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LPD Associated with Epstein–Barr Virus Infection
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Laboratory features: (i) variable numbers of lymphocyte subsets including decreased or increased T cells, B cells, and NK cells, (ii) impaired T-cell re-stimulation-induced cell death (males with XLP1) or increased susceptibility to T-cell re-stimulation-induced cell death (XLP2), (iii) impaired 2B4-mediated cytotoxicity (XLP1), (iv) impaired NOD2 signaling (XLP2) [14].
Recognition of microbe-associated molecular patterns by pattern recognition receptors
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
NOD2 is constitutively or inducibly expressed in monocytes, macrophages, T and B cells, dendritic cells, epithelial cells, and Paneth cells. In contrast, NOD1 is ubiquitously expressed in many tissues and cells. NOD2 protein has been detected throughout the cytoplasm of cells, but redistribution to the cell membrane is required for the induction of downstream effects after ligand recognition. NOD1 expression is regulated by interferon-γ (IFN-γ), and NOD2 expression by LPS, tumor necrosis factor-α (TNF-α), and IFN-γ. On activation, NOD1 and NOD2 induce the downstream production and release of chemokines and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6. NOD2 activation critically induces autophagy and mediates bacterial clearance. Both NOD1 and NOD2 interact with the inhibitor of apoptosis proteins cIAP1 and cIAP2.
Autologous Hematopoietic Stem Cell Transplantation for Crohn’s Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Robert M. Craig, Richard K. Burt
The occurrence of a Th1 cytokine imbalance in Crohn’s is probably multi-factorial involving multiple environmental stimuli interacting with genetic predisposition resulting in a skewed but sometimes reversible cytokine imbalance. It is anticipated, but unproven, that HSCT will restore the normal cytokine balance. NOD2 is a Crohn’s associated gene contributing to, but not sufficient to cause, disease.32 NOD (nucleotide-binding oligomerization domain) proteins are involved in programmed cell death and innate immune responses.33 NOD2 is restricted to monocytes and activates NF-kappaB in response to bacterial products. Premature truncation of the NOD2 gene confers disease susceptibility in a subset of Crohn’s patients.34 Besides cytokine imbalance, and T cell immune responses to Saccharomyces cerevisiae and enteric bacteria, NOD2 gene polymorphisms which probably contribute to the immune deviation seen in Crohns, could be analyzed in patients undergoing HSCT.
Corneal Ulcers with NOD2 Mutations Presenting with Mixed Syndromic Phenotype
Published in Ocular Immunology and Inflammation, 2023
Travis Scott Schofield, Chang Sup Lee, Brian Patrick Peppers, Thomas Mauger
NOD2 mutations have been identified as causes of syndromic phenotypes like Blau syndrome and Crohn’s disease—the former typically being associated with the triad of granulomatous arthritis, dermatitis, and uveitis, and the latter being associated with gastrointestinal pathology and the potential for extraintestinal manifestations.1 NOD2 serves as a pattern recognition receptor in the innate immune system. NOD2 ligand muramyl dipeptide (MDP, a bacterial cell wall peptidoglycan degradation product) binds NOD2’s leucine-rich repeat (LRR) motif and leads to downstream signaling molecules NF-κB and MAP kinase. This ultimately leads to the production of inflammatory cytokines—a process that affords cells a defense system against pathogens.2 While this antimicrobial pathway has been well studied, the exact link between NOD2 dysregulation and ocular pathologies such as uveitis remains unclear. Recent findings suggest that NOD2 may also be involved in Th17 suppression that is key to the excessive inflammation of uveitis and that investigating CD4+ T-cell corrective therapies might be an important future step in the treatment of uveitis in Blau syndrome.3
DNA methyltransferase inhibitors increase NOD-like receptor activity and expression in a monocytic cell line
Published in Immunopharmacology and Immunotoxicology, 2022
Claire L. Feerick, Declan P. McKernan
The effects reported here are not restricted to NOD receptors only, and we have previously reported different effects of these drugs on TLR3 in intestinal epithelial cells [27]. We expect there are many other proteins and pathways affected by these drugs. This study is limited due to the fact it is conducted in a cell line and future research should focus on animal models and human tissue/samples. It also does not demonstrate the precise events at the promoter level including changes in methylation and/or histone recruitment. Future research, therefore, should focus on how inhibition of DNA methylation may increase NOD expression at the level of the promoter. By expanding our knowledge of expression regulation, it could potentially accommodate the development of new therapeutics for treatment of NOD1/NOD2 associated disease. The clinical use of these drugs, alongside what is learned from this research, instills optimism for these current therapies to evolve and expand to treat a wider spectrum of ailments including chronic inflammatory diseases. It also highlights a previously unknown side-effect of these drugs with potential consequences for patients currently taking them.
Inflammatory bowel disease manifestations in spondyloarthritis: considerations for the clinician
Published in Expert Review of Clinical Immunology, 2021
Ennio Lubrano, Michele Maria Luchetti, Devis Benfaremo, Daniele Mauro, Francesco Ciccia, Fabio Massimo Perrotta
A recent meta-analysis showed that the risk of developing CD was increased to 17.1 times in NOD2 homozygotes or compound heterozygotes and to 2.4 times in simple NOD2 heterozygotes. Three major variants in the NOD2 gene have been identified (i) a frameshift mutation at position 1007 (1007fs); (ii) a conversion from glycine to arginine to the amino acid residue 908 (G908R); and (iii) a conversion from arginine to tryptophan to the amino acid residue 702 (R702W). All three mutations are found in or near the LRR domain that recognizes the muramyl dipeptide. Indeed, patients with ileal CD showed reduced levels of antimicrobial peptides derived from Paneth cells with dysfunctional aspects of the cells themselves. Although Paneth cells appear to be involved in the pathogenesis of SpA, as they are activated to produce antimicrobial peptides [30] and represent the main source of IL-23 in the intestine of patients with SpA [31], NOD2 variants do not significantly affect the risk of developing SpA, but may influence susceptibility to, and clinical manifestations of intestinal inflammation in SpA [32].