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Nat Microbiol. 2019 May;4(5):766-773. doi: 10.1038/s41564-019-0381-1. Epub 2019 Mar 4.

Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity.

Author information

1
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
2
Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China.
3
Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, Singapore.
4
Division of Infectious Diseases, University Medicine Cluster, National University Health System, Singapore, Singapore.
5
Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
6
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
7
Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
8
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands.
9
Clinical Immunology Laboratory, Tan Tock Seng Hospital, Singapore, Singapore.
10
Department of Rheumatology, Allergy and Immunology Laboratory, Tan Tock Seng Hospital, Singapore, Singapore.
11
Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore, Singapore.
12
Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technology University, Singapore, Singapore.
13
Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
14
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore. mcbwangy@imcb.a-star.edu.sg.
15
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. mcbwangy@imcb.a-star.edu.sg.

Abstract

The human microbiota provides tonic signals that calibrate the host immune response1,2, but their identity is unknown. Bacterial peptidoglycan (PGN) subunits are likely candidates since they are well-known immunity-enhancing adjuvants, released by most bacteria during growth, and have been found in the blood of healthy people3-7. We developed a monoclonal antibody (mAb), 2E7, that targets muramyl-L-alanyl-D-isoglutamine (MDP), a conserved and minimal immunostimulatory structure of PGN. Using 2E7-based assays, we detected PGN ubiquitously in human blood at a broad range of concentrations that is relatively stable in each individual. We also detected PGN in the serum of several warm-blooded animals. However, PGN is barely detectable in the serum of germ-free mice, indicating that its origin is the host microbiota. Neutralization of circulating PGN via intraperitoneal administration of 2E7 suppressed the development of autoimmune arthritis and experimental autoimmune encephalomyelitis in mice. Arthritic NOD2-/- mice lacking the MDP sensor did not respond to 2E7, indicating that 2E7 dampens inflammation by blocking nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-mediated pathways. We propose that circulating PGN acts as a natural immune potentiator that tunes the host immune response; altering its level is a promising therapeutic strategy for immune-mediated diseases.

PMID:
30833732
DOI:
10.1038/s41564-019-0381-1
[Indexed for MEDLINE]

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