The Regulatory B Cell Compartment Expands Transiently During Childhood and Is Contracted in Children With Autoimmunity

Abstract

Objective Regulatory B cells that inhibit immune responses through interleukin-10 (IL-10) secretion (B10 cells) have been characterized in adults with autoimmune disease. This study examines B10 cells across the entire age range of normal human development, and their changes during pediatric autoimmunity. Methods The phenotype and numbers of blood B10 cells were examined in healthy individuals and children with autoimmunity by flow cytometry. B10 cell function was assessed by measuring the effect of B cell-derived IL-10 on CD4+ T cell interferon-gamma (IFN-γ) expression. Serum cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Results B10 cell frequencies transiently increase during childhood when up to 30% of B cells were competent to produce IL-10, compared to the low frequencies in healthy newborns (3–4%) and adults (7–%). The surface phenotype of B10 cells in children revealed age-dependent variability. B10 cells from children were distinct from proinflammatory cytokine-producing B cells and down-regulated CD4+ T cell IFN-γ production in vitro. Compared to age-matched healthy controls, children with autoimmunity had lower B10 cell frequencies and numbers (decreased by 39% and 48%, respectively), higher IFN-γ and lower interleukin-21 (IL-21) serum levels. IFN-γ inhibited whereas IL-21 promoted B cell IL-10 competence in vitro. Conclusion B10 cells, a functionally-defined subset with variable surface phenotype reflective of overall B cell development, transiently expand during childhood. The decreased B10 cell frequencies and numbers in children with autoimmunity may be partially explained by the differential regulation of B10 cell development by IFN-γ and IL-21 and alterations in serum cytokine levels.

Regulatory B cells in autoimmune rheumatic diseases

“…11 In humans, B10 cells of peripheral blood are increased in childhood (8-10 years-old) and are low in adults. 12 Interestingly, B10 cells are very low in advanced age where they exhibit a negative correlation with serum levels of rheumatoid factor; 13 a finding that is in line with the concept that deficiency of Breg cells likely contributes to loss of immunological tolerance and the development of autoimmunity. Breg cells are very low in peripheral blood and have to be increased in order to be studied.…”

CD19+CD24hiCD38hi B Cells Are Expanded in Juvenile Dermatomyositis and Exhibit a Pro-Inflammatory Phenotype After Activation Through Toll-Like Receptor 7 and Interferon-α

“…We next investigated whether there was an intrinsic IL-10 defect in patient B cells using the CD40–CD40L interaction which is key for B cell development and induces IL-10 in B cells ( 80 ) Contrary to Kalampokis et al, who reported a reduction in Breg IL-10 in JDM patients ( 81 ), we did not observe a difference in JDM patients pre-treatment and controls with the CD40L stimulus, indicating that patient B cells can produce IL-10 with CD40 activation. These results suggest that activation through CD40 is not defective in these patients.…”

Phenotypes, Functions, and Clinical Relevance of Regulatory B Cells in Cancer

“…Besides, B cells also act to suppress immune responses. Accumulating studies have revealed that an immunoregulatory subset of B cells exists and exerts multifaceted functions (7)(8)(9)(10). In the 1970s, a suppressive subset of B cells was firstly hypothesized to exist and modulate immune responses, based on reports indicating that the depletion of B cells in splenocytes was correlated with increased severity and duration of delayed-type hypersensitivity in a guinea pig model (11,12).…”