Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Franziska Sotzny; Igor Salerno Filgueiras; Claudia Kedor; Helma Freitag; Kirsten Wittke; Sandra Bauer; Nuno Sepúlveda; Dennyson Leandro Mathias da Fonseca; Gabriela Crispim Baiocchi; Alexandre H.C. Marques; Myungjin Kim; Tanja Lange; Desirée Rodrigues Plaça; Finn Luebber; Frieder M. Paulus; Roberta De Vito; Igor Jurisica; Kai Schulze-Forster; Friedemann Paul; Judith Bellmann-Strobl; Rebekka Rust; Uta Hoppmann; Yehuda Shoenfeld; Gabriela Riemekasten; Harald Heidecke; Otavio Cabral-Marques; Carmen Scheibenbogen

doi:10.3389/fimmu.2022.981532

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Franziska Sotzny^*, Igor Salerno Filgueiras^*, Claudia Kedor, Helma Freitag, Kirsten Wittke, Sandra Bauer, Nuno Sepúlveda, Dennyson Leandro Mathias da Fonseca, Gabriela Crispim Baiocchi, Alexandre H.C. Marques, Myungjin Kim, Tanja Lange, Desirée Rodrigues Plaça, Finn Luebber, Frieder M. Paulus, Roberta De Vito, Igor Jurisica, Kai Schulze-Forster, Friedemann Paul, Judith Bellmann-StroblRebekka Rust, Uta Hoppmann, Yehuda Shoenfeld, Gabriela Riemekasten, Harald Heidecke, Otavio Cabral-Marques^*, Carmen Scheibenbogen^*

^*Corresponding author for this work

81 Citations (Scopus)

Abstract

Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

Original language	English
Article number	981532
Journal	Frontiers in Immunology
Volume	13
ISSN	1664-3224
DOIs	https://doi.org/10.3389/fimmu.2022.981532
Publication status	Published - 27.09.2022

Funding

CS, FS, HF, CK and KW thank the Weidenhammer Zoebele and CS the Lost Voices Foundation, Germany for financial support. We also thank the São Paulo Research Foundation (FAPESP grants 2020/07972-1 to GB; 2018/18886-9, 2020/01688-0, and 2020/07069-0 to OC-M; 2020/16246-2 to DF; 2020/11710-2 to DP), and the Coordination for the Improvement of Higher Education Personnel (CAPES) Financial Code 001 (grant to IF) for financial support. IJ was supported in part by the grants from Ontario Research Fund (#34876), Natural Sciences Research Council (NSERC #203475) and Canada Foundation for Innovation (CFI #29272, #225404, #33536). NS received funding from FCT - Fundação para a Ciência e Tecnologia, Portugal (ref. grant: UIDB/00006/2020) and NAWA - Polish National Agency for Academic Exchange (ref. grant: PPN/ULM/2020/1/00069/U/00001). The authors declare that HH and KS-F are managing directors of CellTrend. CellTrend holds together with Charité a patent for the diagnostic use of AABs against ADRB2. CS has a consulting agreement with CellTrend. FP reports grants from the Guthy Jackson Charitable Foundation, during the conduct of the study.

UN SDGs

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

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

2.22-18 Rheumatology
2.21-05 Immunology

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

Access to Document

10.3389/fimmu.2022.981532

Cite this

Sotzny, F., Filgueiras, I. S., Kedor, C., Freitag, H., Wittke, K., Bauer, S., Sepúlveda, N., Mathias da Fonseca, D. L., Baiocchi, G. C., Marques, A. H. C., Kim, M., Lange, T., Plaça, D. R., Luebber, F., Paulus, F. M., De Vito, R., Jurisica, I., Schulze-Forster, K., Paul, F., ... Scheibenbogen, C. (2022). Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Frontiers in Immunology, 13, Article 981532. https://doi.org/10.3389/fimmu.2022.981532

@article{66563662f1b1479fbcba9978baf4a963,

title = "Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity",

abstract = "Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.",

author = "Franziska Sotzny and Filgueiras, \{Igor Salerno\} and Claudia Kedor and Helma Freitag and Kirsten Wittke and Sandra Bauer and Nuno Sep{\'u}lveda and \{Mathias da Fonseca\}, \{Dennyson Leandro\} and Baiocchi, \{Gabriela Crispim\} and Marques, \{Alexandre H.C.\} and Myungjin Kim and Tanja Lange and Pla{\c c}a, \{Desir{\'e}e Rodrigues\} and Finn Luebber and Paulus, \{Frieder M.\} and \{De Vito\}, Roberta and Igor Jurisica and Kai Schulze-Forster and Friedemann Paul and Judith Bellmann-Strobl and Rebekka Rust and Uta Hoppmann and Yehuda Shoenfeld and Gabriela Riemekasten and Harald Heidecke and Otavio Cabral-Marques and Carmen Scheibenbogen",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 Sotzny, Filgueiras, Kedor, Freitag, Wittke, Bauer, Sep{\'u}lveda, Mathias da Fonseca, Baiocchi, Marques, Kim, Lange, Pla{\c c}a, Luebber, Paulus, De Vito, Jurisica, Schulze-Forster, Paul, Bellmann-Strobl, Rust, Hoppmann, Shoenfeld, Riemekasten, Heidecke, Cabral-Marques and Scheibenbogen.",

year = "2022",

month = sep,

day = "27",

doi = "10.3389/fimmu.2022.981532",

language = "English",

volume = "13",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Media",

}

Sotzny, F, Filgueiras, IS, Kedor, C, Freitag, H, Wittke, K, Bauer, S, Sepúlveda, N, Mathias da Fonseca, DL, Baiocchi, GC, Marques, AHC, Kim, M, Lange, T, Plaça, DR, Luebber, F, Paulus, FM, De Vito, R, Jurisica, I, Schulze-Forster, K, Paul, F, Bellmann-Strobl, J, Rust, R, Hoppmann, U, Shoenfeld, Y, Riemekasten, G, Heidecke, H, Cabral-Marques, O & Scheibenbogen, C 2022, 'Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity', Frontiers in Immunology, vol. 13, 981532. https://doi.org/10.3389/fimmu.2022.981532

TY - JOUR

T1 - Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

AU - Sotzny, Franziska

AU - Filgueiras, Igor Salerno

AU - Kedor, Claudia

AU - Freitag, Helma

AU - Wittke, Kirsten

AU - Bauer, Sandra

AU - Sepúlveda, Nuno

AU - Mathias da Fonseca, Dennyson Leandro

AU - Baiocchi, Gabriela Crispim

AU - Marques, Alexandre H.C.

AU - Kim, Myungjin

AU - Lange, Tanja

AU - Plaça, Desirée Rodrigues

AU - Luebber, Finn

AU - Paulus, Frieder M.

AU - De Vito, Roberta

AU - Jurisica, Igor

AU - Schulze-Forster, Kai

AU - Paul, Friedemann

AU - Bellmann-Strobl, Judith

AU - Rust, Rebekka

AU - Hoppmann, Uta

AU - Shoenfeld, Yehuda

AU - Riemekasten, Gabriela

AU - Heidecke, Harald

AU - Cabral-Marques, Otavio

AU - Scheibenbogen, Carmen

N1 - Publisher Copyright: Copyright © 2022 Sotzny, Filgueiras, Kedor, Freitag, Wittke, Bauer, Sepúlveda, Mathias da Fonseca, Baiocchi, Marques, Kim, Lange, Plaça, Luebber, Paulus, De Vito, Jurisica, Schulze-Forster, Paul, Bellmann-Strobl, Rust, Hoppmann, Shoenfeld, Riemekasten, Heidecke, Cabral-Marques and Scheibenbogen.

PY - 2022/9/27

Y1 - 2022/9/27

N2 - Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

AB - Most patients with Post COVID Syndrome (PCS) present with a plethora of symptoms without clear evidence of organ dysfunction. A subset of them fulfills diagnostic criteria of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Symptom severity of ME/CFS correlates with natural regulatory autoantibody (AAB) levels targeting several G-protein coupled receptors (GPCR). In this exploratory study, we analyzed serum AAB levels against vaso- and immunoregulatory receptors, mostly GPCRs, in 80 PCS patients following mild-to-moderate COVID-19, with 40 of them fulfilling diagnostic criteria of ME/CFS. Healthy seronegative (n=38) and asymptomatic post COVID-19 controls (n=40) were also included in the study as control groups. We found lower levels for various AABs in PCS compared to at least one control group, accompanied by alterations in the correlations among AABs. Classification using random forest indicated AABs targeting ADRB2, STAB1, and ADRA2A as the strongest classifiers (AABs stratifying patients according to disease outcomes) of post COVID-19 outcomes. Several AABs correlated with symptom severity in PCS groups. Remarkably, severity of fatigue and vasomotor symptoms were associated with ADRB2 AAB levels in PCS/ME/CFS patients. Our study identified dysregulation of AAB against various receptors involved in the autonomous nervous system (ANS), vaso-, and immunoregulation and their correlation with symptom severity, pointing to their role in the pathogenesis of PCS.

UR - https://www.scopus.com/pages/publications/85139568724

U2 - 10.3389/fimmu.2022.981532

DO - 10.3389/fimmu.2022.981532

M3 - Journal articles

C2 - 36238301

AN - SCOPUS:85139568724

SN - 1664-3224

VL - 13

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 981532

ER -

Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity

Abstract

Funding

UN SDGs

Research Areas and Centers

DFG Research Classification Scheme

Coronavirus related work

Access to Document

Other files and links

Fingerprint

Cite this