Format

Send to

Choose Destination
Nat Immunol. 2019 Oct;20(10):1311-1321. doi: 10.1038/s41590-019-0482-2. Epub 2019 Sep 16.

SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.

Author information

1
Immunobiology Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.
2
Cambridge Institute of Therapeutic Immunology & Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, UK.
3
Immunodeficiency Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.
4
Division of Dermatology and Dermatology Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.
5
Competence Center for Personalized Medicine University of Zürich/Eidgenössische Technische Hochschule, Zürich, Switzerland.
6
Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
7
Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, MI, USA.
8
Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
9
Department of Physiology, McGill University, Montreal, Quebec, Canada.
10
Epigenomics Group, D-BSSE, Eidgenössische Technische Hochschule, Basel, Switzerland.
11
Immunobiology Laboratory, entro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
12
Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Washington DC, USA.
13
Bioinformatics Facility, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland.
14
Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
15
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
16
Electron Microscopy Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
17
Division of Hematology and Oncology, Claraspital, Basel, Switzerland.
18
Division Medical Immunology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.
19
Division of Hematology, Cantonal Hospital of Aarau, Aargau, Switzerland.
20
Division of Internal Medicine and Rheumatology, Hospital St. Anna, Luzern, Switzerland.
21
Division of Infectious Diseases, Children's Hospital of St. Gallen, St. Gallen, Switzerland.
22
Immunobiology Laboratory, Department of Biomedicine, University and University Hospital of Basel, Basel, Switzerland. chess@uhbs.ch.
23
Cambridge Institute of Therapeutic Immunology & Infectious Disease, Department of Medicine, University of Cambridge, Cambridge, UK. chess@uhbs.ch.

Abstract

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.

PMID:
31527833
DOI:
10.1038/s41590-019-0482-2

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center