GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

Otavio Cabral-Marques; Alexandre Marques; Lasse Melvær Giil; Roberta De Vito; Judith Rademacher; Jeannine Günther; Tanja Lange; Jens Y. Humrich; Sebastian Klapa; Susanne Schinke; Lena F. Schimke; Gabriele Marschner; Silke Pitann; Sabine Adler; Ralf Dechend; Dominik N. Müller; Ioana Braicu; Jalid Sehouli; Kai Schulze-Forster; Tobias Trippel; Carmen Scheibenbogen; Annetine Staff; Peter R. Mertens; Madlen Löbel; Justin Mastroianni; Corinna Plattfaut; Frank Gieseler; Duska Dragun; Barbara Elizabeth Engelhardt; Maria J. Fernandez-Cabezudo; Hans D. Ochs; Basel K. al-Ramadi; Peter Lamprecht; Antje Mueller; Harald Heidecke; Gabriela Riemekasten

doi:10.1038/s41467-018-07598-9

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

Otavio Cabral-Marques^*, Alexandre Marques, Lasse Melvær Giil, Roberta De Vito, Judith Rademacher, Jeannine Günther, Tanja Lange, Jens Y. Humrich, Sebastian Klapa, Susanne Schinke, Lena F. Schimke, Gabriele Marschner, Silke Pitann, Sabine Adler, Ralf Dechend, Dominik N. Müller, Ioana Braicu, Jalid Sehouli, Kai Schulze-Forster, Tobias TrippelCarmen Scheibenbogen, Annetine Staff, Peter R. Mertens, Madlen Löbel, Justin Mastroianni, Corinna Plattfaut, Frank Gieseler, Duska Dragun, Barbara Elizabeth Engelhardt, Maria J. Fernandez-Cabezudo, Hans D. Ochs, Basel K. al-Ramadi, Peter Lamprecht, Antje Mueller, Harald Heidecke, Gabriela Riemekasten

^*Corresponding author for this work

133 Citations (Scopus)

Abstract

Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.

Original language	English
Article number	5224
Journal	Nature Communications
Volume	9
Issue number	1
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-018-07598-9
Publication status	Published - 01.12.2018

Funding

We thank all patients and HD for their participation in this study. We acknowledge Prof. Xinhua Yu and Prof. Frank Petersen from the Research Center Borstel, Airway Research Center North (ARCN), and Members of the German Center for Lung Research (DZL), Borstel, Germany, for providing sera from EDNRA-immunized and non-immunized mice. We thank the Mirjam Lichy Foundation for their support as well as the DFG (grant no. RI 1056-11/12) for financial support. We also thank Actelion Pharmaceutical GmbH, the Eppenauer/Gutzeit Foundation, the German Network of Systemic Sclerosis and the EUSTAR network for their support. This study was supported by the Charité University Hospital in Berlin and University Hospital of Schleswig-Holstein, Campus Lübeck.

Research Areas and Centers

Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

UN SDGs

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

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10.1038/s41467-018-07598-9

Cite this

Cabral-Marques, O., Marques, A., Giil, L. M., De Vito, R., Rademacher, J., Günther, J., Lange, T., Humrich, J. Y., Klapa, S., Schinke, S., Schimke, L. F., Marschner, G., Pitann, S., Adler, S., Dechend, R., Müller, D. N., Braicu, I., Sehouli, J., Schulze-Forster, K., ... Riemekasten, G. (2018). GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis. Nature Communications, 9(1), Article 5224. https://doi.org/10.1038/s41467-018-07598-9

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title = "GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis",

abstract = "Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer{\textquoteright}s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.",

author = "Otavio Cabral-Marques and Alexandre Marques and Giil, \{Lasse Melv{\ae}r\} and \{De Vito\}, Roberta and Judith Rademacher and Jeannine G{\"u}nther and Tanja Lange and Humrich, \{Jens Y.\} and Sebastian Klapa and Susanne Schinke and Schimke, \{Lena F.\} and Gabriele Marschner and Silke Pitann and Sabine Adler and Ralf Dechend and M{\"u}ller, \{Dominik N.\} and Ioana Braicu and Jalid Sehouli and Kai Schulze-Forster and Tobias Trippel and Carmen Scheibenbogen and Annetine Staff and Mertens, \{Peter R.\} and Madlen L{\"o}bel and Justin Mastroianni and Corinna Plattfaut and Frank Gieseler and Duska Dragun and Engelhardt, \{Barbara Elizabeth\} and Fernandez-Cabezudo, \{Maria J.\} and Ochs, \{Hans D.\} and al-Ramadi, \{Basel K.\} and Peter Lamprecht and Antje Mueller and Harald Heidecke and Gabriela Riemekasten",

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Cabral-Marques, O, Marques, A, Giil, LM, De Vito, R, Rademacher, J, Günther, J, Lange, T , Humrich, JY, Klapa, S, Schinke, S, Schimke, LF, Marschner, G, Pitann, S, Adler, S, Dechend, R, Müller, DN, Braicu, I, Sehouli, J, Schulze-Forster, K, Trippel, T, Scheibenbogen, C, Staff, A, Mertens, PR, Löbel, M, Mastroianni, J, Plattfaut, C, Gieseler, F, Dragun, D, Engelhardt, BE, Fernandez-Cabezudo, MJ, Ochs, HD, al-Ramadi, BK, Lamprecht, P , Mueller, A, Heidecke, H & Riemekasten, G 2018, 'GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis', Nature Communications, vol. 9, no. 1, 5224. https://doi.org/10.1038/s41467-018-07598-9

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T1 - GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

AU - Cabral-Marques, Otavio

AU - Marques, Alexandre

AU - Giil, Lasse Melvær

AU - De Vito, Roberta

AU - Rademacher, Judith

AU - Günther, Jeannine

AU - Lange, Tanja

AU - Humrich, Jens Y.

AU - Klapa, Sebastian

AU - Schinke, Susanne

AU - Schimke, Lena F.

AU - Marschner, Gabriele

AU - Pitann, Silke

AU - Adler, Sabine

AU - Dechend, Ralf

AU - Müller, Dominik N.

AU - Braicu, Ioana

AU - Sehouli, Jalid

AU - Schulze-Forster, Kai

AU - Trippel, Tobias

AU - Scheibenbogen, Carmen

AU - Staff, Annetine

AU - Mertens, Peter R.

AU - Löbel, Madlen

AU - Mastroianni, Justin

AU - Plattfaut, Corinna

AU - Gieseler, Frank

AU - Dragun, Duska

AU - Engelhardt, Barbara Elizabeth

AU - Fernandez-Cabezudo, Maria J.

AU - Ochs, Hans D.

AU - al-Ramadi, Basel K.

AU - Lamprecht, Peter

AU - Mueller, Antje

AU - Heidecke, Harald

AU - Riemekasten, Gabriela

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.

AB - Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.

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DO - 10.1038/s41467-018-07598-9

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SN - 1751-8628

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5224

ER -

GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

Abstract

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UN SDGs

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