Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in Lyme arthritis

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Abstract

Pathogen specific antibody responses need to be tightly regulated to generate protective but limit self-reactive immune responses. While loss of humoral tolerance has been associated with microbial infections, the pathways involved in balancing protective versus autoreactive antibody responses in humans are incompletely understood. Studies in classical mouse model systems have provided evidence that balancing of immune responses through inhibitory receptors is an important quality control checkpoint. Genetic differences between inbred mouse models and the outbred human population and allelic receptor variants not present in mice, however, argue for caution when directly translating these findings to the human system. By studying Borrelia burgdorferi infection in humanized mice reconstituted with human hematopoietic stem cells from donors homozygous for a functional or non-functional FcgRIIb allele, we show that the human inhibitory FcgRIIb is a critical checkpoint balancing protective and autoreactive immune responses, linking infection with induction of autoimmunity in the human immune system.

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All data generated and analysed during the study are included in the manuscript. Source data files can be provided on request.

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Heike Danzer

Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

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The authors declare that no competing interests exist.
Joachim Glaesner

Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany

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The authors declare that no competing interests exist.
Anne Baerenwaldt

Biomedicine, University Hospital Basel, Basel, Switzerland

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The authors declare that no competing interests exist.
Carmen Reitinger

Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

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The authors declare that no competing interests exist.
Anja Lux

Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

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The authors declare that no competing interests exist.
Lukas Heger

Dermatology, University Hospital Erlangen, Erlangen, Germany

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The authors declare that no competing interests exist.
Diane Dudziak

Dermatology, University Hospital Erlangen, Erlangen, Germany

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The authors declare that no competing interests exist.
Thomas Harrer

Medicine III, University Hospital Erlangen, Erlangen, Germany

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The authors declare that no competing interests exist.
André Gessner

Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4316-2408
Falk Nimmerjahn

Departemtn of Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

For correspondence
falk.nimmerjahn@fau.de

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The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5418-316X

Funding

Deutsche Forschungsgemeinschaft (TRR130-P13)

Falk Nimmerjahn

Deutsche Forschungsgemeinschaft (FOR 2886)

Falk Nimmerjahn

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were performed in strict accordance to the rules and regulations of the German animal welfare law. All animal experiments were approved by the government of lower Franconia (Permit Numbers: 2532-2-469 and 2532.2-817-11).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.