TLR-9 activation of marginal zone B cells in lupus mice regulates immunity through increased IL-10 production.
Bacterial DNA triggers B-cell proliferation and induces immunoglobulin secretion. Chromatin-IgG complexes activate autoreactive B cells by co-engaging B-cell receptor (BCR) and TLR-9, thus suggesting a role for innate signaling in systemic autoimmunity. Spleen cells from lupus prone Palmerston North (PN) mice produce several fold less IL-12p40 than controls in response to CpG-oligodeoxynucleotides (ODNs). Here we show that B cells are primarily responsible for this abnormality. The removal of B cells from PN cultures markedly increased IL-12p40. Moreover, the addition of purified B cells back to PN splenocyte cultures resulted in a B-cell number dependent/ IL-10-mediated suppression of IL-12p40. The B cells were the major source of IL-10. In response to CpG, B cells from several lupus strains produced twice as a much IL-10 as controls, but failed to produce IL-10 when stimulated through BCR or CD40. PN and control mice expressed IL-10R similarly, and the difference in IL-10 secretion remained when anti-IL-10R blocking antibodies were used. IFN-gamma and IL-4 regulated CpG-induced IL-10 secretion in opposite directions. The abnormal IL-10 response in lupus mice was derived from B cells with the marginal zone phenotype, and could be downregulated with inhibitory ODNs. We hypothesize that TLR-9 activated lupus B cells can modulate T-cell mediated inflammatory responses through IL-10 production. Therefore, B cells may contribute to the lupus pathogenesis in many different ways: as antigen-presenting cells for self antigens, as effector cells for autoantibody production, and as IL-10 secreting regulatory cells.
Lenert
Petar
P
Division of Rheumatology, Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA. petar-lenert@uiowa.edu
Brummel
Rachel
R
Field
Elizabeth H
EH
Ashman
Robert F
RF
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis; D053762:Interleukin-12 Subunit p40; D015847:Interleukin-4 / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008811:Mice, Inbred DBA; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D021122:Protein Subunits / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D051217:Toll-Like Receptor 9
C408982:CPG-oligonucleotide; D004268:DNA-Binding Proteins; D053762:Interleukin-12 Subunit p40; D009838:Oligodeoxyribonucleotides; D021122:Protein Subunits; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma
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