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. 2023 Feb:135:102988.
doi: 10.1016/j.jaut.2022.102988. Epub 2023 Jan 11.

Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis

Jean-Baptiste Vulsteke  1 , Vanessa Smith  2 , Carolien Bonroy  3 , Rita Derua  4 , Daniel Blockmans  5 , Petra De Haes  6 , Steven Vanderschueren  7 , Jan L Lenaerts  8 , Kristl G Claeys  9 , Wim A Wuyts  10 , Patrick Verschueren  1 , Gilles Vanhandsaeme  11 , Yves Piette  12 , Ellen De Langhe  13 , Xavier Bossuyt  14
Affiliations

Identification of new telomere- and telomerase-associated autoantigens in systemic sclerosis

Jean-Baptiste Vulsteke et al. J Autoimmun. 2023 Feb.

Abstract

Purpose: In up to 20% of patients with systemic sclerosis (SSc) no known autoantibody specificity can be identified. Recently discovered autoantigens, such as telomeric repeat binding factor 1 (TERF1), as well as established autoantigens, like RuvBL1/2, are associated with telomere and telomerase biology. We aimed to identify new telomere- and telomerase-associated autoantigens in patients with SSc without known autoantibody specificity.

Methods: Unlabelled protein immunoprecipitation combined with gel-free liquid chromatography-tandem mass spectrometry (IP-MS) was performed with sera of 106 patients with SSc from two tertiary referral centres that had a nuclear pattern on HEp-2 indirect immunofluorescence without previously identified autoantibody. Telomere- or telomerase-associated proteins or protein complexes precipitated by individual sera were identified. Candidate autoantigens were confirmed through immunoprecipitation-western blot (IP-WB). A custom Luminex xMAP assay for 5 proteins was evaluated with sera from persons with SSc (n = 467), other systemic autoimmune rheumatic diseases (n = 923), non-rheumatic disease controls (n = 187) and healthy controls (n = 199).

Results: Eight telomere- and telomerase-associated autoantigens were identified in a total of 11 index patients, including the THO complex (n = 3, all with interstitial lung disease and two with cardiac involvement), telomeric repeat-binding factor 2 (TERF2, n = 1), homeobox-containing protein 1 (HMBOX1, n = 2), regulator of chromosome condensation 1 (RCC1, n = 1), nucleolar and coiled-body phosphoprotein 1 (NOLC1, n = 1), dyskerin (DKC1, n = 1), probable 28S rRNA (cytosine(4447)-C(5))-methyltransferase (NOP2, n = 1) and nuclear valosin-containing protein-like (NVL, n = 2). A Luminex xMAP assay for THO complex subunit 1 (THOC1), TERF2, NOLC1, NOP2 and NVL revealed high reactivity in all index patients, but also in other patients with SSc and disease controls. However, the reactivity by xMAP assay in these other patients was not confirmed by IP-WB.

Conclusion: IP-MS revealed key telomere- and telomerase-associated proteins and protein complexes as autoantigens in patients with SSc.

Keywords: Autoantibodies; Mass spectrometry; Systemic sclerosis; Telomerase; Telomere.

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Conflict of interest statement

Declaration of competing interest VS: grants: Janssen. WW: grants: Roche, Boehringer Ingelheim, Galapagos; consulting fees: Roche, Boehringer Ingelheim, Galapagos. EDL: payment or honoraria for lectures: Actelion, Lilly; support for attending meetings: Pfizer, Boehringer Ingelheim, Lilly, MSD, participation on advisory board: AC Immune, Boehringer Ingelheim, Amgen, Astra Zeneca, GSK, Novartis, Otsuka. Leadership role: co-president of the Working Group Rare Diseases, Belgian Royal Society of Rheumatology. XB: payment or honoraria for lectures: Werfen, Thermo Fisher Scientific, participation on advisory board: Werfen, Thermo Fisher Scientific. All abovementioned interests were outside the scope of the current work. JV, EDL and XB have filed a patent for detection of anti-THO autoantibodies. VS, CB, RD, DB, PDH, SV, JLL, KGC, PV, GV and YP do not declare any competing interests.

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