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

Abstract

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‐DR + CD38 + 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‐DR + CD38 + NK cells and plasma IL‐8 levels was associated with an increased risk of transplant or death by day 360. Conclusion: 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.

COL3A1, CXCL8, VCAN, THBS2, and COL1A2 are correlated with the onset of biliary atresia

“…Many of the KEGG pathways were related to the immune response, which was consistent with some previous studies. [22,23] A recent study has demonstrated that IL-17A signaling pathway was probably involved in chronic inflammation of the bile duct in primary biliary cirrhosis, [24] in which, chronic inflammation was associated with biliary innate immune responses. [25] It seems to be linked to our study.…”

Circulating maternal chimeric cells have an impact on the outcome of biliary atresia

“…GVHD-like immune interaction (CD8+ effector lymphocytes are MC cells), whereas an indirect cause implies that MC cells are cytokeratin-positive cells, which are targets of autologous T lymphocytes. The other possible indirect cause is regulatory T cell (Treg) dysfunction (6)(7)(8), which is affected by MMc, leading to host immune responses toward self-antigens. To distinguish these alloimmune reactions, we quantified MC-DNA separately in the buffy coat, which reflects the number of maternal lymphocytes and in the plasma, representing the number of MC cells incorporated in host tissue that shed their DNA.…”

Predicting the outcomes of Kasai portoenterostomy for biliary atresia: a cohort study

“…DB and ALB are factors reflecting the excretory and synthetic functions of liver; the results indicate that only patients with excellent comprehensive liver functions can survive with their native liver. Some studies have been reported about predicting NLS for infants after KPE, most focused on factors before jaundice resolution, and some are not routine parameters, [9][10][11][12][13][14][15] the predictive values are not certain.…”