The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis

Shimoda, Shinji; Tsuneyama, Koichi; Kikuchi, Kentaro; Harada, Kenichi; Nakanuma, Yasuni; Nakamura, Minoru; Ishibashi, Hiromi; Hisamoto, Satomi; Niiro, Hiroaki; Leung, Patrick S.C.; Ansari, Aftab A.; Gershwin, M. Eric; Akashi, Koichi

doi:10.1111/j.1365-2249.2012.04581.x

Cited by 26 publications

(18 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Shimoda et al [41] demonstrated killing activity of human NK cells targeting autologous biliary epithelial cells isolated from PBC patients and accumulation of CD56 + NK cells in close proximity to destructed bile ducts in PBC livers. Furthermore, murine PBC models have shown that depletion of NK cells at early stages might abrogate disease initiation [42]. These findings might be reflected by our observations showing a specific regulation of peripheral and intrahepatic NK cells in autoimmune/biliary disease comprising several cases of PBC patients.…”

Section: Discussionsupporting

confidence: 71%

Frequency and Phenotype of Human Circulating and Intrahepatic Natural Killer Cell Subsets Is Differentially Regulated according to Stage of Chronic Liver Disease

Zimmermann

Mueller²,

Seidler³

et al. 2013

Digestion

View full text Add to dashboard Cite

Background/Aims: Experimental liver injury models have indicated that natural killer (NK) cells are critical regulators of inflammation and fibrosis. However, data on NK cells and subsets in patients with liver diseases are limited. We thus comprehensively characterized peripheral and hepatic NK cell subsets in patients with chronic liver diseases (CLDs) of different etiologies and fibrosis stages. Methods: NK cells and other lymphocyte populations were characterized by FACS in 189 CLD patients (71 non-cirrhosis, 118 cirrhosis) and 153 healthy controls in blood and liver biopsies (n = 40). Results: In contrast to other lymphocyte subsets, circulating NK cells were generally reduced in CLD patients. Patients with fibrosis displayed a distinct increase of CD16^- NK cells in blood and of the CD16⁺ NK cell subset in liver. Patients with cirrhosis had overall lymphopenia, including reduced peripheral NK cells. Most pronounced shifts in NK cell subsets in blood and liver were found in cholestatic and autoimmune CLDs. Blood NK cells and subsets correlated with liver function, and inversely with fibrosis markers and inflammatory cytokines. Conclusions: The close association of humanNK cells with disease severity and the intrahepatic accumulation of CD16⁺ NK cells in early fibrosis favor the concept of beneficial NK cell functions in hepatofibrogenesis.

show abstract

Section: Discussionsupporting

confidence: 71%

Frequency and Phenotype of Human Circulating and Intrahepatic Natural Killer Cell Subsets Is Differentially Regulated according to Stage of Chronic Liver Disease

Zimmermann

Mueller²,

Seidler³

et al. 2013

Digestion

View full text Add to dashboard Cite

show abstract

“…Eosinophils may also constitute some proportion of inflammatory cells (9,26,27). Natural killer (NK) cells and NK T cells account for approximately 5% of the cellular infiltrate and play important roles in initiating the breakdown of tolerance (28). Interdigitating dendritic cells have been detected between biliary epithelial cells, often near breaks in the basement membrane and in the periductal granulomatous response (4,29,30).…”

Section: Immunopathological Characteristics Of Damaged Biliary Epithementioning

confidence: 99%

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

et al. 2017

View full text Add to dashboard Cite

: Primary biliary cholangitis (PBC), formerly known as primary biliary cirrhosis, is an organ-specific autoimmune disease that predominantly affects middle-aged women and is characterized by the chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and, ultimately, fibrosis. The serological hallmark of PBC is the presence of anti-mitochondrial autoantibodies (AMA). Several mechanisms have been proposed for immune-mediated bile duct damage in PBC, including the roles of T cells, B cells, other cell phenotypes, and AMA. A sign of fragility of biliary epithelial cells caused by apoptosis, senescence, and autophagy has also been noted. Several complex steps and mechanisms appear to be involved in the induction and progression of cholangitis and biliary degeneration in patients with PBC.

show abstract

“…PBC is considered to have an autoimmune aetiology, because highly specific anti-mitochondrial antibodies are present in nearly 95% of patients. The abnormal immune response during PBC development leads to the activation and expansion of autoreactive T and B lymphocytes, followed by the production of numerous inflammatory mediators345. As a result, the liver is subjected to a cascade of destructive events, including oxidative stress.…”

mentioning

confidence: 99%

Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis

Wasik

Milkiewicz

Kempińska-Podhorodecka

et al. 2017

Sci Rep

View full text Add to dashboard Cite

In response to oxidative stress, nuclear factor (erythroid-derived 2)-like2 (Nrf2) induces expression of cytoprotective genes. The Nrf2 pathway is controlled by microRNAs and Kelch-like ECH-associated protein1 (Keap1). Nrf2 is stabilized when Keap1 is degraded through the autophagy pathway in a p62-dependent manner. The inhibition of autophagy causes protein accumulation, and Keap1 is inactivated by binding to p62. We investigated the role of the Nrf2/Keap1 axis in the amelioration of oxidative stress in primary biliary cholangitis (PBC). Liver specimens from patients with PBC, with (n = 24) or without cirrhosis (n = 14), and from controls (n = 16) were used for molecular analyses. We found that Nrf2 protein levels were elevated in PBC compared to controls, but Nrf2 gene expression was significantly reduced in cirrhotic PBC. Nrf2 target gene products, HO-1 and GCLC proteins, were reduced compared to controls and reduction of Nrf2 gene expression was associated with elevated levels of microRNA-132 and microRNA-34a. Both Keap1 and p62 protein levels were substantially increased in PBC compared to controls. PBC was associated with reduced Nrf2 expression and autophagy deterioration and these impairments were more advanced in patients with cirrhosis. Aberrant Nrf2/Keap1 system integrity may affect self-defence mechanisms against oxidative stress in PBC.

show abstract

The role of natural killer (NK) and NK T cells in the loss of tolerance in murine primary biliary cirrhosis

Abstract: SummaryOne of the major obstacles in dissecting the mechanism of pathology in human primary biliary cirrhosis (

Cited by 26 publications

References 50 publications

Frequency and Phenotype of Human Circulating and Intrahepatic Natural Killer Cell Subsets Is Differentially Regulated according to Stage of Chronic Liver Disease

Frequency and Phenotype of Human Circulating and Intrahepatic Natural Killer Cell Subsets Is Differentially Regulated according to Stage of Chronic Liver Disease

Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms

Protection against oxidative stress mediated by the Nrf2/Keap1 axis is impaired in Primary Biliary Cholangitis

Contact Info

Product

Resources

About