Genetic variants of TRAF6 modulate peritoneal immunity and the risk of spontaneous bacterial peritonitis in cirrhosis: A combined prospective-retrospective study

Abstract

Alterations of the innate immunity contribute to the development of spontaneous bacterial peritonitis (SBP) in liver cirrhosis. Given its role in immune signaling, antimicrobial function, and macrophage differentiation, we hypothesized that genetic polymorphisms of TRAF6 modulate the risk of SBP. Thus, we determined theTRAF6 haplotype in 432 patients with cirrhosis and ascites using the haplotype-tagging single nucleotide polymorphisms rs331457 and rs5030419. In addition, peritoneal macrophages were immunomagnetically isolated and characterized. Overall, 122 (28%) patients had an episode of SBP. In the combined prospective-retrospective analysis the frequency of SBP differed between the four haplotypes (P = 0.014) and was the highest in 102 patients carrying the rs331457 but not the rs5030419 variant, when compared to other haplotypes (odds ratio 1.95 [1.22–3.12]) or to the wild-type (odds ratio 1.71 [1.04–2.82]). This association was confirmed in multivariate logistic regression (adjusted odds ratio 2.00 [1.24–3.22]) and in prospective sensitivity analysis (hazard ratio 2.09 [1.08–4.07]; P = 0.03). The risk haplotype was associated with lower concentrations of the immune activation marker soluble CD87 in ascitic fluid and with a decreased expression of IL-6 and CXCL8 in isolated peritoneal macrophages. In conclusion, genetic polymorphisms of TRAF6 are associated with decreased peritoneal immune activation and an increased risk of SBP.

Functional polymorphisms of innate immunity receptors are not risk factors for the non‐SBP type bacterial infections in cirrhosis

“…Similar to most of the previous studies, the presence of NOD2 allele variants was a risk factor for SBP in our cohort as well. A recent large association study in patients with decompensated cirrhosis however, did not demonstrate a role of NOD2 variant in mediating susceptibility for SBP . In our study development of SBP was not more frequent in patients with TLR2 (−16934 T>A, rs4696480) and TLR4 (D299G, rs4986790) polymorphisms.…”

“…A recent large association study in patients with decompensated cirrhosis however, did not demonstrate a role of NOD2 variant in mediating susceptibility for SBP. 23 In our study development of SBP was not more frequent in patients with TLR2 (−16934 T>A, rs4696480) and TLR4 (D299G, rs4986790) polymorphisms. This latter finding is a novelty.…”

COVID‐19 mortality in cirrhosis is determined by cirrhosis‐associated comorbidities and extrahepatic organ failure: Results from the multinational LEOSS registry

“…To compare case fatality rates in cirrhosis to non‐SARS‐CoV‐2 infections in patients with cirrhosis, a historical cohort of 169 patients with cirrhosis and SBP recruited for previous studies at the Jena University Hospital was analysed. 23 , 24 Spontaneous bacterial peritonitis was diagnosed per current guidelines by neutrophil concentration >250/μl ascites fluid and the exclusion of secondary causes of peritonitis. The recorded clinical characteristics included age, aetiology cirrhosis, cirrhosis severity as assessed by Child‐Pugh Score, Model‐of‐End‐Stage‐Liver‐Disease (MELD) score, laboratory parameters, and 28‐day mortality.…”

Mucosal-Associated Invariant T Cells Redistribute to the Peritoneal Cavity During Spontaneous Bacterial Peritonitis and Contribute to Peritoneal Inflammation

“…[5][6][7] Particularly, innate immune responses of intestinal, circulating, and peritoneal myeloid cells are believed to critically contribute to pathologic bacterial translocation, the susceptibility, and the outcome of SBP. [8][9][10][11] In addition, evidence suggests impaired adaptive immune responses in patients with advanced cirrhosis by conventional and unconventional T cells. 6,12,13 Mucosal-associated invariant T (MAIT) cells are unconventional T cells that act as a bridge between the adaptive and the innate arm of the immune system.…”