Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis

Eva Maria Stork; Danique M H van Rijswijck; Karin A van Schie; Max Hoek; Theresa Kissel; Hans Ulrich Scherer; Tom W J Huizinga; Albert J R Heck; Rene E M Toes; Albert Bondt

doi:10.1038/s41467-024-47337-x

Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis

Eva Maria Stork, Danique M H van Rijswijck, Karin A van Schie, Max Hoek, Theresa Kissel, Hans Ulrich Scherer, Tom W J Huizinga, Albert J R Heck, Rene E M Toes, Albert Bondt^*

^*Corresponding author for this work

Leiden University Medical Center

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance mechanisms, but unknown due to limitations of the currently applied technologies. Here, we introduce an autoantigen-specific liquid chromatography-mass spectrometry-based IgG1 Fab profiling approach using the anti-citrullinated protein antibody (ACPA) repertoire in rheumatoid arthritis (RA) as an example. We show that each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab glycans, and different glycovariants of the same clone can be detected. Together, our data indicate that the autoantibody response in a prominent human autoimmune disease is complex, unique to each patient and dominated by a relatively low number of clones.

Original language	English
Article number	3114
Number of pages	12
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47337-x
Publication status	Published - 10 Apr 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Funding

This research received funding through the Dutch Research Council (NWO) funding the Netherlands Proteomics Center through the X-omics Road Map program (project 184.034.019) as well as from the NWO gravitation program \u201CInstitute for Chemical Immunology\u201D (Subgrant 00022, NWO-024.002.009 to T.W.J.H. and A.J.R.H.), ReumaNederland (LLP5 to T.W.J.H. and R.E.M.T.), the IMI funded project RTCure (777357 to T.W.J.H. and R.E.M.T.), Target to B! (LSHM18055-5GF to R.E.M.T.) and the European Research Council (ERC, GlycanSwitch, 101071386 to T.W.J.H.). A.J.R.H. acknowledges support from NWO through the Spinoza Award SPI.2017.028. R.E.M.T. acknowledges support from the ERC as the recipient of an ERC advanced grant (AdG2019-884796). Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them. We moreover thank Gerrie Stoeken-Rijsbergen and Mirjam Damen for technical assistance, Dietmar Reusch and Markus Haberger (Roche, Penzberg) for the kind donation of trastuzumab, Genmab for the donation of alemtuzumab, as well as Jan Wouter Drijfhout for kindly providing the citrullinated and non-modified peptides.

Funders	Funder number
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
European Research Executive Agency
Netherlands Proteomics Center	184.034.019, NWO-024.002.009, 00022
European Research Council	101071386, AdG2019-884796
Innovative Medicines Initiative	777357, LSHM18055-5GF

Keywords

Anti-Citrullinated Protein Antibodies
Arthritis, Rheumatoid
Autoantibodies
Autoantigens
Humans
Immunoglobulin G

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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s41467-024-47337-xFinal published version, 1.46 MBLicence: CC BY

Cite this

Stork, E. M., van Rijswijck, D. M. H., van Schie, K. A., Hoek, M., Kissel, T., Scherer, H. U., Huizinga, T. W. J., Heck, A. J. R., Toes, R. E. M., & Bondt, A. (2024). Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis. Nature Communications, 15(1), Article 3114. https://doi.org/10.1038/s41467-024-47337-x

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Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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