Evidence that Yaa-induced loss of marginal zone B cells is a result of dendritic cell-mediated enhanced activation.
The development of systemic lupus is accelerated by the Yaa (Y-linked autoimmune acceleration) mutation, which is the consequence of a translocation of the telomeric end containing the Tlr7 gene from the X chromosome onto the Y chromosome. However, the loss of marginal zone (MZ) B cells, one of the Yaa-linked cellular abnormalities, has previously been shown to be unrelated to the Tlr7 gene duplication, and the present study therefore aimed to investigate the mechanism responsible for MZ B-cell loss. Analyses of Yaa and non-Yaa C57BL/6 male mice expressing an MD4 anti-HEL IgM transgene or those deficient in fms-like tyrosine kinase 3 ligand (FL) revealed that the proportion of MZ B cells in these Yaa mice was comparable to that of the respective non-Yaa control mice. Notably, the activation of MZ B cells was compromised in both of these transgenic model systems, due to the absence of cognate antigens or the impaired development of dendritic cells, respectively. These results contrasted with the loss of MZ B cells in non-Yaa mice treated with FL and the lack of accumulation of MZ B cells in Yaa mice treated with a B-cell survival factor, BAFF. Taken together, our results suggest that the persistent and enhanced activation of Yaa-bearing hyperactive MZ B cells by dendritic cells is responsible for the loss of this B-cell subset in Yaa mice.
Santiago-Raber
Marie-Laure
ML
Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva 1211, Switzerland.
Amano
Hirofumi
H
Amano
Eri
E
Fossati-Jimack
Liliane
L
Swee
Lee Kim
LK
Rolink
Antonio
A
Izui
Shozo
S
D000818:Animals; D016175:B-Lymphocyte Subsets; D001402:B-Lymphocytes / Q000473:pathology*; D003713:Dendritic Cells / Q000276:immunology*; D050173:Genes, Y-Linked / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000473:pathology; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D051199:Toll-Like Receptor 7 / Q000235:genetics*; D014178:Translocation, Genetic
D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7