These gene mutations are associated with the clinical entities of ABCB4 deficiency and cystic fibrosis–associated liver disease, respectively.1 Most recently, anion

exchanger 2 (AE2), a variant of the Cl−/HCO exchanger, has been shown to influence prognosis in patients with PBC under treatment with ursodeoxycholic acid (UDCA).4 This finding supports the view that impaired AE2 activity and thereby reduced biliary HCO secretion may play a key role in the pathogenesis of PBC.5-9 A variant of GPBAR1, Volasertib purchase the gene coding for the G-protein–coupled bile acid receptor 1, also called TGR5, appeared as a likely disease gene in the first genome-wide association analysis of primary sclerosing cholangitis.10 TGR5 is expressed on apical cholangiocyte membranes and is putatively involved in cAMP-dependent modulation of cholangiocellular HCO secretion. Thus, functional modifications in proteins involved JNK inhibitor order in apical transport of pH modifying bile contents may contribute to development and progression of chronic forms of sclerosing/fibrosing cholangitis such as PBC, PSC, cystic fibrosis–associated liver disease, and ABCB4 deficiency. AE2, anion exchanger 2; ADP, adenosine diphosphate;

AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; norUDCA, norursodeoxycholic acid; PBC, primary biliary cirrhosis; PKC, protein kinase C; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid. The cholangiocyte is exposed to millimolar concentrations of hydrophobic bile salts,11, 12 which are toxic to other cells such as hepatocytes at moderate micromolar medroxyprogesterone levels.13 Resistance against these noxious compounds and their cytolytic potential is therefore essential. Which

strategies help cholangiocytes survive in the unfriendly environment of bile? One protective mechanism is the formation of mixed micelles of phospholipids and bile salts in bile.11 High millimolar amounts of bile salts are buffered by micelle formation with phospholipids. However, although this mechanism protects cells from bile salts in micelles, it has no effect on the toxicity of bile salt monomers that are always present at submicellar concentrations. Formation of mixed micelles is critically dependent on adequate biliary phospholipid secretion. Its impairment by mutations of ABCB4/MDR3 leads to progressive familial intrahepatic cholestasis (PFIC type 3) in children and in milder forms to sclerosing cholangitis, ductopenia, and occasionally biliary cirrhosis in adults.3 Thus, micelle formation in bile appears to be crucial for bile ductular integrity. A second protective mechanism known as dilution of bile or flushing of bile is more speculative. This mechanism involves secretion of an alkaline, HCO-rich, mainly cholangiocyte-derived fluid11, 14 that reduces the concentration of toxic compounds in bile.

These gene mutations are associated with the clinical entities of ABCB4 deficiency and cystic fibrosis–associated liver disease, respectively.1 Most recently, anion

exchanger 2 (AE2), a variant of the Cl−/HCO exchanger, has been shown to influence prognosis in patients with PBC under treatment with ursodeoxycholic acid (UDCA).4 This finding supports the view that impaired AE2 activity and thereby reduced biliary HCO secretion may play a key role in the pathogenesis of PBC.5-9 A variant of GPBAR1, HM781-36B chemical structure the gene coding for the G-protein–coupled bile acid receptor 1, also called TGR5, appeared as a likely disease gene in the first genome-wide association analysis of primary sclerosing cholangitis.10 TGR5 is expressed on apical cholangiocyte membranes and is putatively involved in cAMP-dependent modulation of cholangiocellular HCO secretion. Thus, functional modifications in proteins involved ATR cancer in apical transport of pH modifying bile contents may contribute to development and progression of chronic forms of sclerosing/fibrosing cholangitis such as PBC, PSC, cystic fibrosis–associated liver disease, and ABCB4 deficiency. AE2, anion exchanger 2; ADP, adenosine diphosphate;

AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; norUDCA, norursodeoxycholic acid; PBC, primary biliary cirrhosis; PKC, protein kinase C; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid. The cholangiocyte is exposed to millimolar concentrations of hydrophobic bile salts,11, 12 which are toxic to other cells such as hepatocytes at moderate micromolar Sclareol levels.13 Resistance against these noxious compounds and their cytolytic potential is therefore essential. Which

strategies help cholangiocytes survive in the unfriendly environment of bile? One protective mechanism is the formation of mixed micelles of phospholipids and bile salts in bile.11 High millimolar amounts of bile salts are buffered by micelle formation with phospholipids. However, although this mechanism protects cells from bile salts in micelles, it has no effect on the toxicity of bile salt monomers that are always present at submicellar concentrations. Formation of mixed micelles is critically dependent on adequate biliary phospholipid secretion. Its impairment by mutations of ABCB4/MDR3 leads to progressive familial intrahepatic cholestasis (PFIC type 3) in children and in milder forms to sclerosing cholangitis, ductopenia, and occasionally biliary cirrhosis in adults.3 Thus, micelle formation in bile appears to be crucial for bile ductular integrity. A second protective mechanism known as dilution of bile or flushing of bile is more speculative. This mechanism involves secretion of an alkaline, HCO-rich, mainly cholangiocyte-derived fluid11, 14 that reduces the concentration of toxic compounds in bile.

25% in entangled

northern fur seals despite increased resting time (Feldkamp et al. 1988). Though fecal glucocorticoid studies have shown markedly elevated stress hormone levels in a severely entangled right whale (Hunt et al. 2006), the relationships between entanglement stress and metabolic rate are too complex to be considered here. High energy requirements and negative energy balance are not uncommon in large whales. Right whales routinely enter a phase of energy deficit during the fasting cycle associated with annual migrations between high-latitude foraging habitats and low-latitude calving areas. Sufficient endurance to survive the fasting phase and subsequently recoup losses in the following foraging season are likely adaptations, though prolonged periods of an imbalance of greater magnitude TSA HDAC cost may impact an individual’s energy reserve to a point beyond which recovery is not possible (Millar and Hickling 1990). The magnitude of power output due to drag of entangling gear almost

certainly would make such long distance (~2,900 km, from the Gulf of Maine to Florida; Kraus et al. 1986) fasting migrations much more energetically costly for an entangled whale. A simple calculation can illustrate both the effects of increased drag, and of reduced swimming ACP-196 speed (Watson and Granger 1998, Jones et al. 2011). Using our most conservative estimate, a nonentangled right whale swimming 2,900 km, at an average speed of 1.5 m/s could complete a one-way

migration in 22 d, expending 7.3 × 109 J PIK3C2G of energy. Entangled in the gear-only configuration, an individual could migrate at the same speed, arriving on time and expending 9.3 × 109 J of energy (a 27% increase) or could swim at a reduced speed to arrive 5 d late, expending 9.6 × 109 J (a 31% increase). If this same calculation is made with a more energetically costly entanglement scenario (e.g., gear-and-buoys), the entangled individual could arrive on-time, expending 1.0 × 1010 J (a 37% increase), or 5 d late expending essentially the same 1.0 × 1010 J. Under both entanglement and speed maintenance or reduction scenarios, the energy store budgeted for a nonentangled one-way migration (7.3 × 109 J) would be exhausted between 71% and 78% of the distance to the destination. These results provide the first visualization of significant alteration to swimming patterns associated with entanglement. Understanding the major behavioral and energetic implications of towing accessory gear is crucial in considering the sub-lethal effects of persistent entanglement in a critically endangered population. We gratefully acknowledge the collaborative efforts of Florida FWC, EcoHealth Alliance, Georgia DNR, NOAA SER, Provincetown Center for Coastal Studies, Georgia Aquarium, St.

25% in entangled

northern fur seals despite increased resting time (Feldkamp et al. 1988). Though fecal glucocorticoid studies have shown markedly elevated stress hormone levels in a severely entangled right whale (Hunt et al. 2006), the relationships between entanglement stress and metabolic rate are too complex to be considered here. High energy requirements and negative energy balance are not uncommon in large whales. Right whales routinely enter a phase of energy deficit during the fasting cycle associated with annual migrations between high-latitude foraging habitats and low-latitude calving areas. Sufficient endurance to survive the fasting phase and subsequently recoup losses in the following foraging season are likely adaptations, though prolonged periods of an imbalance of greater magnitude LY294002 manufacturer may impact an individual’s energy reserve to a point beyond which recovery is not possible (Millar and Hickling 1990). The magnitude of power output due to drag of entangling gear almost

certainly would make such long distance (~2,900 km, from the Gulf of Maine to Florida; Kraus et al. 1986) fasting migrations much more energetically costly for an entangled whale. A simple calculation can illustrate both the effects of increased drag, and of reduced swimming GDC0449 speed (Watson and Granger 1998, Jones et al. 2011). Using our most conservative estimate, a nonentangled right whale swimming 2,900 km, at an average speed of 1.5 m/s could complete a one-way

migration in 22 d, expending 7.3 × 109 J Reverse transcriptase of energy. Entangled in the gear-only configuration, an individual could migrate at the same speed, arriving on time and expending 9.3 × 109 J of energy (a 27% increase) or could swim at a reduced speed to arrive 5 d late, expending 9.6 × 109 J (a 31% increase). If this same calculation is made with a more energetically costly entanglement scenario (e.g., gear-and-buoys), the entangled individual could arrive on-time, expending 1.0 × 1010 J (a 37% increase), or 5 d late expending essentially the same 1.0 × 1010 J. Under both entanglement and speed maintenance or reduction scenarios, the energy store budgeted for a nonentangled one-way migration (7.3 × 109 J) would be exhausted between 71% and 78% of the distance to the destination. These results provide the first visualization of significant alteration to swimming patterns associated with entanglement. Understanding the major behavioral and energetic implications of towing accessory gear is crucial in considering the sub-lethal effects of persistent entanglement in a critically endangered population. We gratefully acknowledge the collaborative efforts of Florida FWC, EcoHealth Alliance, Georgia DNR, NOAA SER, Provincetown Center for Coastal Studies, Georgia Aquarium, St.

As described earlier, hepcidin

is the central mediator of systemic iron homeostasis through its interaction with ferroportin and control of its cell surface expression. Mutations in hepcidin are very rare possibly because of the small size of the molecule and account for only a small proportion of patients with JH. Roetto et al. originally identified HAMP as the gene responsible for JH in two families http://www.selleckchem.com/products/bmn-673.html who did not have linkage to the chromosome 1q region.[38] To date, only 12 mutations have been reported in the hepcidin coding sequence or promoter region that have either been associated with JH or have been implicated as modifiers of the HFE-HH phenotype. Within the Asia-Pacific region, three mutations have been reported (Fig. 2). The C78T mutation was detected in a consanguineous family of Middle Eastern origin residing in Australia.[39] The R42Sfs mutation was reported in a consanguineous family from Pakistan; this frameshift mutation results in an abnormally elongated protein with complete disruption of the mature peptide

sequence.[34] Finally, the R75X mutation was recently reported in a Japanese patient with early onset hemochromatosis.[40] Interestingly, this mutation would be predicted to result in a truncated, 15 amino acid version of the mature peptide. However, no detectable hepcidin, either full length or truncated, was detected in the patient’s serum or urine, suggesting that there may have been defective processing or secretion of the mutant SPTLC1 peptide.[40]

Mutations in TFR2 as the cause of type 3 HH were first reported in 2000.[41] TFR2 is highly expressed in the hepatocytes FK866 of the liver where it has been implicated in the regulation of hepcidin. Cell surface TFR2 has the capacity to bind and internalize transferrin, although the affinity is significantly lower than that of TFR1.[42] Exactly how TFR2 in the hepatocyte regulates hepcidin is unclear. Some studies have suggested that TFR2 forms a complex with HFE and possibly HJV that is responsible for regulating hepcidin.[43-45] However, other reports suggest that a complex between HFE and TFR2 is not required for hepcidin regulation.[46, 47] While the mechanism of TFR2 action and the signal transduction to hepcidin remain unclear, reduced hepcidin relative to iron stores has been shown to be responsible for iron overload in patients with TFR2-HH.[48] While TFR2-HH was originally described as an adult-onset disease with similar age of presentation to HFE-HH, more recent evidence suggests that it has an earlier age of onset and a more severe clinical course.[49] Despite the earlier onset of TFR2-HH, the iron indices, tissue iron distribution, and clinical features are similar to HFE-HH. It now appears that TFR2-HH has a phenotypic severity that is intermediate between JH caused by HJV or HAMP mutations at one end of the spectrum and HFE-HH at the other. In contrast with JH, hypogonadism and cardiomyopathy are less common.

Because the use of ABS also results in growth arrest, absence of fetal growth factors, and/or presence of differentiation-inducing factors in adult serum could partly explain the observed changes. We hypothesize that the absence of growth-stimulating factors allows for growth arrest and provides the opportunity to form cell–cell contacts and tight junctions. Cell–cell contacts, in turn, are important factors in facilitating intercellular communication

and have been linked to increased hepatic functionality, including bile secretion, glycogenolysis, and ALB secretion.[9] Our current data suggest that an important difference between cells cultured in ABS-supplemented (or DMSO-supplemented) media PD332991 and cells cultured in HS-supplemented media is the intracellular lipid

stores. Our study indicates that only in HS is the lipid droplet content increased. The increased lipid content can, in turn, facilitate activation of lipid-dependent nuclear receptors, such as LXR-α, PPAR-α, and PPAR-γ, enabling de novo synthesis of lipids and lipoprotein secretion. The method we have presented in this study for culturing hepatoma cells provides a convenient, cost-effective model for the study of liver disease, lipoprotein secretion, and other liver-related processes. AZD2281 mouse We have used this model to produce HCV strain JFH-1 at high titers. When cells are differentiated, JFH-1 production in HS media exceeded that in FBS media by 1,000 times or more. We have achieved production of viral titers of over 108 RNA copies/mL for extended periods of time. Besides functioning as a production platform for HCV, this model can also provide further insight into the cellular factors and processes P-type ATPase essential for efficient production of HCV, resulting in virus that closely resembles HCV derived from patient sera. Additional Supporting Information may be found in the online version of this article. Supplemental figure 1. Comparison to DMSO and Adult bovine serum mediated growth arrest Historically, fetal serum has been used in

cell cultures because of the presence of high levels of growth stimulating factors. We wanted to determine if some of the same effects seen in HS (adult human serum) could be achieved by switching FBS to ABS (adult bovine serum). Also, HuH-7 or HuH-7-derived cells become contact inhibited by DMSO, as reported previously (4). We therefore characterized Huh7.5 cells grown in either FBS media further supplemented with DMSO (1%) or in media supplemented with adult bovine serum (ABS, 2%). Both ABS and DMSO supplementation resulted in growth arrest and changes in cellular morphology, however these changes were less pronounced than in HS; for example the increase in cells size that was observed under HS conditions was not observed in DMSO or ABS containing medium.

79 This finding underscores the existence of common mechanisms of alcohol action on the liver across species. Interestingly, increase in number of differentially expressed genes correlated with disease severity in human ALD, and was most prominent in fibrosis, ECM and immune-related genes confirming known genes in ALD and identifying novel molecules/pathways,77,78,83 expanding knowledge regarding unexplored mechanisms of alcohol action on the liver. Alcoholic steatosis (AS), the earliest and the most common manifestation of heavy drinking, is an important contributor to the progression

of hepatic injury.84 In alcoholics, mitochondrial damage during lipid peroxidation Akt inhibitor increases degradation of ApoB100, in turn reducing secretion of hepatic lipoproteins. Consequentially, hepatic microvesicular steatosis is evident in heavy drinkers reflecting mitochondrial injury.85 This is complicated by associated lipoprotein glycosylation in the Golgi, leading to macrovesicular steatosis.86 Increased degradation of newly synthesized ApoB100 by post-ER presecretory proteolysis (PERPP) decreases its secretion from liver, restored by antioxidants and vitamin E. This is a novel pathway linking cellular lipid peroxidation and oxidant stress.87 Chronic

alcohol ingestion redirects metabolic pathways in the hepatocytes en route for intracellular lipid (triglyceride) accumulation.88 The lipid accumulation occurs due to impaired Selleck 5-Fluoracil lipogenic as well as anti-lipogenic processes in hepatocytes and via signals from neighboring cells. Adipogec regulation

is induced in hepatocytes causing fatty liver in steatohepatitis, while adipogenic transcription factors, such as, peroxisome proliferator-activated receptorα (PPARα), insulin-sensitive sterol-regulatory element binding protein-1 (SREBP-1), liver X receptor-α (LXR-α) and CCAAT/enhancer binding protein (C/EBP) in HSCs are inhibited, Chorioepithelioma resulting in fibrosis.89 Recent discoveries on the mechanisms of alcohol-induced fat accumulation88,90 include regulators that: (i) stimulate fatty acid synthesis, such as SREBP-1; (ii) inhibit fatty acid oxidation, for example PPARα and adenosine monophosphate (AMP)-activated protein kinase (AMPK); (iii) impair methionine metabolism, (iv) alter complement and innate immune systems and (v) novel cytokines effectors (adiponectin, osteopontin).88 Peroxisome proliferator-activated receptor-α is a nuclear receptor for ligands such as eicosanoids, leukotrines, prostaglandins and free fatty acids (FFAs). On forming dimeric complexes with retinoid-X receptor (RXR), it binds DNA recognition sites to induce transcriptional activity of genes that enhance fatty acid oxidation. Chronic alcohol downregulates PPARα, inhibiting fatty acid oxidation and thus resulting in lipid accumulation,91 reversed on PPARα agonists treatment.92 PPARα knockout animals have increased liver injury with chronic alcohol compared to wild type, supporting a protective role for PPARα in ALD.

Here, we show that rapamycin further aggravated the RB defect of PMNs from patients with cirrhosis (Fig. 2). The residual PMN production of ROS not inhibitable by rapamycin was very low, approximately 35% only of that of healthy PMNs (Fig. 2C). This amount of ROS is similar to that produced

by PMNs from patients with chronic granulomatous diseases,35 which may contribute to the increased sensitivity of the patient to bacterial infections. Although one cannot exclude that the rapamycin-inhibitory effects described here could result from nonspecific effects, a role of mTOR Selleck CCI-779 to the NOX2 activation process was further confirmed by depletion of mTOR with siRNA (Fig. 5C) or antisense oligonucleotides (data not shown). Together, these results indicate that fMLP induced a rapid activation of mTOR (Fig. 2) involved in RB, which represents a novel function of mTOR in phagocyte oxygen-dependent defense systems, as supported here by the impaired bacterial killing induced by rapamycin (Fig. 6C). The mechanism by which mTOR contributes to the PMN RB is not known. However, a possible model can be proposed based on the degree of inhibition of internal effectors induced by rapamycin (Fig. 7). Indeed, the rapamycin concentration that inhibits 50% of the fMLP-induced mTOR

phosphorylation (IC50 of 3-5 nM; Fig. 2) was similar to that obtained for the phospho-p38-MAPK (Fig. 3E) and phospho-p47phox (Fig. 3C), whereas that obtained for phospho-ERK was much higher (IC50 of 20 nM; Fig. 3F). These results Inhibitor Library suggest that mTOR preferentially induces the activation of p38-MAPK, which may, in turn, phosphorylate p47phox(S345). Whether mTOR activates p38-MAPK directly or indirectly by its upstream effector MEK3/6 remains to be elucidated. Interestingly, mTOR does not appear to regulate the translocation of both p38-MAPK and p47phox from the cytosol to the membranes Celecoxib (Figs. 4A,B and 5D,E). Thus, mTOR regulates the activation of NOX2 through the phosphorylation

of its effectors, but not by the assembly process of the NADPH oxidase complex. Our data do not exclude the possibility that mTOR directly phosphorylated p47phox, NOX2, or other partners (p67phox and p40phox). Alternatively, mTOR may regulate other signaling effectors of the RB, such as PKC. Consistent with this hypothesis, we observed that the PKC-dependent phosphorylation site of p47phox (S320) induced by fMLP was also inhibited by rapamycin (data not shown). However, when PKCs were directly activated by phorbol myristate acetate, RB was not altered by rapamycin (Supporting Fig. 3C). Thus, mTOR antagonists should be useful to dissect the activation mechanism of NOX2 and to attenuate its hyperactivity in pathological situations. However, rapamycin may have detrimental effects in PMNs from immuno-depressed patients.

Until further data are available, i.v. infusion of high-dose PPI after endoscopic treatment of bleeding peptic ulcers remains the most studied and best proven strategy. “
“Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, et al. Variants at IRF5-TNPO3, 17q12-21

and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 2010;42:655-657. (Reprinted with permission.) We genotyped individuals with primary Wnt antagonist biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10−4) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10−13), 17q12-21 (combined P = 3.50 × 10−13) and MMEL1 (combined P = 3.15 × 10−8) as new

primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 2010;42:658-660. (Reprinted with permission.) A genome-wide association screen for primary see more biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and Dynein 17q12-21 (P = 1.7 × 10−10, OR = 1.38). The 2009 publication of the first genome-wide association study (GWAS) of primary biliary cirrhosis (PBC)

represented a key point in the evolution of our understanding of the genetic basis and thus pathogenesis of this disease.1 This landmark study identified, in a reproducible fashion, genetic associations between PBC and human leukocyte antigen as well as polymorphisms in the genes encoding the interleukin-12 (IL-12) α-chain and the IL-12 receptor β-chain. Two recent publications from Canadian, American, and Italian groups add an important further dimension to our knowledge base with respect to the genetic basis of PBC and build on the original study.2, 3 Taken together, these two new studies replicate the original genetic associations with the IL-12 pathway, and importantly, through individual and combined analyses, they identify further associated loci. Critically, the newly identified loci are again associated with the biology of the interaction between antigen-presenting cells (APCs) and CD4+ T cells, which is thought to be critical to the development of the autoreactive immune responses underpinning PBC.4 The advent of these new data make now a good time to reflect on what we now know and to identify potential future directions for research.

Until further data are available, i.v. infusion of high-dose PPI after endoscopic treatment of bleeding peptic ulcers remains the most studied and best proven strategy. “
“Hirschfield GM, Liu X, Han Y, Gorlov IP, Lu Y, Xu C, et al. Variants at IRF5-TNPO3, 17q12-21

and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 2010;42:655-657. (Reprinted with permission.) We genotyped individuals with primary GSI-IX biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10−4) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10−13), 17q12-21 (combined P = 3.50 × 10−13) and MMEL1 (combined P = 3.15 × 10−8) as new

primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases. Liu X, Invernizzi P, Lu Y, Kosoy R, Lu Y, Bianchi I, et al. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis. Nat Genet 2010;42:658-660. (Reprinted with permission.) A genome-wide association screen for primary A-769662 nmr biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10−11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10−10, OR = 1.63) and GNE-0877 17q12-21 (P = 1.7 × 10−10, OR = 1.38). The 2009 publication of the first genome-wide association study (GWAS) of primary biliary cirrhosis (PBC)

represented a key point in the evolution of our understanding of the genetic basis and thus pathogenesis of this disease.1 This landmark study identified, in a reproducible fashion, genetic associations between PBC and human leukocyte antigen as well as polymorphisms in the genes encoding the interleukin-12 (IL-12) α-chain and the IL-12 receptor β-chain. Two recent publications from Canadian, American, and Italian groups add an important further dimension to our knowledge base with respect to the genetic basis of PBC and build on the original study.2, 3 Taken together, these two new studies replicate the original genetic associations with the IL-12 pathway, and importantly, through individual and combined analyses, they identify further associated loci. Critically, the newly identified loci are again associated with the biology of the interaction between antigen-presenting cells (APCs) and CD4+ T cells, which is thought to be critical to the development of the autoreactive immune responses underpinning PBC.4 The advent of these new data make now a good time to reflect on what we now know and to identify potential future directions for research.