Down‐Regulation–Resistant STAT4 Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon‐γ Production

Autor: Iris K. Madera‐Salcedo, Ada L. Ramírez‐Sánchez, Noé Rodríguez‐Rodríguez, Roberto García‐Quintero, Rosa M. Rubio, Gabriela Morales‐Montes de Oca, Emmanuel Dávalos, Rogelio Cuervo, Janette Furuzawa‐Carballeda, Jorge Alcocer‐Varela, Diana Gómez‐Martín, Marysol González‐Yáñez, Abigail de la Cruz, Adrián Albarrán‐Godínez, Gerardo Suárez‐Rojas, Juanita Romero‐Díaz, Norma O. Uribe‐Uribe, Marta Alarcón‐Riquelme, Mayra Furlan‐Magaril, Juan Manuel Mejía‐Vilet, José C. Crispín, Florencia Rosetti
Rok vydání: 2023
Předmět:
Zdroj: Arthritis & Rheumatology.
ISSN: 2326-5205
2326-5191
Popis: Variants in STAT4 are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. How disease-associated variants affect STAT4 expression, in particular in CD4 T cells where STAT4 plays an essential role, is unknown.We compared Th1 differentiation between naïve CD4 T cells from healthy donors (HD) homozygous for the risk (R/R) or non-risk (NR/NR) alleles. We analyzed epigenetic marks in STAT4 and evaluated the relevance of its third intron. We assessed the consequences of Stat4 overexpression in vivo. We analyzed the effects of the STAT4 genotype in patients with lupus nephritis.Naïve CD4 T cells from NR/NR HD, downregulated STAT4 in response to IL-12. In contrast, cells from R/R HD maintained high levels. R/R cells exhibited higher abundance of transcriptionally active STAT4 and increased IFN-γ production. Accordingly, R/R HD exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the STAT4 third intron, where most of the SLE-associated STAT4 SNPs are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis. Accordingly, the R/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis.The SLE-associated STAT4 haplotype is associated with abnormal IL-12-mediated STAT4 transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4 pro-inflammatory capacities that, in the context of SLE, contribute to a more severe disease. R/R patients may benefit from blockade of the IL-12-STAT4 pathway. This article is protected by copyright. All rights reserved.
Databáze: OpenAIRE
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