title: Autoregulatory function of interleukin-10-producing pre-naïve B cells is defective in systemic lupus erythematosus.
abstract: BACKGROUND
  Pre-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.
  
  
  METHODS
  Pre-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.
  
  
  RESULTS
  CD40-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.
  
  
  CONCLUSIONS
  There 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.
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Daehak-ro 103, Seoul, 110-799, Republic of Korea. jihyunsim@snu.ac.kr.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Sim
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Daehak-ro 103, Seoul, 110-799, Republic of Korea. hangrae2@snu.ac.kr.|Department of Biomedical Sciences, Seoul National University College of Medicine, Daehak-ro 103, Seoul, 110-799, Republic of Korea. hangrae2@snu.ac.kr.
authors.forename: Hang-Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Anatomy, Seoul National University College of Medicine, Daehak-ro 103, Seoul, 110-799, Republic of Korea. adel1216@hanmail.net.
authors.forename: Soog-Hee
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Division of Rheumatology, Ewha Womans University School of Medicine, Anyangcheon-gil 1071, Seoul, 158-710, Korea. iminze@hanmail.net.
authors.forename: In Je
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: , 1545 London Road, Charlottesville, VA, 20901, USA. peterlipsky@comcast.net.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Lipsky
authors.affiliation: Division of Rheumatology, Ewha Womans University School of Medicine, Anyangcheon-gil 1071, Seoul, 158-710, Korea. leejisoo@ewha.ac.kr.
authors.forename: Jisoo
authors.initials: J
authors.lastname: Lee
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D056724:Immunity, Humoral / Q000502:physiology; D016753:Interleukin-10 / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: C508609:IL10 protein, human; D016753:Interleukin-10