Inducible co-stimulator null MRL-Faslpr mice: uncoupling of autoantibodies and T cell responses in lupus.
MRL/MpJ-Tnfrsf6lpr (MRL-Faslpr) mice develop a spontaneous T cell-dependent autoimmune disease that shares features with human lupus, including fatal nephritis, systemic pathology, and autoantibodies (autoAb). The inducible co-stimulator (ICOS) is upregulated on activated T cells and modulates T cell-mediated responses. To investigate whether ICOS has an essential role in regulating autoimmune lupus nephritis and the systemic illness in MRL-Faslpr mice, ICOS null (-/-) MRL Faslpr and ICOS intact (+/+) MRL-Faslpr strains (wild-type [WT]) were generated and compared. It was determined that in ICOS-/- MRL-Faslpr as compared with the WT strain, (1) there is a significant reduction in circulating IgG and double-stranded DNA autoantibody isotype titers, and (2) there is an amplification of the frequency of intrarenal T cells generating IFN-gamma and TNF-alpha in ICOS-/- versus WT mice. Of note, eliminating ICOS in the MRL-Faslpr strain does not alter renal pathology or function. Despite the reduction in circulating IgG and autoantibody isotypes (G1, G2a, and G2b), the amount of these IgG isotypes depositing in kidneys is similar. Furthermore, the systemic illness (skin, salivary and lacrimal glands, lungs, lymphadenopathy, and splenomegaly) is equivalent in ICOS-/- MRL-Faslpr and WT mice. These findings highlight the danger of relying on individual parameters, such as quantitative serum Ig levels and T cell functions, as prognostic indicators of lupus.
Zeller
Geraldine C
GC
Laboratory of Molecular Autoimmune Disease, Renal Divison, Brigham and Womens' Hospital, Boston, MA 02115, USA.
Hirahashi
Junichi
J
Schwarting
Andreas
A
Sharpe
Arlene H
AH
Kelley
Vicki R
VR
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D001323:Autoantibodies / Q000096:biosynthesis*; D001806:Blood Urea Nitrogen; D007074:Immunoglobulin G / Q000097:blood; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D011507:Proteinuria / Q000209:etiology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000945:Antigens, Differentiation, T-Lymphocyte; D001323:Autoantibodies; C556692:ICOS protein, human; C556694:Icos protein, mouse; D007074:Immunoglobulin G; D060889:Inducible T-Cell Co-Stimulator Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma