title: Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice.
abstract: MRL/MpJ-Fas(lpr)/J (MRL/lpr) mice represent a well-established mouse model of human systemic lupus erythematosus. MRL/lpr mice homozygous for the spontaneous lymphoproliferation mutation (lpr) are characterized by systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, splenomegaly, hypergammaglobulinemia, arthritis, and fatal immune complex-mediated glomerulonephritis. It was reported previously that steady-state mRNA levels for the chemokine (C-C motif) receptor 2 (Ccr2) continuously increase in kidneys of MRL/lpr mice. For examining the role of Ccr2 for development and progression of immune complex-mediated glomerulonephritis, Ccr2-deficient mice were generated and backcrossed onto the MRL/lpr genetic background. Ccr2-deficient MRL/lpr mice developed less lymphadenopathy, had less proteinuria, had reduced lesion scores, and had less infiltration by T cells and macrophages in the glomerular and tubulointerstitial compartment. Ccr2-deficient MRL/lpr mice survived significantly longer than MRL/lpr wild-type mice despite similar levels of circulating immunoglobulins and comparable immune complex depositions in the glomeruli of both groups. Anti-dsDNA antibody levels, however, were reduced in the absence of Ccr2. The frequency of CD8+ T cells in peripheral blood was significantly lower in Ccr2-deficient MRL/lpr mice. Thus Ccr2 deficiency influenced not only monocyte/macrophage and T cell infiltration in the kidney but also the systemic T cell response in MRL/lpr mice. These data suggest an important role for Ccr2 both in the general development of autoimmunity and in the renal involvement of the lupus-like disease. These results identify Ccr2 as an additional possible target for the treatment of lupus nephritis.
authors.affiliation: Klinikum der Universität München, Medizinische Poliklinik - Innenstadt, Munich, Germany.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pérez de Lema
authors.forename: Holger
authors.initials: H
authors.lastname: Maier
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Franz
authors.forename: Maríia
authors.initials: M
authors.lastname: Escribese
authors.forename: Silvia
authors.initials: S
authors.lastname: Chilla
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Natalia
authors.initials: N
authors.lastname: Camarasa
authors.forename: Holger
authors.initials: H
authors.lastname: Schmid
authors.forename: Bernhard
authors.initials: B
authors.lastname: Banas
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Kalaydjiev
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Francisco
authors.initials: F
authors.lastname: Mampaso
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Bruno
authors.initials: B
authors.lastname: Luckow
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D019085:Fluorescent Antibody Technique, Direct; D007150:Immunohistochemistry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015996:Survival Rate
chemical_list: D019707:Receptors, Chemokine