Dendritic cells from lupus-prone mice are defective in repressing immunoglobulin secretion.
Autoimmunity results from a breakdown in tolerance mechanisms that regulate autoreactive lymphocytes. We recently showed that during innate immune responses, secretion of IL-6 by dendritic cells (DCs) maintained autoreactive B cells in an unresponsive state. In this study, we describe that TLR4-activated DCs from lupus-prone mice are defective in repressing autoantibody secretion, coincident with diminished IL-6 secretion. Reduced secretion of IL-6 by MRL/lpr DCs reflected diminished synthesis and failure to sustain IL-6 mRNA production. This occurred coincident with lack of NF-kappaB and AP-1 DNA binding and failure to sustain IkappaBalpha phosphorylation. Analysis of individual mice showed that some animals partially repressed Ig secretion despite reduced levels of IL-6. This suggests that in addition to IL-6, DCs secrete other soluble factor(s) that regulate autoreactive B cells. Collectively, the data show that MRL/lpr mice are defective in DC/IL-6-mediated tolerance, but that some individuals maintain the ability to repress autoantibody secretion by an alternative mechanism.
Gilbert
Mileka R
MR
Department of Microbiology/Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Carnathan
Diane G
DG
Cogswell
Patricia C
PC
Lin
Li
L
Baldwin
Albert S
AS
Vilen
Barbara J
BJ
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D007108:Immune Tolerance; D007136:Immunoglobulins / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology
D001323:Autoantibodies; D007136:Immunoglobulins; D015850:Interleukin-6; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D004247:DNA