Sialic Acid-Binding Immunoglobulin-Type Lectin H-Positive Plasmacytoid Dendritic Cells Drive Spontaneous Lupus-like Disease Development in B6.Nba2 Mice

作者：Davison Laura M; Jorgensen Trine N^*

来源：Arthritis & Rheumatology, 2015, 67(4): 1012-1022.

DOI：10.1002/art.38989

Objective. Patients with systemic lupus erythematosus (SLE) often present with elevated levels of interferon-alpha (IFN alpha) in serum. Plasmacytoid dendritic cells (pDCs) have been suggested to be the primary source of IFN alpha in SLE due to their capacity to produce high levels of IFN alpha. During viral infection, a subset of pDCs expressing sialic acid-binding immunoglobulin-type lectin H (Siglec H) produces the majority of pDC-derived IFN alpha. The aim of this study was to provide evidence that Siglec H-positive pDCs are pathogenic in the IFN alpha-dependent B6.Nba2 mouse model of lupus.
Methods. B6.Nba2 blood dendritic cell antigen 2 (BDCA-2)-diphtheria toxin receptor (DTR)-transgenic (Tg) mice were treated intraperitoneally with DT 3 times weekly starting at 4 weeks or 12 weeks of age and analyzed at 12 weeks and 18 weeks of age, respectively. Lupus-like disease development was measured by the presence of elevated levels of autoantibodies in serum (as determined by enzyme-linked immunosorbent assay), increased expression of IFN-inducible genes (as determined by real-time reverse transcription-polymerase chain reaction), increased IgG immune complex deposition in kidney glomeruli (as determined by immunofluorescence staining), spontaneous lymphocyte activation, and differentiation of B cells into antibody-producing plasma cells (as determined by flow cytometry).
Results. B6.Nba2 mice in which Siglec H-positive pDCs were depleted for 6-8 weeks displayed reduced levels of IFN alpha-induced gene transcripts and decreased anti-chromatin autoantibody levels in serum, and significantly fewer activated splenic T cells and B cells, germinal center B cells, follicular helper T cells, and splenic plasma cells. In 18-week-old mice, IgG immune complex deposition in kidney glomeruli was similarly reduced.
Conclusion. The development of lupus-like disease in congenic B6.Nba2 mice depends on Siglec H-positive pDCs. We suggest that depletion of Siglec H-positive pDCs represents a novel cellular target in SLE.

• 出版日期2015-4