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

  1. Heike Danzer
  2. Joachim Glaesner
  3. Anne Baerenwaldt
  4. Carmen Reitinger
  5. Anja Lux
  6. Lukas Heger
  7. Diane Dudziak
  8. Thomas Harrer
  9. André Gessner
  10. Falk Nimmerjahn  Is a corresponding author
  1. Division of Genetics, University of Erlangen-Nuremberg, Germany
  2. University Hospital Regensburg, Germany
  3. University Hospital Basel, Switzerland
  4. University Hospital Erlangen, Germany

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.

Data availability

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

Article and author information

Author details

  1. Heike Danzer

    Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Joachim Glaesner

    Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Anne Baerenwaldt

    Biomedicine, University Hospital Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  4. Carmen Reitinger

    Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Anja Lux

    Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Lukas Heger

    Dermatology, University Hospital Erlangen, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Diane Dudziak

    Dermatology, University Hospital Erlangen, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Thomas Harrer

    Medicine III, University Hospital Erlangen, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. André Gessner

    Institute of Clinical Microbiology and Hygiene, University Hospital Regensburg, Regensburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4316-2408
  10. Falk Nimmerjahn

    Departemtn of Biology, Division of Genetics, University of Erlangen-Nuremberg, Erlangen, Germany
    For correspondence
    falk.nimmerjahn@fau.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "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).

Reviewing Editor

  1. Tomohiro Kurosaki, Osaka University, Japan

Publication history

  1. Received: January 20, 2020
  2. Accepted: July 2, 2020
  3. Accepted Manuscript published: July 2, 2020 (version 1)
  4. Version of Record published: August 19, 2020 (version 2)

Copyright

© 2020, Danzer et al.

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.

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  1. Heike Danzer
  2. Joachim Glaesner
  3. Anne Baerenwaldt
  4. Carmen Reitinger
  5. Anja Lux
  6. Lukas Heger
  7. Diane Dudziak
  8. Thomas Harrer
  9. André Gessner
  10. Falk Nimmerjahn
(2020)
Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in Lyme arthritis
eLife 9:e55319.
https://doi.org/10.7554/eLife.55319

Further reading

    1. Epidemiology and Global Health
    2. Immunology and Inflammation
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    Research Article Updated

    Background:

    The combined impact of immunity and SARS-CoV-2 variants on viral kinetics during infections has been unclear.

    Methods:

    We characterized 1,280 infections from the National Basketball Association occupational health cohort identified between June 2020 and January 2022 using serial RT-qPCR testing. Logistic regression and semi-mechanistic viral RNA kinetics models were used to quantify the effect of age, variant, symptom status, infection history, vaccination status and antibody titer to the founder SARS-CoV-2 strain on the duration of potential infectiousness and overall viral kinetics. The frequency of viral rebounds was quantified under multiple cycle threshold (Ct) value-based definitions.

    Results:

    Among individuals detected partway through their infection, 51.0% (95% credible interval [CrI]: 48.3–53.6%) remained potentially infectious (Ct <30) 5 days post detection, with small differences across variants and vaccination status. Only seven viral rebounds (0.7%; N=999) were observed, with rebound defined as 3+days with Ct <30 following an initial clearance of 3+days with Ct ≥30. High antibody titers against the founder SARS-CoV-2 strain predicted lower peak viral loads and shorter durations of infection. Among Omicron BA.1 infections, boosted individuals had lower pre-booster antibody titers and longer clearance times than non-boosted individuals.

    Conclusions:

    SARS-CoV-2 viral kinetics are partly determined by immunity and variant but dominated by individual-level variation. Since booster vaccination protects against infection, longer clearance times for BA.1-infected, boosted individuals may reflect a less effective immune response, more common in older individuals, that increases infection risk and reduces viral RNA clearance rate. The shifting landscape of viral kinetics underscores the need for continued monitoring to optimize isolation policies and to contextualize the health impacts of therapeutics and vaccines.

    Funding:

    Supported in part by CDC contract #200-2016-91779, a sponsored research agreement to Yale University from the National Basketball Association contract #21-003529, and the National Basketball Players Association.

    1. Immunology and Inflammation
    Sara E Vazquez, Sabrina A Mann ... Joseph L DeRisi
    Research Advance Updated

    Phage immunoprecipitation sequencing (PhIP-seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-seq for autoantigen discovery, including our previous work (Vazquez et al., 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki disease (KD), multisystem inflammatory syndrome in children (MIS-C), and finally, mild and severe forms of COVID-19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as prodynorphin (PDYN) in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in two patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID-19, including the endosomal protein EEA1. Together, scaled PhIP-seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.