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1.  Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties 
The Journal of Experimental Medicine  2014;211(5):987-1000.
Identification in humans of a bona fide marginal zone B cell population, which differentiates from a splenic marginal zone precursor through a NOTCH2 signaling pathway.
Mouse splenic marginal zone precursors (MZPs) differentiate into marginal zone B (MZB) cells under a signaling pathway involving Notch2 and its ligand, delta-like 1 ligand (Dll1). We report the identification of an MZP subset in the spleen of young children. These MZPs differentiate into MZ-like B cells in vitro in the presence of OP9 cells expressing human DLL1, as demonstrated by the up-regulation of classical MZB cell markers. A set of diagnostic genes discriminating IgM+IgD+CD27+ blood and splenic MZB cells from switched B cells was identified (up-regulation of SOX7, down-regulation of TOX, COCH, and HOPX), and their expression during the induction assay mirrored the one of MZB cells. Moreover, Alagille patients with a NOTCH2 haploinsufficiency display a marked reduction of IgM+IgD+CD27+ B cells in blood, whereas their switched memory B cells are not affected. Altogether, these results argue in favor of the existence of a rodent-like MZB cell lineage in humans.
PMCID: PMC4010902  PMID: 24733829
3.  Secondary Mitochondrial Respiratory Chain Defect Can Delay Accurate PFIC2 Diagnosis 
JIMD Reports  2013;14:17-21.
Multiple respiratory chain deficiencies represent a common cause of mitochondrial diseases and often result in hepatic failure. There is no gold-standard test for diagnosing mitochondrial disease, and the current diagnosis relies on establishing a consistent pattern of evidence from clinical data, neuroimaging, tissue biopsy, and biochemical investigations. In some patients, the mitochondrial respiratory chain defect (MRCD) diagnosis is confirmed by genetic investigations. In most cases, genetic investigations are not informative and a number of cases remain unexplained.
Here, we report on two children presenting with liver disease in whom first investigations suggested MRCD, due to decreased liver respiratory chain activities and decreased mitochondrial DNA copy number. However, sequencing of the genes known to be associated with mitochondrial DNA instability did not identify any pathogenic mutations. Further investigations including exome analysis, biliary bile salt analysis, and/or BSEP immunostaining detected a defect in the bile salt export pump (BSEP). Diagnosis of progressive familial intrahepatic cholestasis type 2 (PFIC2), a hereditary disorder in bile formation due to BSEP deficiency was confirmed by ABCB11 gene sequencing. Deleterious mutations were identified in both patients: one harboring compound heterozygous mutations (p.Arg470*/c.1308+2T>A) and the other homozygous nonsense mutation (p.Tyr354*). This report increases awareness of a possible secondary mitochondrial respiratory chain defect in the liver tissue associated with other underlying causes such as PFIC2.
PMCID: PMC4213329  PMID: 24214725
4.  Mitochondrial Infantile Liver Disease due to TRMU Gene Mutations: Three New Cases 
JIMD Reports  2013;11:117-123.
Combined respiratory chain defect is a common feature in mitochondrial liver disease during early infancy. Mitochondrial DNA depletions, induced by mutations of the nuclear genes POLG, DGUOK, and MPV17, are the major causes of these combined deficiencies. More recently, mutations in TRMU gene encoding the mitochondrial tRNA-specific 2-thiouridylase were found in infantile hepatopathy related to mitochondrial translation defect. It is characterized by a combined defect of respiratory chain complexes without mitochondrial DNA depletion.
We report here clinical, biochemical, and genetic findings from three unrelated children presenting with hepatopathy associated with hyperlactatemia and respiratory chain defect due to bi-allelic mutations in TRMU gene. Two patients recovered spontaneously in a few months, whereas the other one died of acute liver failure. Spontaneous remission is a rare feature in mitochondrial liver diseases, and early identification of TRMU mutations could impact on clinical management. Our results extend the small number of TRMU mutations reported in mitochondrial liver disorders and allowed accumulating data for genotype–phenotype correlation.
PMCID: PMC3755544  PMID: 23625533
5.  Differences in presentation and progression between severe FIC1 and BSEP deficiencies 
Journal of hepatology  2010;53(1):170-178.
Background & Aims
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 “FIC1 patients”) or ABCB11 (84 “BSEP patients”) were evaluated.
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
PMCID: PMC3042805  PMID: 20447715
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
6.  CD25 Appears Non Essential for Human Peripheral Treg Maintenance In Vivo 
PLoS ONE  2010;5(7):e11784.
IL-2 has been reported to be critical for peripheral Treg survival in mouse models. Here, we examined Treg maintenance in a series of paediatric liver transplant recipients who received basiliximab, a therapeutic anti-CD25 monoclonal antibody.
Methodology/Principal Findings
FoxP3+ CD4 T cells were analyzed by flow cytometry before liver grafting and more than 9 months later. We found that in vivo CD25 blockade did not lead to Treg depletion: the proportion of FoxP3+ cells among CD4 T cells and the level of FoxP3 expression were both unchanged. IL-2Rβ expression was enhanced in FoxP3+ cells both before and after basiliximab treatment, while the level of IL-2Rγ expression was similar in Tregs and non-Tregs. No significant change in the weak or absent expression of IL-7Rα and IL-15Rα expression on FoxP3+ cells was observed. Although the proportion of FoxP3+ cells among CD4 T cells did not vary, food allergies occurred more rapidly after liver grafting in patients who received basiliximab, raising questions as to Treg functionality in vivo in the absence of functional CD25.
CD25 appears non essential for human Treg peripheral maintenance in vivo. However, our results raise questions as to Treg functionality after therapeutic CD25 targeting.
PMCID: PMC2912775  PMID: 20689592
7.  Progressive familial intrahepatic cholestasis 
Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births.
Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT) activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP). Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3), impair biliary phospholipid secretion resulting in PFIC3.
Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis can be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA) therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation. Monitoring of hepatocellular carcinoma, especially in PFIC2 patients, should be offered from the first year of life. Hepatocyte transplantation, gene therapy or specific targeted pharmacotherapy may represent alternative treatments in the future.
PMCID: PMC2647530  PMID: 19133130
8.  Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus 
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.
PMCID: PMC2773349  PMID: 19030215
Albumin dialysis; Intractable pruritus; Pregnancy; Cholestatic liver disease

Results 1-8 (8)