Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Type I IFN-Dependent CD86high Marginal Zone-Precursor B Cells Are Potent T Cell Costimulators in the BXD2 Mouse Model of Lupus.
Wang3, John S., Wu3, Qi, Yang1, PingAr, Li1, Hao, Li1, Jun, Mountz2, John D., Hsu1, Hui-Chen
We previously showed that type I-IFN producing plasmacytoid dendritic cells (pDCs) upregulated the expression of CD69 on CD1dhiCD21hiIgMhiCD23hi marginal zone precursor (MZ-P) B cells in the spleens of lupus prone BXD2 mice. This action promotes the follicular migration of antigen delivering MZ-P B cells directly to the germinal centers (GC) in BXD2 spleen. In the present study, we determined if type I IFN can promote T-dependent antibody responses in BXD2 mice via its augmentation of the costimulatory function of MZ-P B cells.
Confocal imaging was used to determine the location of pDCs, MZ-Ps and CD4 T cells in the spleens of BXD2 and BXD2-Ifnar-/- mice. H&E staining of spleen and kidney was used to determine the presence of IgGbright cells in BXD2 and BXD2-Cd86-/- mice. ELISA was used to determine serum levels of IFN-a, autoantibody, and NP-CGG- or NP-Ficoll-induced anti-NP2 antibody titers. The level of type I IFN transcripts in the peripheral blood was determined by quantitative real-time PCR. [3H]-thymidine was used to measure T cell proliferation.
Summary of the Results:
There was increased clustering of pDCs located in the marginal sinus in the spleens of BXD2 mice, compared with B6 spleens. Consistent with this, RNA isolated from the peripheral blood of 36-mo-old BXD2 mice expressed >5-fold higher levels of Ifna1, Ifna4, and Ifna11, compared with those from B6 mice. Type I IFN receptor (IFNAR) deletion abrogated development of IgGbright cell formation and suppressed a T-dependent but not T-independent antibody response in BXD2 mice. Type I IFN signaling induced the expression of CD86, but not CD80, on CD1dloCD21loIgMloCD23hi follicular (FO), CD1dhiCD21hiIgMhiCD23lo marginal zone, and MZ-P B cells. However, MZ-P B cells demonstrated the highest expression of CD86 and the highest capacity for T-cell costimulation with intact IFNAR. In BXD2, but not BXD2-Ifnar-/- mice, MZ-P B cells clustered at the intra-follicular T-B border, an important immunological junction where GC formation is initiated. Both IFNAR and CD86 deletion suppressed GC formation, autoantibody production, and IgG deposits in the kidney.
Our study proposes that type I IFN can offer a new avenue by which T-dependent autoantibody responses are generated in BXD2 mice. First, type I IFN is critical in bringing MZ-Ps to the T-B border in the FO interior at the pre-GC stage. Second, type I IFN significantly increases the levels of CD86 on MZ-Ps, providing potent costimulation to CD4 T cells. Because pDCs are systemically circulated between the peripheral blood and the spleen, the present study exhibit important pathogenic and mechanistic implication for the IFN signature in the peripheral blood of human lupus patients.
To cite this abstract, please use the following information:
Wang, John S., Wu, Qi, Yang, PingAr, Li, Hao, Li, Jun, Mountz, John D., et al; Type I IFN-Dependent CD86high Marginal Zone-Precursor B Cells Are Potent T Cell Costimulators in the BXD2 Mouse Model of Lupus. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2189