Adenosine-generating CD39+ plasmablasts predispose to successful infliximab therapy in pediatric IBD

TL;DR

This study shows that CD39+ plasmablasts and their ability to produce adenosine may predict successful infliximab treatment in children with inflammatory bowel disease.

Contribution

Identifies CD39+ plasmablasts and adenosine production as novel predictors of infliximab response in pediatric IBD.

Findings

IFX responders had higher CD39 expression on plasmablasts and increased adenosine production before treatment.

Responders showed elevated IL10-producing and α4β7hi plasmablasts compared to nonresponders.

CD39+ plasmablasts were reduced in inflamed tissues, especially in nonresponders.

Abstract

IFX responders showed increased CD39 expression on plasmablasts and higher levels of CD39/CD73 co-expression on naïve and memory B cells, along with enhanced ATP degradation and adenosine production before treatment. Response was associated with increased IL10-producing plasmablasts and α4β7hi plasmablasts.

B cells display several immunoregulatory mechanisms including the production of interleukin-10. Ectonucleotidases like CD39 and CD73 influence immune homeostasis by metabolizing eATP and generating immunosuppressive adenosine. The major objective was to examine the expression of those immunoregulatory molecules on B-cell subsets, and, more specifically, to determine their association with an infliximab (IFX) treatment in a pediatric inflammatory bowel disease (IBD) cohort. 42 IBD patients were assessed for IFX response after 12 mo of therapy and compared against 14 healthy controls (HC). Although IL10-producing plasmablasts were decreased in IFX nonresponders (NRS), we detected an up-regulation of CD39 on plasmablasts and increased fractions of CD39/CD73-co-expressing naïve and memory B cells in responding patients (RS). In addition, B cells of responders proved to have superior ATP degradation capacities and adenosine production before therapy initiation compared with NRS and HC. Moreover, IFX nonresponders had a marked deficiency of α4β7hi plasmablasts, whereas both cohorts had fewer CCR9-expressing plasmablasts. Consequently, CD39+ plasmablasts were decreased in biopsies of inflamed mucosal tissues, especially in IFX nonresponders. Our results highlight the regulatory potential of CD39/CD73-expressing B cells in pediatric IBD and suggest CD39+ plasmablasts as a potential determinant of a successful immunosuppressive therapy with IFX.

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