The Ox40/Ox40 Ligand Pathway Promotes Pathogenic Th Cell Responses, Plasmablast Accumulation, and Lupus Nephritis in NZB/W F1 Mice.
J Immunol
; 199(4): 1238-1249, 2017 08 15.
Article
en En
| MEDLINE
| ID: mdl-28696253
ABSTRACT
Ox40 ligand (Ox40L) locus genetic variants are associated with the risk for systemic lupus erythematosus (SLE); however, it is unclear how Ox40L contributes to SLE pathogenesis. In this study, we evaluated the contribution of Ox40L and its cognate receptor, Ox40, using in vivo agonist and antagonist approaches in the NZB × NZW (NZB/W) F1 mouse model of SLE. Ox40 was highly expressed on several CD4 Th cell subsets in the spleen and kidney of diseased mice, and expression correlated with disease severity. Treatment of aged NZB/W F1 mice with agonist anti-Ox40 mAbs potently exacerbated renal disease, which was accompanied by activation of kidney-infiltrating T cells and cytokine production. The agonist mAbs also induced activation and inflammatory gene expression in splenic CD4 T cells, including IFN-regulated genes, increased the number of follicular helper T cells and plasmablasts in the spleen, and led to elevated levels of serum IgM and enhanced renal glomerular IgM deposition. In a type I IFN-accelerated lupus model, treatment with an antagonist Ox40Fc fusion protein significantly delayed the onset of severe proteinuria and improved survival. These data support the hypothesis that the Ox40/Ox40L pathway drives cellular and humoral autoimmune responses during lupus nephritis in NZB/W F1 mice and emphasize the potential clinical value of targeting this pathway in human lupus.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Células Plasmáticas
/
Nefritis Lúpica
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Glicoproteínas de Membrana
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Linfocitos T Colaboradores-Inductores
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Factores de Necrosis Tumoral
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Receptores OX40
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Immunol
Año:
2017
Tipo del documento:
Article