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Expansion of Bone Marrow IFN--Producing Dendritic Cells in New Zealand Black (NZB) Mice: High Level Expression of TLR9 and Secretion of IFN- in NZB Bone Marrow

Zhe-Xiong Lian^*, Kentaro Kikuchi^*, Guo-Xiang Yang^*, Aftab A. Ansari, Susumu Ikehara and M. Eric Gershwin^1,*

^* Division of Rheumatology/Allergy and Clinical Immunology, University of California, Davis, CA 95616; Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322; and First Department of Pathology, Kansai Medical University, Moriguchi, Osaka, Japan

Patients with systemic lupus erythematosus have elevated IFN- production. Furthermore, sera IFN- levels correlate with disease activity. We have focused our attention on whether this phenotype is also seen in the New Zealand Black (NZB) mice and simultaneously addressed the underlying mechanisms. Specifically, we analyzed: 1) levels of sera IFN- after type A CpG ODN 2216 injection in autoimmunity-prone NZB and control mice, and 2) levels of IFN- synthesized by IFN--producing dendritic cells (IPDCs) using highly enriched populations of CD11c⁺B220⁺ IPDCs derived from NZB and control mice; IPDCs are divided into two subpopulations (CD4⁺CD11c⁺B220⁺ and CD4^–CD11c⁺B220⁺). Our data demonstrate that NZB mice produced higher levels of sera IFN- after type A CpG ODN 2216 injection when compared with control mice (p < 0.01). In addition, the cell numbers, frequency, and TLR9 mRNA levels of CD4⁺ and CD4^– IPDC were markedly increased in the bone marrow (BM) of NZB mice. Upon in vitro stimulation with TLR9 ligand-CpG ODN 2216, higher levels of IFN- were synthesized by IPDCs from the BM of NZB. The major contributor of IFN- was the CD4^–CD11c⁺B220⁺ IPDC subpopulation. Furthermore, NZB BM IPDCs manifest impaired expression of homing chemokine CCR7 and CD62L, and IL-12 production. These data on the functional characteristics of the IPDC lineages explain in part the mechanism of hyper-IFN- production and help clarify the mechanism for the expansion of NZB BM IPDCs.

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