Identification of a Novel Auto-Antibody Highly Prevalent in Patients with Hepatitis-Associated and Idiopathic Aplastic Anemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3200-3200
Author(s):  
Hiroyuki Takamatsu ◽  
Zhirong Qi ◽  
Tomoyuki Sakurai ◽  
Luis Espinoza ◽  
Naomi Sugimori ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Lines ◽  
Leukemia Cell ◽  
Peptide Mass Fingerprinting ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Healthy Individuals ◽  
Peptide Mass ◽  
Leukemia Cell Lines ◽  
Cd34 Cells

Abstract Abstract 3200 Poster Board III-137 Hepatitis-associated aplastic anemia (HAA) is a subset of acquired AA that is highly responsive to immunosuppressive therapy. The target antigens of the immune system attack in HAA are thought to be a protein shared by both liver and hematopoietic stem cells, since it is usually associated with severe hepatitis of unknown etiology. Screening sera from patients with HAA for the presence of antibodies (Abs) recognizing liver cell-derived proteins may be useful in identifying novel auto-antigens in AA. To test this hypothesis, sera from HAA patients were examined using immunoblotting with a lysate of a hepatocellular carcinoma cell line Huh7 and subsequent peptide mass fingerprinting. Methods and Results The serum of a patient with typical HAA (a 23 year-old male) possessing a small population of paroxysmal nocturnal hemoglobinuria (PNH)-type cells was used for Western blotting (WB) with the lysates of Huh7. A distinct band of 70 kDa protein was revealed. The same band was revealed when the culture supernatant of Huh7 cells was subjected to WB. The peptide mass fingerprinting of the 70 kDa band identified this protein to be heat shock protein (HSP) 72. HSP72 is a stress-inducible protein and extracellular HSP72 enhances the cytotoxicity of CD4+ T cells and NK cells. An examination of the sera from HAA patients, idiopathic acquired AA (IAA) patients and healthy individuals with WB revealed the anti-HSP72 Abs to be detected in 10 of 12 (83%) HAA patients and in 57 of 80 (71%) IAA patients while it was detected only in 8 of 59 (14%) healthy individuals. The prevalence of anti-HSP72 Abs in AA was markedly higher than that of anti-kinectin Abs (39%), anti-PMS1 Abs (10%), anti-DRS-1 Abs (38%) or anti-moesin Abs (37%) reported previously. Anti-HSP72 Abs were frequently detectable both in patients with IAA possessing PNH-type cells (63%) and in patients without PNH-type cells (86%), a finding contrasting to the higher prevalence of anti-DRS-1 Abs and anti-moesin Abs in patients with PNH-type cells than in those without PNH-type cells reported previously. Although anti-HSP72 Abs were detectable in the sera of patients with rheumatoid arthritis and systemic lupus erythematosus, the prevalence was 15% (4 of 27) and 20% (1 of 5), respectively. In contrast to a previous report that detected anti-HSP72 Abs in 24% of patients with chronic hepatitis C, WB failed to detect the Abs in the sera of 4 patients with autoimmune hepatitis and 5 with hepatitis B or C. Ten patients with HAA were treated with immunosuppressive therapy, and 7 of the 8 responders expressed anti-HSP72 Abs. The quantification of the gene expression level of HSP72 by blood cells using real-time PCR demonstrated that the HSP72 mRNA levels were markedly higher in myeloid leukemia cell lines as well as CD34+ cells isolated from 3 healthy individuals in comparison to that in lymphoid or monocytoid leukemia cell lines. HSP72/GAPDH ratios of PBMCs and CD34+ cells from 3 healthy individuals, K562, KH88, OUN-1 were 0.51, 1.31, 1.02, 0.07 and 0.09 respectively. Other leukemia cell lines such as Daudi, Molt-4 and THP-1 did not display detectable levels of HSP72 mRNA. The cell surface expression of HSP72 was examined in various kinds of leukemia cell lines and CD34+ bone marrow (BM) cells derived from 3 healthy individuals using Ab to HSP72 (Clone C92F3A-5) because previous studies demonstrated heat-inducible expression of HSP72 by K562. Flow cytometry detected cell surface HSP72 on immature CML cell lines such as K562 but not on CD34+ BM cells, acute promyelocytic leukemia cell lines such as NB-4 and HL-60, and lymphoid leukemia cell lines such as Molt-4 and Daudi. Exposure to 42°C for 2 h increased the HSP72 expression on K562 cells and Molt-4 cells but not on CD34+ cells. Conclusion Anti-HSP72 Ab is the most prevalent auto-Ab in AA among the auto-Abs previously detected. Given the increased expression of HSP72 by immature myeloid cells as well as stress-inducible cell surface expression of the molecule, immune responses to HSP72 may thus play an essential role in the pathogenesis of HAA and IAA. Disclosures No relevant conflicts of interest to declare.

BCR-ABL Regulates Death Receptor Expression for TNF-Related Apoptosis-Inducing Ligand (TRAIL) in Philadelphia Chromosome-Positive Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2740-2740
Author(s):  
Itaru Kuroda ◽  
Takeshi Inukai ◽  
Xiaochun Zhang ◽  
Jiro Kikuchi ◽  
Yusuke Furukawa ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Cell Line ◽  
Cell Lines ◽  
Leukemia Cell ◽  
Surface Expression ◽  
Leukemia Cells ◽  
Cell Surface Expression ◽  
Leukemia Cell Lines ◽  
Apoptotic Activity

Abstract Abstract 2740 Allogeneic stem cell transplantation (allo-SCT) is potentially curative therapy for CML and Ph+ ALL patients. Graft-versus-leukemia (GVL) effect plays a central role in eradication of residual leukemia after allo-SCT, and GVL effect is mediated by cytotoxic T-lymphocytes (CTLs) and NK cells though cytotoxic ligands. TNF-related apoptosis-inducing ligand (TRAIL) is one of cytotoxic ligands expressed on CTLs and NK cells, and it has been shown that TRAIL mediates GVL effect in mice model. We and others previously demonstrated that Ph+ leukemic cells frequently express death-inducing receptors (DR4 and DR5) for TRAIL resulting in high sensitivity to pro-apoptotic activity of recombinant human soluble TRAIL (rhsTRAIL), suggesting that TRAIL-DR4/DR5 interaction mediates GVL effect against Ph+ leukemia cells at least in part. Despite the fact that TRAIL mediates tumor-specific immunity and plays a role in GVL effect, mechanisms of the DR4 and DR5 expression in leukemia cells have yet to be elucidated fully. Since we found that Ph+ leukemia cells express DR4 and/or DR5 more frequently than Ph- leukemia cells, we assumed that BCR-ABL plays a role in DR4 and DR5 expression in Ph+ leukemia cells. To verify this assumption, we analyzed the effect of imatinib on DR4 and DR5 expression in Ph+ leukemia cells. Of note, imatinib effectively downregulated gene and cell surface expression of DR4 and DR5 in all of the 12 Ph+ leukemia cell lines tested, while it did not in Ph- leukemia cell lines. Moreover, imatinib downregulated DR4 and DR5 expression on primary samples from Ph+ ALL patients. Not only imatinib but also second-generation TKIs, dasatinib and nilotinib, downregulated DR4 and DR5 expression of Ph+ leukemia cell lines. Imatinib also downregulated promoter activities of the DR4 and DR5 gene in luciferase assay. In contrast, imatinib failed to downregulate gene and cell surface expression of DR4 and DR5 in Ph+ ALL cell line having T315I mutation of BCR-ABL. These observations strongly suggested that BCR-ABL plays a role in DR4 and DR5 expression of Ph+ leukemia cells. To further verify this possibility, we transfected shRNA against bcr-abl using lentivirus vector into Ph+ leukemia cell line, and found downregulation of gene and cell surface expression of DR4 and DR5. Moreover, transfection of bcr-abl into Ph- leukemia cell line TF-1 induced gene and cell surface expression of DR4 and DR5 that was abrogated by imatinib treatment. Since BCR-ABL promotes growth and survival of Ph+ leukemia cells though activation of the MAPK, PI3K, and JAK/STAT pathways, we tested the effect of inhibitor of each pathway on the DR4 and DR5 expression of Ph+ leukemia cell lines. U0126, an inhibitor of the MAPK pathway, and LY294002, an inhibitor of the PI3K pathway, but not SD1029, an inhibitor of the JAK/STAT pathway, partially downregulated gene and cell surface expression of DR4 and DR5. These observations demonstrated a unique finding that an oncogenic fusion product derived form chromosomal translocation is implicated in DR4 and DR5 expression on leukemia cells, and provide new insight into the mechanisms of tumor-specific cytotoxic activities of TRAIL. Considering that imatinib downregulates cell surface expression of DR4 and DR5 in Ph+ leukemia cells, it is assumed that the pro-apoptotic activity of TRAIL against Ph+ leukemia cells may be functionally impaired by pretreatment with imatinib. Thus, we analyzed the effect of imatinib on the sensitivity of Ph+ leukemia cell lines to rhsTRAIL, and found that imatinib pretreatment impaired the pro-apoptotic activity of rhsTRAIL in 6 of the 7 TRAIL-sensitive Ph+ leukemia cell lines tested. Of note, imatinib pretreatment of Ph+ ALL cell line, in which DR4 and DR5 expression was not downregulated due to the T315I mutation, did not impair TRAIL sensitivity whereas imatinib pretreatment of its parental cell line with intact BCR-ABL substantially impaired TRAIL sensitivity. These observations suggested that imatinib partially attenuate the in vivo activity of CTLs and NK cells against Ph+ leukemia cells that is mediated by the TRAIL-DR4/DR5 interaction. Since imatinib is now widely used for prophylaxis of relapse and controlling hematological relapse of patients with CML and Ph+ ALL after allo-SCT, our findings are important from the clinical point of view, and suggest that careful observation is required in the clinical use of imatinib during the post-transplant period. Disclosures: No relevant conflicts of interest to declare.

Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3449-3456 ◽  
Author(s):  
Yasuhiko Munakata ◽  
Takako Saito-Ito ◽  
Keiko Kumura-Ishii ◽  
Jie Huang ◽  
Takao Kodera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Surface ◽  
Cell Lines ◽  
Bone Marrow Cells ◽  
Parvovirus B19 ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Human Parvovirus B19 ◽  
Erythroid Cells ◽  
Interfering Rna

AbstractHuman parvovirus B19 (B19) infects human erythroid cells expressing P antigen. However, some cell lines that were positive for P antigen failed to bind B19, whereas some cell lines had an ability to bind B19 despite undetectable expression of P antigen. We here demonstrate that B19 specifically binds with Ku80 autoantigen on the cell surface. Furthermore, transfection of HeLa cells with the gene of Ku80 enabled the binding of B19 and allowed its entry into cells. Moreover, reduction of cell-surface expression of Ku80 in KU812Ep6 cells, which was a high-sensitive cell line for B19 infection, by short interfering RNA for Ku80 resulted in the marked inhibition of B19 binding in KU812Ep6 cells. Although Ku80 originally has been described as a nuclear protein, human bone marrow erythroid cells with glycophorin A or CD36, B cells with CD20, or T cells with CD3 were all positive for cell-surface expression of Ku80. B19 infection of KU812Ep6 cells and bone marrow cells was inhibited in the presence of anti-Ku80 antibody. Our data suggest that Ku80 functions as a novel coreceptor for B19 infection, and this finding may provide an explanation for the pathologic immunity associated with B19 infection.

Stimulation of TNF-α Production from Monocytes by Anti-Moesin Antibodies in the Serum of Patients with Aplastic Anemia: A Novel Mechanism of Myelosuppression by Autoantibodies.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 976-976
Author(s):  
Hiroyuki Takamatsu ◽  
Xingmin Feng ◽  
Xuzhang Lu ◽  
Tatsuya Chuhjo ◽  
Katsuya Okawa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Western Blotting ◽  
Blood Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Surface Proteins ◽  
Healthy Individuals ◽  
Monocytic Leukemia ◽  
Leukemia Cell Lines ◽  
Tnf Α

Abstract Although aplastic anemia (AA) is a T-cell mediated disease, recent studies have revealed the presence of antibodies (Abs) specific to proteins derived from hematopoietic progenitor cells in the serum of AA patients. It is as yet unclear whether these auto-Abs play some roles in the pathophysiology of AA. We previously demonstrated that Abs specific to moesin, a membrane-cytoskeleton linker protein in the cytoplasm, were detectable in approximately 37% of AA patients. Some reports identified moesin-like molecules on the surface of blood cells such as T cells and macrophages. It is therefore conceivable that anti-moesin Ab in AA patients may bind these immune cells and modulate hematopoietic function of AA patients. To test these hypotheses, we first studied the expression of moesin on various types of blood cells using monoclonal Ab specific to moesin (clone 38/87). Flow cytometry detected the expression of the protein recognized by anti-moesin Ab on T cells and monocytes from healthy individuals, acute monocytic leukemia cells lines including U937 and THP-1, and an acute T-lymphoblastic leukemia cell line, Molt-4, but failed to detect the molecule on CD34+ cells from healthy individuals and myeloid leukemia cell lines as well as B-lymphoblastic leukemia cell lines. Treatment of THP-1 cells with phorbol 12-myristate 13-acetate (PMA)/lipopolysaccharide (LPS) augmented the expression level of moesin. To confirm the expression of the moesin-like protein on the surface of monocytic leukemia cell lines, Molt-4 and THP-1 were treated with sulfo-NHS-SS-biotin, and the cell surface proteins were isolated with avidin-fixed column, and were subjected to Western blotting and peptide mass fingerprinting. Western blotting with anti-moesin monoclonal Abs showed two clear bands of proteins (75 kD and 80 kD); an amino acid sequence compatible with moesin was confirmed in the protein eluted from the 80 kD band. Next, we purified anti-moesin Abs from AA patients’ sera using affinity chromatography with recombinant moesin protein. Western blotting showed binding of the serum-derived Abs to a fraction of surface proteins of Molt-4, U937 and THP-1. When THP-1 cells were incubated in the presence of PMA and LPS with 5 αg/ml of control IgG or anti-moesin Abs derived from an AA patient’s serum, TNF-α production from THP-1 cells stimulated by anti-moesin Abs was 1.9–2.3 times as much as that from the control culture depending on the concentration of LPS. Incubation of THP-1 cells in the presence of monoclonal anti-moesin Abs showed the similar augmentation of TNF-α production. These results indicate that anti-moesin Abs may be involved in the suppression of hematopoiesis of AA patients by stimulating TNF-α production from monocytes.

Nampt/SIRT2 Hyperactivation Lead to Activation of ß-Catenin: a Possible Mechanism of Leukomogenic Transformation In CN Patients.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1486-1486
Author(s):  
Lan Dan ◽  
Ana Gigina ◽  
Karl Welte ◽  
Julia Skokowa
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Myeloid Cells ◽  
Nuclear Accumulation ◽  
Healthy Individuals ◽  
Leukemia Cell Lines ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Abstract Abstract 1486 Recently we demonstrated that nicotinamide phosphoribosyltransferase (NAMPT) is an essential enzyme mediating granulocyte colony-stimulating factor (G-CSF)-triggered granulopoiesis via activation of NAD+/sirtuins/C/EBPs signaling cascade. Nampt levels were significantly elevated in plasma and in myeloid cells of patients with severe congenital neutropenia (CN). CN is characterized by a “maturation arrest” of granulopoiesis on the promyelocytic stage of differentiation and by leukemogenic tansformation of hematopoiesis in ca. 20 % of patients. The mechanism of the leukemic transformation is still unclear. Previously, we reported elevated levels of activated oncogene ß-catenin in nuclei of myeloid progenitor cells of CN patients. The activity and nuclear translocation of ß-catenin is regulated by glycogen synthase kinase-3 ß (GSK3ß), which activates ß-catenin degradation complex. In the present study we found that in myeloid cells of CN patients GSK3ß was inhibited by phosphorylation on Ser9, as compared to healthy individuals. Therefore, we assume that GSK3ß-ß-catenin pathway could be involved in the leukemogenic transformation of hematopoiesis. Since, Nampt was also elevated in CN patients, we aimed to investigate the connection between hyperactivated Nampt and ß-catenin in leukemogenesis. The Nampt functions in hematopoiesis are dependent on the dose of Nampt and NAD+. Thus, in vitro stimulation of CD34+ cells with Nampt led to granulocytic differentiation via activation of sirtuin/C/EBP-dependent pathway. At the same time, inhibitors of NAMPT have been identified as therapeutical targets for some cancers including leukemia. This suggested that different mechanisms are operating downstream of NAMPT in the “normal” and leukemogenic myeloid cells. Screening of the different sirtuins in primary acute myeloid leukemia (AML) blasts revealed significant upregulation of SIRT2 mRNA and protein levels, as compared to CD34+ and CD33+ hematopoietic cells of healthy individuals. SIRT2 levels were also elevated in myeloid cells of CN patients treated with G-CSF. Specific inhibition of NAMPT (using 10 nMol of FK866) or SIRT2 (using 100nMol of AC93253) significantly reduced proliferation and induced apoptosis in human myeloid leukemia cell lines (NB4, HL60 and U937). We further tested if inhibition of Nampt or SIRT2 has an effect on GSK3ß/ß-catenin pathway. GSK3ß is known to be inhibited by Akt and treatment of the acute myeloid leukemia cell lines NB4 and HL60 with FK866 or AC93253 resulted in the activation of Akt via phosphorylation on Thr308 and Ser473 and inactivation of GSK-3ß via inhibition of phosphorylation on Ser9. Moreover, activated ß-catenin protein was almost completely disappeared from the nucleus of cells treated with FK866. Taken together, our results provide strong evidence that NAMPT and SIRT2 participate in leukemogenic transformation via inactivation of GSK3ß leading to nuclear accumulation of oncogenic ß-catenin. Disclosures: No relevant conflicts of interest to declare.

RASSF2 Functions As a Tumor Suppressor in t(8;21) AML Via Promotion of Apoptosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3590-3590
Author(s):  
Samuel A Stoner ◽  
Russell Dekelver ◽  
Miao-Chia Lo ◽  
Dong-Er Zhang
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Cell Lines ◽  
Hematopoietic Cells ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Mrna Levels ◽  
Human Cd34 ◽  
Leukemia Cell Lines ◽  
Cd34 Cells

Abstract The t(8;21) chromosomal translocation is one of the most common chromosomal translocations associated with acute myeloid leukemia (AML), found in approximately 12% of de novo AML cases. The majority of these cases are classified as FAB-subtype M2 AML. The t(8;21) results in the stable fusion of the AML1 (RUNX1) and ETO (RUNX1T1) genes. The AML1-ETO fusion protein is composed of the N-terminal portion of AML1, which includes the DNA-binding Runt-homology domain, and nearly the full-length ETO protein. The primary accepted mechanism by which AML1-ETO promotes leukemia development is through the aberrant recruitment of transcriptional repression/activation complexes to normal AML1 target genes. Therefore, the identification of individual genes or biological pathways that are specifically disrupted in the presence of AML1-ETO will provide further molecular insight into the pathogenesis of t(8;21) AML and lead to the possibility for improved treatment for these patients. We identified RASSF2 as a gene that is specifically downregulated in (2-4 fold) in total bone marrow of t(8;21) patients compared to non-t(8;21) FAB-subtype M2 AML patients by analyzing publicly available gene expression datasets. Similarly, using a mouse model of t(8;21) AML we found Rassf2 mRNA levels to be nearly 30-fold lower in t(8;21) leukemia cells compared to wild-type Lin-Sca-cKit+ (LK) myeloid progenitors. Gene expression analysis by RT-qPCR in leukemia cell lines confirmed that RASSF2 mRNA levels are significantly downregulated (8-10-fold) in both Kasumi-1 and SKNO-1 t(8;21) cell lines as compared to a similar non-t(8;21) HL-60 cell line and to primary human CD34+ control cells. In addition, expression of AML1-ETO in HL-60 or CD34+ cells results in a decrease in RASSF2 mRNA expression, which further suggests that RASSF2 is a target for regulation by AML1-ETO. Assessment of published ChIP-seq data shows that AML1-ETO binds the RASSF2 gene locus at two distinct regions in both primary t(8;21) AML patient samples and in the Kasumi-1 and SKNO-1 cell lines. These regions are similarly bound by several important hematopoietic transcription factors in primary human CD34+ cells, including AML1, ERG, FLI1, and TCF7L2, implicating these two regions as important for the regulation of RASSF2 expression during blood cell differentiation. Overexpression of RASSF2 in human leukemia cell lines using an MSCV-IRES-GFP (MIG) construct revealed that RASSF2 has a strong negative effect on leukemia cell proliferation and viability. The overall percentage of GFP-positive cells in MIG-RASSF2 transduced cells markedly decreased compared to MIG-control transduced cells over a period of 14 days. This effect was primarily due to significantly increased apoptosis in the RASSF2 expressing cell populations. Similarly, we found that expression of RASSF2 significantly inhibits the long-term self-renewal capability of hematopoietic cells transduced with AML1-ETO in a serial replating/colony formation assay. AML1-ETO transduced hematopoietic cells were normally capable of serial replating for more than 6 weeks. However, AML1-ETO transduced cells co-expressing RASSF2 consistently had reduced colony number and lost their ability to replate after 3-4 weeks. This was due to a dramatically increased rate of apoptosis in RASSF2 expressing cells. RASSF2 is reported to be a tumor suppressor that is frequently downregulated at the transcriptional level by hypermethylation in primary tumor samples, but not healthy controls. Here we have identified RASSF2 as a target for repression, and demonstrated its tumor suppressive function in t(8;21) leukemia cells. Further insights into the molecular mechanisms of RASSF2 function in AML will continue to be explored. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cholangiocyte expression of α2β1-integrin confers susceptibility to rotavirus-induced experimental biliary atresia

2008 ◽  
Vol 295 (1) ◽  
pp. G16-G26 ◽  
Author(s):  
Mubeen Jafri ◽  
Bryan Donnelly ◽  
Steven Allen ◽  
Alex Bondoc ◽  
Monica McNeal ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Surface ◽  
Biliary Atresia ◽  
Cell Lines ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Newborn Mice ◽  
A Cell

Inoculation of BALB/c mice with rhesus rotavirus (RRV) in the newborn period results in biliary epithelial cell (cholangiocyte) infection and the murine model of biliary atresia. Rotavirus infection of a cell requires attachment, which is governed in part by cell-surface expression of integrins such as α2β1. We hypothesized that cholangiocytes were susceptible to RRV infection because they express α2β1. RRV attachment and replication was measured in cell lines derived from cholangiocytes and hepatocytes. Flow cytometry was performed on these cell lines to determine whether α2β1 was present. Cholangiocytes were blocked with natural ligands, a monoclonal antibody, or small interfering RNA against the α2-subunit and were infected with RRV. The extrahepatic biliary tract of newborn mice was screened for the expression of the α2β1-integrin. Newborn mice were pretreated with a monoclonal antibody against the α2-subunit and were inoculated with RRV. RRV attached and replicated significantly better in cholangiocytes than in hepatocytes. Cholangiocytes, but not hepatocytes, expressed α2β1 in vitro and in vivo. Blocking assays led to a significant reduction in attachment and yield of virus in RRV-infected cholangiocytes. Pretreatment of newborn pups with an anti-α2 monoclonal antibody reduced the ability of RRV to cause biliary atresia in mice. Cell-surface expression of the α2β1-integrin plays a role in the mechanism that confers cholangiocyte susceptibility to RRV infection.

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