Antibody neutralization of microbiota-derived circulating peptidoglycan dampens inflammation and ameliorates autoimmunity
| Autor: | Kong-Peng Lam, Wern Cui Chu, Jianhe Wang, Leo A. B. Joosten, Haishan Wang, Khai Pang Leong, Norman Pavelka, Yuan Qiao, Yue Wang, Fabien Cottier, Marije Oosting, Xiaoli Xu, Zhen-Xing Huang, Shengli Xu, Louis Yi Ann Chai, Mihai G. Netea, Sven Pettersson, Carol Ng, Parag Kundu |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine), Singapore Centre for Environmental Life Sciences and Engineering (SCELSE) |
| Rok vydání: | 2019 |
| Předmět: |
Microbiology (medical)
medicine.drug_class Immunology lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] medicine.disease_cause Monoclonal antibody Applied Microbiology and Biotechnology Microbiology Autoimmune Diseases Autoimmunity 03 medical and health sciences chemistry.chemical_compound All institutes and research themes of the Radboud University Medical Center Immune system Antimicrobial Responses NOD2 Genetics medicine Medicine [Science] 030304 developmental biology Autoimmune disease 0303 health sciences biology 030306 microbiology Experimental autoimmune encephalomyelitis Cell Biology medicine.disease chemistry biology.protein Peptidoglycan Antibody |
| Zdroj: | Nature Microbiology, 4, 766-773 Nature Microbiology, 4, 5, pp. 766-773 |
| ISSN: | 2058-5276 |
| DOI: | 10.1038/s41564-019-0381-1 |
| Popis: | 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. National Medical Research Council (NMRC) This work was supported by National Medical Research Council grant no. BMRC/ BnB/0001b/2012 awarded to Y.W., L.C., and N.P. |
| Databáze: | OpenAIRE |
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