantibodies

KW - rheumatoid arthritis

U2 - 10.1016/j.jaut.2017.06.004

DO - 10.1016/j.jaut.2017.06.004

M3 - Abstract

JO - Journal of Autoimmunity

JF - Journal of Autoimmunity

SN - 0896-8411

ER -