Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease

doi:10.1016/S0140-6736(05)66582-8

The Lancet

Volume 365, Issue 9473, 21–27 May 2005, Pages 1794-1796

https://doi.org/10.1016/S0140-6736(05)66582-8 Get rights and content

Summary

Both NOD2 (CARD15) alleles are mutated in roughly 15% of patients with Crohn's disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFα or interleukin 1β, but strong interleukin-8 secretion. MDP also substantially upregulated secretion of TNFα and interleukin 1β induced by toll-like receptor ligands. These effects were abolished by the most common Crohn's NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn's disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NOD2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.

References (8)

S Lesage et al.
CARD15/ NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease
Am J Hum Genet
(2002)
N Inohara et al.
Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease
J Biol Chem
(2003)
SE Girardin et al.
Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection
J Biol Chem
(2003)
S Traub et al.
Structural requirements of synthetic muropeptides to synergize with lipopolysaccharide in cytokine induction
J Biol Chem
(2004)

There are more references available in the full text version of this article.

Cited by (274)

Genetic and Clinical Features of Blau Syndrome among Chinese Patients with Uveitis
2022, Ophthalmology
The American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology call for cautious interpretation of variants as causative of a monogenic disorder by stringent standards. We aimed to reclassify the pathogenicity of nucleotide binding oligomerization domain containing 2 (NOD2) variants according to the ACMG guidelines and to characterize clinical features in patients whose ocular disease might actually be explained by Blau syndrome.
Genetic analysis and descriptive study.
A total of 1003 unrelated healthy individuals and 3921 sporadic patients who presented with uveitis.
Whole-exome sequencing was performed on all healthy participants and 551 patients with uveitis, and targeted NOD2 resequencing was performed on the remaining 3370 patients with uveitis. Pathogenicity for Blau syndrome was classified for NOD2 variants identified by sequencing in study participants according to the ACMG guidelines. Clinical manifestations were compared among NOD2 variants of different levels of classification.
Pathogenicity of variants.
Eight NOD2 gain-of-function mutations, p.R334W, p.R334Q, p.E383K, p.G481D, p.W490S, p.M513T, p.R587C, and p.N670K, were classified as pathogenic, and 66 patients (1.7%) with uveitis were diagnosed with Blau syndrome due to these mutations. Of 66 with Blau syndrome, anterior uveitis accounted for 39.4%, posterior uveitis for 9.1%, and panuveitis for 51.5%. A proportion of 21.2% of Blau syndrome presented as multifocal choroiditis, 48.5% had papillitis, and 74.2% showed retinal microvasculitis detected by fundus fluorescein angiography. Six NOD2 variants, p.P268S, p.R311W, p.R471C, p.A612T, p.R702W, and p.V955I, were considered nonpathogenic for Blau syndrome and were identified in 96 patients with uveitis. The incidence of bilateral uveitis (86.4%), secondary glaucoma (47.0%), epiretinal membrane (7.6%), choroidal neovascularization (4.6%), retinal atrophy (10.6%), arthritis (69.7%), joint deformity (51.5%), and skin rash (40.9%) was higher in Blau syndrome than in patients with uveitis carrying non–Blau-causing NOD2 variants. Patients with Blau syndrome permanently experienced overall poorer best-corrected visual acuity. Several rare NOD2 mutations, p.I722L (2 cases), p.T476P (1 case), p.T476del (1 case), and p.R439H (1 case), were newly identified.
Pathogenic NOD2 variants for Blau syndrome were limited to those gain-of-function mutations and were associated with a high risk for arthritis, skin rash, permanent visual loss, and ocular complications in patients with uveitis.
Influence of NOD-like receptor 2 gene polymorphisms on muramyl dipeptide induced pro-inflammatory response in patients with active pulmonary tuberculosis and household contacts
2021, Immunobiology
The immune response induced by nucleotide-binding oligomerization domain-2(NOD2) is associated with the production of cytokines affected by the host's genetic background. The present study aimed to examine the effects of NOD2; 802C > T, 2105G > A polymorphisms associated with altered cytokine levels in patients with active pulmonary tuberculosis disease, Latent TB subjects (household contacts(HHC) and healthy controls(HC).
Genetic polymorphisms were analyzed by Restriction Fragment Length Polymorphism(RFLP) in 102-PTB patients, 102-HHC, and 132-HC. QuantiFERON-TB Gold In-Tube test was performed to identify latent TB infection in 60-HHC. Estimated their cytokine levels by ELISA in MDP (muramyl dipeptide) stimulated culture supernatants of all the groups. Further, we studied pre-mRNA structures by insilico analysis and relative gene expression by RT-PCR.
Recessive genetic models of NOD2 802C > T SNP with TT genotype and AA genotype of NOD2 2105G > A SNP were significantly associated with increased TB risk in PTB patients and HHC compared with HC. In vitro stimulations were performed with NOD2 ligand MDP in PTB patients and latent TB subjects: QuantiFERON positive household contacts (QFT + ve HHC)and QuantiFERON negative household contacts(QFT-ve HHC). The results showed that reduced TNF-α and enhanced IL-12, IL-1β indicate that these cytokines may play an essential role in the initial maintenance of cell-mediated immunity. Our study demonstrated the correlation between NOD2 polymorphism with IL-1β, TNF-α, IL-12 levels. Insilico analysis represents the pre-mRNA secondary structures affected by NOD2 SNPs. We also observed the difference in m RNA levels in variant and wild genotypes.
This finding may lead to the forthcoming development of immunotherapy and may be used as predictive markers to identify high-risk individuals for TB disease.
Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease
2024, Scientific Reports
γδ T cells: origin and fate, subsets, diseases and immunotherapy
2023, Signal Transduction and Targeted Therapy
Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease
2023, Research Square
Exploring the Potential of Fecal Microbiota Transplantation as a Therapy in Tuberculosis and Inflammatory Bowel Disease
2023, Pathogens

View all citing articles on Scopus

View full text

Article preview

The Lancet

Summary

References (8)

CARD15/ NOD2 mutational analysis and genotype-phenotype correlation in 612 patients with inflammatory bowel disease

Am J Hum Genet

Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease

J Biol Chem

Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection

J Biol Chem

Structural requirements of synthetic muropeptides to synergize with lipopolysaccharide in cytokine induction

J Biol Chem

Cited by (274)

Genetic and Clinical Features of Blau Syndrome among Chinese Patients with Uveitis

Influence of NOD-like receptor 2 gene polymorphisms on muramyl dipeptide induced pro-inflammatory response in patients with active pulmonary tuberculosis and household contacts

Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease

γδ T cells: origin and fate, subsets, diseases and immunotherapy

Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease

Exploring the Potential of Fecal Microbiota Transplantation as a Therapy in Tuberculosis and Inflammatory Bowel Disease

Research LettersMuramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease

Summary

Am J Hum Genet

J Biol Chem

J Biol Chem

J Biol Chem

Research Letters
Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease