FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis.
Lupus glomerulonephritis is initiated by deposition of IgG-containing immune complexes in renal glomeruli. FcR engagement by immune complexes (IC) is crucial to disease development as uncoupling this pathway in FcRgamma(-/-) abrogates inflammatory responses in (NZB x NZW)F1 mice. To define the roles of FcR-bearing hemopoietic cells and of kidney resident mesangial cells in pathogenesis, (NZB x NZW)F1 bone marrow chimeras were generated. Nephritis developed in (NZB x NZW)F1 mice expressing activating FcRs in hemopoietic cells. Conversely, recipients of FcRgamma(-/-) bone marrow were protected from disease development despite persistent expression of FcRgamma in mesangial cell populations. Thus, activating FcRs on circulating hemopoietic cells, rather than on mesangial cells, are required for IC-mediated pathogenesis in (NZB x NZW)F1. Transgenic FcRgamma(-/-) mice expressing FcRgamma limited to the CD11b+ monocyte/macrophage compartment developed glomerulonephritis in the anti-glomerular basement disease model, whereas nontransgenic FcRgamma(-/-) mice were completely protected. Thus, direct activation of circulating FcR-bearing myeloid cells, including monocytes/macrophages, by glomerular IC deposits is sufficient to initiate inflammatory responses.
Bergtold
Amy
A
Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Gavhane
Anamika
A
D'Agati
Vivette
V
Madaio
Michael
M
Clynes
Raphael
R
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D005260:Female; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000276:immunology* / Q000378:metabolism*; D017452:Receptors, IgG / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000936:Antigen-Antibody Complex; D017452:Receptors, IgG