Autoregulatory function of interleukin-10-producing pre-naïve B cells is defective in systemic lupus erythematosus

Abstract

IntroductionPre-naïve B cells represent an intermediate stage in human B-cell development with some functions of mature cells, but their involvement in immune responses is unknown. The aim of this study was to determine the functional role of normal pre-naïve B cells during immune responses and possible abnormalities in systemic lupus erythematosus (SLE) that might contribute to disease pathogenesis.MethodsPre-naïve, naïve, and memory B cells from healthy individuals and SLE patients were stimulated through CD40 and were analyzed for interleukin-10 (IL-10) production and co-stimulatory molecule expression and their regulation of T-cell activation. Autoreactivity of antibodies produced by pre-naïve B cells was tested by measuring immunoglobulin M (IgM) autoantibodies in culture supernatants after differentiation.ResultsCD40-stimulated pre-naïve B cells produce larger amounts of IL-10 but did not suppress CD4+ T-cell cytokine production. Activated pre-naïve B cells demonstrated IL-10-mediated ineffective promotion of CD4+ T-cell proliferation and induction of CD4+FoxP3+ T cells and IL-10 independent impairment of co-stimulatory molecule expression and tumor necrosis factor-alpha (TNF-α) and IL-6 production. IgM antibodies produced by differentiated pre-naïve B cells were reactive to single-stranded deoxyribonucleic acid. SLE pre-naïve B cells were defective in producing IL-10, and co-stimulatory molecule expression was enhanced, resulting in promotion of robust CD4+ T-cell proliferation.ConclusionsThere is an inherent and IL-10-mediated mechanism that limits the capacity of normal pre-naïve B cells from participating in cellular immune response, but these cells can differentiate into autoantibody-secreting plasma cells. In SLE, defects in IL-10 secretion permit pre-naïve B cells to promote CD4+ T-cell activation and may thereby enhance the development of autoimmunity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0687-1) contains supplementary material, which is available to authorized users.

CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity

“…Emab affects the production of cytokines in response to BCR/TLR stimulation, by skewing B cells to produce immunoregulatory cytokines such as IL-10 while inhibiting IL-6 and TNF alpha production ( 104 , 105 ). Thus, targeting CD22 may restore IL-10 production by regulatory B cells, reported to be impaired in SLE patients ( 126 ). Emab inhibits the activation and the expression of PRDM1/Blimp1 in response to BCR and TLR7 stimulation in a subset of CD27 − IgD − double-negative (DN) memory B-cells ( 104 ), known to be elevated in SLE patients with more active disease ( 127 ).…”

Effector and regulatory B cells in immune-mediated kidney disease

“…This defect in IL-10 production leads to a reduced ability of CD19 + CD24 hi CD38 hi B cells from patients with SLE to inhibit Th1 responses compared to those of healthy individuals (56). In addition, the frequency of IL-10-producing cells within the naïve B cell pool (CD19 + CD27 -CD38 int IgD + B cells) is reduced in patients with SLE and these cells express higher levels of co-stimulatory molecules than those from healthy individuals leading to enhanced T cell activation (126). Although IL-21 usually drives Breg cell differentiation, in patients with SLE it promotes a population of CD11c + Tbet + memory B cells that can differentiate into short lived plasma cells and this memory population correlates with disease activity (127).…”

The 2014 ACR annual meeting: a bird’s eye view of autoimmunity in 2015

“…A regulatory role has been proposed for IL-10 producing B cells in autoimmunity and this was addressed in SLE by Sim Ji-Hyun and Colleagues [177]. Pre-naïve, naïve and memory B cells from healthy individuals and SLE patients were stimulated through CD40 and were analyzed for IL-10 production and co-stimulatory molecule expression, and their regulation of T cell activation.…”