Oligoclonal immunoglobulin repertoire in biliary remnants of biliary atresia

Sarah A Taylor,Padmini Malladi,Joshua B Wechsler,Kathryn E Hulse,Xiaomin Pan,Harris Perlman,Peter F Whitington

doi:10.1038/s41598-019-41148-7

Sarah A Taylor, Padmini Malladi + Show 5 more

Open Access

https://doi.org/10.1038/s41598-019-41148-7

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Abstract

Biliary atresia (BA) is a neonatal cholestatic liver disease that is the leading cause of pediatric liver transplantation, however, the mechanism of disease remains unknown. There are two major forms of BA: isolated BA (iBA) comprises the majority of cases and is thought to result from an aberrant immune response to an environmental trigger, whereas syndromic BA (BASM) has associated malformations and is thought to arise from a congenital insult. To determine whether B cells in BA biliary remnants are antigen driven, we examined the immunoglobulin (Ig) repertoire of diseased tissue from each BA group. Deep sequencing of the Ig chain DNA was performed on iBA and BASM biliary remnants and lymph nodes obtained from the Childhood Liver Disease Research Network (ChiLDReN) repository. Statistical analysis of the Ig repertoire provided measures of Ig clonality and the Ig phenotype. Our data demonstrate that B cells infiltrate diseased iBA and BASM biliary remnant tissue. The Ig repertoires of iBA and BASM disease groups were oligoclonal supporting a role for an antigen-driven immune response in both sub-types. These findings shift the current understanding of BA and suggest a role for antigen stimulation in early iBA and BASM disease pathogenesis.

Highlights

Biliary atresia (BA) is a progressive obliterative cholangiopathy of infancy, which often leads to end-stage liver disease and the need for transplantation in the first two years of life
Having demonstrated a highly clonal B cell population in the biliary remnants of isolated BA (iBA) and BA with splenic malformation syndrome (BASM) samples, we evaluated the Ig repertoire of the local lymph nodes from these same cases, the site where the B cell responses were likely generated
Similar to the T cell receptor repertoire[6], the human B cell receptor (BCR) repertoire is highly clonal strongly supporting a role for antigen stimulation early in disease pathogenesis

Summary

Introduction

Biliary atresia (BA) is a progressive obliterative cholangiopathy of infancy, which often leads to end-stage liver disease and the need for transplantation in the first two years of life. An oligoclonal T cell receptor repertoire in diseased human BA liver and bile duct remnant samples supports the hypothesis that antigen stimulation is involved early in the disease course of BA6. Increasing work on the immunoglobulin (Ig) repertoire in specific disease states has provided insight into the role that B cell immunity plays in pathogenesis[11]. The variable region of Ig is responsible for binding a specific antigen and consists of a unique combination of heavy (V, D, and J) and light (V and J) chain variable gene segments[12] Recombination of these variable gene segments is the primary mechanism by which each B cell generates a unique Ig sequence. Somatic hypermutation of variable region genes allows for additional variable gene sequence diversity and selection of high-affinity, antigen-specific Igs that provide a focused disease-specific antibody repertoire

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