Sarcoidosis and NOD1 variation with impaired recognition of intracellular Propionibacterium acnes

Abstract

Sarcoidosis is a systemic granulomatous disease of unknown etiology. NOD2 mutations have been shown to predispose to granulomatous diseases, including Crohn's disease, Blau syndrome, and early-onset sarcoidosis, but not to adult sarcoidosis. We found that intracellular Propionibacterium acnes, a possible causative agent of sarcoidosis, activated NF-kappaB in both NOD1- and NOD2-dependent manners. Systematic search for NOD1 gene polymorphisms in Japanese sarcoidosis patients identified two alleles, 796G-haplotype (156C, 483C, 796G, 1722G) and 796A-haplotype (156G, 483T, 796A, 1722A). Allelic discrimination of 73 sarcoidosis patients and 215 healthy individuals showed that the frequency of 796A-type allele was significantly higher in sarcoidosis patients and the ORs were significantly elevated in NOD1-796G/A and 796A/A genotypes (OR [95% CI]=2.250 [1.084, 4.670] and 3.243 [1.402, 7.502], respectively) as compared to G/G genotype, showing an increasing trend across the 3 genotypes (P=0.006 for trend). A similar association was found when 52 interstitial pneumonia patients were used as disease controls. Functional studies showed that the NOD1 796A-allele was associated with reduced expression leading to diminished NF-kappaB activation in response to intracellular P. acnes. The results indicate that impaired recognition of intracellular P. acnes through NOD1 affects the susceptibility to sarcoidosis in the Japanese population.

Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells

“…A Japanese study implicated a frequent mutation in the NOD1 gene among patients with sarcoidosis as compared with control subjects (12). The NOD1 receptor recognizes peptidoglycanassociated molecules containing the dipeptide iE-DAP present in all gram-negative bacteria (10,36).…”

“…The NOD1-RIP2 complex then recruits TAK1, whose activation is required for the activation of MAP kinase and NF-kB (37,38). Although genetic variations in NOD1 and TLRs (e.g., TLR2) have been implicated in sarcoidosis (12,39), abnormalities in MAP kinase signaling have not been reported in this disease. We have observed the active form of p38 (phosphorylated) in BAL cells of most patients with sarcoidosis even under unstimulated conditions and increased and sustained p38 activation after NOD1 or TLR4 stimulation (Figure 3).…”

“…Aberrant sensing through the NOD1 receptor has been implicated in sarcoidosis: a Japanese study found a frequent 796 A-type allele in the NOD1 gene and impaired response to P. acnes in sarcoidosis (12). Activation of MAPKs is crucial for the syntheses of numerous cytokines and chemokines necessary for eradication of pathogens (13).…”

Immune Recognition in Lung Diseases: Basic Research and Clinical Application

“…An analysis of Japanese patients with sarcoidosis found an association between increased susceptibility to disease and genetic variation in NOD1 [101]. Another study found that NOD2 polymorphism was associated with severe pulmonary sarcoidosis in white patients [102].…”

Genetic polymorphisms or rage, NOD1 and ß-defensis in multiple sclerosis, stroke and pancreatitis

“…It was recently found, that the NOD1 A allele is associated with reduced expression of NOD1 protein, leading to diminished NF-kB activation in response to Propionibacterium acnes [106]. It is suggested that the E266K substitution reduces the stability of NOD1.…”