air-inflation-of-murine-lungs-with-vascular-perfusion-fixation

Air-Inflation of Murine Lungs with Vascular Perfusion-Fixation

Lung histology is often used to investigate the contributions provided by airspace cells during lung homeostasis and disease pathogenesis. However, ...

Children's Hospital Colorado

Biliary atresia (BA) is a neonatal T cell-mediated, inflammatory, sclerosing cholangiopathy. In the rhesus rotavirus (RRV)-induced neonatal mouse model of BA (murine BA), mice lacking B cells do not develop BA, and the lack of B cells is associated with loss of T-cell and macrophage activation. The aim of this study was to determine the mechanism of B cell-mediated immune activation (antigen presentation versus cytokine production) in murine BA. Normal neonatal B cells in the liver are predominantly at pro-B and pre-B cellular development. However, BA mice exhibit a significant increase in the number and activation status of mature liver B cells. Adoptively transferred B cells into RRV-infected, B cell-deficient mice were able to reinstate T-cell and macrophage infiltration and biliary injury. Nonetheless, neonatal liver B cells were incompetent at antigen presentation to T cells. Moreover, 3-83 immunoglobulin transgenic mice, in which B cells only present an irrelevant antigen, developed BA, indicating a B-cell antigen-independent mechanism. B cells from BA mice produced a variety of innate and adaptive immune cytokines associated with immune activation. In vitro trans-well studies revealed that BA B cells secreted cytokines that activated T cells based on increased expression of T-cell activation marker cluster of differentiation 69. Conclusion: Neonatal liver B cells are highly activated in murine BA and contribute to immune activation through production of numerous cytokines involved in innate and adaptive immunity; this work provides increased knowledge on the capacity of neonatal B cells to contribute to an inflammatory disease through cytokine-mediated mechanisms, and future studies should focus on targeting B cells as a therapeutic intervention in human BA.

Cytokine-Producing B Cells Promote Immune-Mediated Bile Duct Injury in Murine Biliary Atresia.

Biliary atresia is a progressive fibroinflammatory cholangiopathy of infancy that is associated with activation of innate and adaptive immune responses targeting bile ducts. A recently completed multicenter phase I/IIA trial of intravenous immunoglobulin in biliary atresia did not improve serum total bilirubin levels at 90 days after hepatoportoenterostomy or survival with the native liver at 1 year. A mechanistic aim of this trial was to determine if the peripheral blood immunophenotype was associated with clinical outcomes. Flow cytometry of peripheral blood cell markers (natural killer [NK], macrophage subsets, T- and B-cell subsets, regulatory T cells), neutrophils, and activation markers (clusters of differentiation [CD]38, CD69, CD86, human leukocyte antigen-DR isotype [HLA-DR]) was performed on 29 patients with biliary atresia at baseline and at 60, 90, 180, and 360 days after hepatoportoenterostomy. Plasma cytokines and neutrophil products were also measured. Spearman correlations of change of an immune marker from baseline to day 90 with change in serum bilirubin revealed that an increase in total bilirubin correlated with 1) increased percentage of HLA-DRCD38 NK cells and expression of NK cell activation markers CD69 and HLA-DR, 2) decreased percentage of regulatory T cells, and 3) increased interleukin (IL)-8 and associated neutrophil products (elastase and neutrophil extracellular traps). Cox modeling revealed that the change from baseline to day 60 of the percentage of HLA-DRCD38 NK cells and plasma IL-8 levels was associated with an increased risk of transplant or death by day 360.  Poor outcomes in biliary atresia correlated with higher peripheral blood NK cells and IL-8 and lower regulatory T cells. Future studies should include immunotherapies targeting these pathways in order to protect the biliary tree from ongoing damage.

Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy.

The etiology of biliary atresia (BA) is not known and is likely multifactorial, including a genetic predisposition, a viral or environmental trigger, an aberrant autoimmune response targeting cholangiocytes and unique susceptibilities of the neonatal bile ducts to injury. Damaged cholangiocytes may express neo self-antigens and elicit autoreactive T cell-mediated inflammation and B cell production of autoantibodies. The aim of this study was to discover novel autoantibodies in BA that correlated with outcomes.

Unique cholangiocyte-targeted IgM autoantibodies correlate with poor outcome in biliary atresia.

Biliary atresia (BA) is an inflammatory pediatric cholangiopathy with only surgical means for treatment. Many contributors to bile acid synthesis and transport have previously been reported to be downregulated in patients with BA; yet, the driving factors of the abnormal bile acid synthesis and transport in regard to BA have not been previously studied.

Article	Year
Cytokine-Producing B Cells Promote Immune-Mediated Bile Duct Injury in Murine Biliary Atresia. Hepatology (Baltimore, Md.)\| PubMed ID: 29679373	2018
Correlation of Immune Markers With Outcomes in Biliary Atresia Following Intravenous Immunoglobulin Therapy. Hepatology communications\| PubMed ID: 31061956	2019
Unique cholangiocyte-targeted IgM autoantibodies correlate with poor outcome in biliary atresia. Hepatology (Baltimore, Md.)\| PubMed ID: 32767570	2020
Inflammation Drives MicroRNAs to Limit Hepatocyte Bile Acid Transport in Murine Biliary Atresia. The Journal of surgical research\| PubMed ID: 32818799	2020

Joseph Bednarek

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