CC-Type chemokine receptor 5-Δ32 mutation protects against primary sclerosing cholangitis

Henckaerts, Liesbet; Fevery, Johan; Steenbergen, Werner Van; Verslype, Chris; Yap, P; Nevens, Frederik; Roskams, Tania; Libbrecht, Louis; Rutgeerts, Paul; Vermeire, Séverine

doi:10.1097/01.mib.0000209790.21737.28

Cited by 25 publications

(14 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, in some situations, there appear to be less harmful inflammation seen, examples of this include increased renal allograft survival; 99 lower incidence of RA, and in those with RA, fewer exacerbations; 100 less Kawasaki disease, 101 lower rates of severe coronary artery disease; 102 increased renal survival with IgA nephropathy 103 and in those with inflammatory bowel disease (IBD), less primary sclerosing cholangitis (PSC). 104 However, these data in the setting of IBD, conflict with those from another observational study which indicated that PSC was more severe in those heterozygotes for the delta 32 deletion. 105 Other observations include less inflammation and fibrosis in hepatitis C virus (HCV) and greater HCV clearance, 106 and lastly decreased cerebral malaria in mice.…”

Section: Theoretical Benefits Of Blocking Ccr5-anti-inflammatory Propcontrasting

confidence: 51%

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

Pett

Emery

Kelleher

et al. 2010

Clinical Medicine Insights: Therapeutics

View full text Add to dashboard Cite

Over a decade has passed since several groups identified the chemokine receptors CXCR4 and CCR5 as key co-receptors for HIV entry. CCR5 is more important in HIV transmission and during the early course of HIV infection. It is also apparent that protection from HIV infection is afforded to those lacking CCR5-the so called delta-32 homozygotes; in those heterozygous for this mutation, an attenuated course of HIV-infection is observed. Provocatively, those with modified expression of CCR5 are physiologically normal with the exception of poorer outcomes with some of the viral encephalitides specifically West Nile virus and Tick Borne encephalitis. The small molecule, orally-bioavailable CCR5 receptor antagonists, including, maraviroc (MVC), are allosteric inhibitors that lock the CCR5 receptor into a conformation such that the receptor is not able to bind HIV envelope protein; the molecules also variably block intracellular signalling induced by different receptor-binding chemokines. The aims of this review on the CCR5 receptor inhibitors are to summarise information relevant to treatment in individuals with HIV-1 infection. Data from the licensing studies, the side-effect profile and putative long-term risks of CCR5 receptor inhibitor exposure, tropism testing and mechanisms of resistance will be reviewed. The potential for using this class of agent as an immunomodulating agent will be detailed. Given that MVC is the only licensed drug in this class at present and reflecting the greater body of work describing this agent, the majority of information in this review relates to MVC. Last, the authors propose the place of MVC in the hierarchy of HIV therapy and future opportunities for research.

show abstract

Section: Theoretical Benefits Of Blocking Ccr5-anti-inflammatory Propcontrasting

confidence: 51%

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

Pett

Emery

Kelleher

et al. 2010

Clinical Medicine Insights: Therapeutics

View full text Add to dashboard Cite

show abstract

“…Three PSC patients had a PSC-AIH overlap syndrome. As noted in an earlier study [29], the male predominance in PSC (overall men to women ratio approximately 3:2) was especially pronounced in the subgroup with IBD (78.3% male). In the subgroup with PSC alone, the sex ratio was more balanced (55.6% male).…”

Section: Resultsmentioning

confidence: 58%

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

Stallhofer¹,

Denk²,

Glas

et al. 2011

Digestion

View full text Add to dashboard Cite

Background/Aims: The chromosome 4q27 region harboring IL2 and IL21 is an established risk locus for ulcerative colitis (UC) and various other autoimmune diseases. Considering the strong coincidence of primary sclerosing cholangitis (PSC) with UC and the increased frequency of other autoimmune disorders in patients with primary biliary cirrhosis (PBC), we investigated whether genetic variation in the IL2/IL21 region may also modulate the susceptibility to these two rare cholestatic liver diseases. Methods: Four strongly UC-associated single nucleotide polymorphisms (SNPs) within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block were genotyped in 124 PBC and 41 PSC patients. Control allele frequencies from 1,487 healthy, unrelated Caucasians were available from a previous UC association study. Results: The minor alleles of all four markers were associated with a decreased susceptibility to PSC (rs13151961: p = 0.013, odds ratio (OR) 0.34; rs13119723: p = 0.023, OR 0.40; rs6822844: p = 0.031, OR 0.41; rs6840978: p = 0.043, OR 0.46). Moreover, a haplotype consisting of the four minor alleles also had a protective effect on PSC susceptibility (p = 0.0084, OR 0.28). A haplotype of the four major alleles was independently associated with PSC when excluding the patients with concomitant inflammatory bowel disease (p = 0.033, OR 4.18). Conclusion: The IL2/IL21 region may be one of the highly suggestive but so far rarely identified shared susceptibility loci for PSC and UC.

show abstract

“…Unfortunately, most of the studies describing an influence of genetic alterations on PSC development are not reproducible. For instance a 32-bp deletion of the chemokine receptor 5 (CR5D32), which is frequently found in Northern European countries, results in a reduced receptor expression on T-cells; a recent study on a Belgian population showed a significant lower frequency of this mutation compared with healthy control subjects suggesting a protective effect [26]. However, this is in contrast to a previous study from Australia, which found a higher frequency of CR5D32 in PSC patients [27].…”

Section: Psc As a Genetic Diseasementioning

confidence: 88%

“…Atypical perinuclear-staining, antineutrophil cytoplasmic antibodies (p-ANCA) can be found in 60-93% of patients with PSC but also in patients with AIH, PBC or UC [34][35][36]. Terjung et al identified a 50-kDa nuclear envelope protein as target antigen in 92% of atypical p-ANCA and proposed the more accurate term ''peripheral antineutrophil nuclear antibodies" (p-ANNA) [37]; nevertheless it is still questionable, whether this target protein or p-ANNAs are -Association with HLA-haplotypes is only weak and not mandatory -Association with certain MHC-and non-MHC-alleles [23][24][25][26][27][28][29][30][31] -Studies on non-HLA polymorphisms are not reproducible or contradictory PSC as an autoimmune disease -Increased incidence of co-existing autoimmune diseases [20] -No response on immunosuppressive treatment -Presence of multiple autoantibodies [33] -Male predominance -Antibodies are not specific and do not correlate with clinical parameters PSC as inflammatory reaction on infectious agents -Co-expression of VAP-1 and MadCAM-1 in the gut and the liver of patients with PSC and IBD allows an enterohepatic lymphocyte circulation [41,42,44,45] -In PSC patients without IBD enterohepatic lymphocyte circulation is not a conclusive concept -In a rat model small intestinal bacterial overgrowth lead to biliary strictures and portal inflammation [48] -No evidence of sign. bacteraemia in UC [46] -Helicobacter species can be found in 24-75% of PSC livers [50,52] - [66,67] involved in pathogenesis.…”

Section: Psc As An Autoimmune Diseasementioning

confidence: 96%

The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy

Weismüller

Wedemeyer

Kubicka

et al. 2008

Journal of Hepatology

148

126

View full text Add to dashboard Cite

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, characterized by progressive inflammation and fibrosis of the bile ducts, resulting in biliary cirrhosis and is associated with a high risk of cholangiocarcinoma. The majority of patients are young, male and have coexisting inflammatory bowel disease. PSC is found with a prevalence of 10/100,000 in Northern European populations. The pathophysiology of PSC is a complex multistep process including immunological mechanisms, immunogenetic susceptibility and disorders of the biliary epithelia. The diagnosis is primarily based on endoscopic cholangiography although magnetic resonance imaging is increasingly used; biochemistry and immunoserology as well as histology play only a minor role. Due to the high risk of developing cholangiocarcinoma and also other tumours of the GI tract, surveillance strategies are essential, however they have yet to be established and evaluated. Biochemical parameters, clinical risk factors, endoscopic procedures and imaging techniques contribute to the early identification of patients at risk. Since medical therapy of PSC with ursodeoxycholic acid does not improve survival, to date, liver transplantation is the only option with a cure potential; if transplantation is accurately timed, transplanted PSC patients have an excellent rate of survival. However if cholangiocarcinoma is detected, a curative treatment is not possible in the majority of cases. The present review critically summarizes the current knowledge on the aetiopathogenesis of PSC and gives an overview of the diagnostic approaches, surveillance strategies and therapeutic options. Primary sclerosing cholangitis is a disease of unknown aetiology and without any further curative treatment options apart from liver transplantation. Therefore it may be regarded as the greatest challenge in hepatology today.

show abstract

CC-Type chemokine receptor 5-Δ32 mutation protects against primary sclerosing cholangitis

Abstract: Because an intact CCR5 receptor is needed for internalization of specific pathogens and homing of memory T lymphocytes to the liver, we hypothesize that a deficient expression of this receptor resulting from the CCR5-Delta32 variant may protect against PSC.

Cited by 25 publications

References 27 publications

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

Analysis of IL2/IL21 Gene Variants in Cholestatic Liver Diseases Reveals an Association with Primary Sclerosing Cholangitis

The challenges in primary sclerosing cholangitis – Aetiopathogenesis, autoimmunity, management and malignancy

Contact Info

Product

Resources

About