Role of the chemokine stromal cell-derived factor 1 in autoantibody production and nephritis in murine lupus.
In normal mice, stromal cell-derived factor 1 (SDF-1/CXCL12) promotes the migration, proliferation, and survival of peritoneal B1a (PerB1a) lymphocytes. Because these cells express a self-reactive repertoire and are expanded in New Zealand Black/New Zealand White (NZB/W) mice, we tested their response to SDF-1 in such mice. PerB1a lymphocytes from NZB/W mice were exceedingly sensitive to SDF-1. This greater sensitivity was due to the NZB genetic background, it was not observed for other B lymphocyte subpopulations, and it was modulated by IL-10. SDF-1 was produced constitutively in the peritoneal cavity and in the spleen. It was also produced by podocytes in the glomeruli of NZB/W mice with nephritis. The administration of antagonists of either SDF-1 or IL-10 early in life prevented the development of autoantibodies, nephritis, and death in NZB/W mice. Initiation of anti-SDF-1 mAb treatment later in life, in mice with established nephritis, inhibited autoantibody production, abolished proteinuria and Ig deposition, and reversed morphological changes in the kidneys. This treatment also counteracted B1a lymphocyte expansion and T lymphocyte activation. Therefore, PerB1a lymphocytes are abnormally sensitive to the combined action of SDF-1 and IL-10 in NZB/W mice, and SDF-1 is key in the development of autoimmunity in this murine model of lupus.
Balabanian
Karl
K
Institut National de la Santé et de la Recherche Médicale Unité 131, Institut Paris-Sud sur les Cytokines, Clamart, France.
Couderc
Jacques
J
Bouchet-Delbos
Laurence
L
Amara
Ali
A
Berrebi
Dominique
D
Foussat
Arnaud
A
Baleux
Françoise
F
Portier
Alain
A
Durand-Gasselin
Ingrid
I
Coffman
Robert L
RL
Galanaud
Pierre
P
Peuchmaur
Michel
M
Emilie
Dominique
D
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001323:Autoantibodies / Q000096:biosynthesis*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D010529:Peritoneal Cavity / Q000473:pathology; D011507:Proteinuria / Q000401:mortality / Q000517:prevention & control; D018123:Receptors, Interleukin / Q000276:immunology; D053701:Receptors, Interleukin-10; D013045:Species Specificity
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10