CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Abstract

Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

Aberrant B-cell homeostasis in chronic GVHD

“…Alternatively, supranormal B-cell populations may also contain a significant component of regulatory B cells that promote immune tolerance through different mechanisms. 42,43 Although the etiology of delayed B-cell recovery in cGVHD remains an area of active investigation, these data support the critical role of bone marrow lymphogenesis and output for the maintenance of B-cell homeostasis and immune tolerance.…”

Circulating T follicular helper cells with increased function during chronic graft-versus-host disease

“…[4][5][6] Both murine models and clinical studies have shown that cGVHD is associated with multiple abnormalities of B-cell reconstitution including decreased numbers of B-cell progenitors, increased representation of memory B cells, and decreased frequency of regulatory B cells. 4,[7][8][9][10][11] cGVHD is also associated with high levels of B-cell activating factor (BAFF), high BAFF-to-B-cell ratios and aberrant B-cell activation. 4,6,10,12,13 The frequent detection of auto-and alloantibodies after HSCT and the clinical benefit of B-cell-targeted therapy also emphasize the important role of B cells in the development of cGVHD.…”

Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice

“…10,11 Reduction of interleukin-10 (IL-10)-producing regulatory B cells was found in cGVHD patients and murine models. [12][13][14] We reported that donor B cells augmented clonal expansion of pathogenic CD4…”