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

Medientyp: E-Artikel
Titel: Down‐Regulation–Resistant STAT4 Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon‐γ Production
Beteiligte: Madera‐Salcedo, Iris K.; Ramírez‐Sánchez, Ada L.; Rodríguez‐Rodríguez, Noé; García‐Quintero, Roberto; Rubio, Rosa M.; Morales‐Montes de Oca, Gabriela; Dávalos, Emmanuel; Cuervo, Rogelio; Furuzawa‐Carballeda, Janette; Alcocer‐Varela, Jorge; Gómez‐Martín, Diana; González‐Yáñez, Marysol; de la Cruz, Abigail; Albarrán‐Godínez, Adrián; Suárez‐Rojas, Gerardo; Romero‐Díaz, Juanita; Uribe‐Uribe, Norma O.; Alarcón‐Riquelme, Marta; Furlan‐Magaril, Mayra; Mejía‐Vilet, Juan Manuel; Crispín, José C.; Rosetti, Florencia
Erschienen: Wiley, 2023
Erschienen in: Arthritis & Rheumatology
Sprache: Englisch
DOI: 10.1002/art.42435
ISSN: 2326-5191; 2326-5205
Schlagwörter: Immunology ; Rheumatology ; Immunology and Allergy
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Beschreibung: <jats:sec><jats:title>Objective</jats:title><jats:p>Variants in <jats:italic>STAT4</jats:italic> are associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. We undertook this study to investigate how disease‐associated variants affect STAT4 expression, in particular in CD4+ T cells where STAT4 plays an essential role.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We compared Th1 differentiation between naive CD4+ T cells from healthy donors homozygous for the risk (R/R) or nonrisk (NR/NR) alleles. We analyzed epigenetic marks in <jats:italic>STAT4</jats:italic> and evaluated the relevance of its third intron, assessed the consequences of Stat4 overexpression in vivo in mice, and analyzed the effects of the <jats:italic>STAT4</jats:italic> genotype in patients with lupus nephritis.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Naive CD4+ T cells from NR/NR healthy donors down‐regulated <jats:italic>STAT4</jats:italic> in response to interleukin‐12 (IL‐12). In contrast, cells from R/R healthy donors maintained high levels. R/R cells exhibited a higher abundance of transcriptionally active STAT4 and increased interferon‐γ production. Accordingly, R/R healthy donors exhibited a stronger induction of local active enhancer marks. Genetic editing confirmed the presence of a negative regulatory region in the <jats:italic>STAT4</jats:italic> third intron, where most of the SLE‐associated <jats:italic>STAT4</jats:italic> single‐nucleotide polymorphisms (SNPs) are located. In vivo forced expression demonstrated that increases in Stat4 levels in T cells enhanced glomerulonephritis in mice. Accordingly, the R/R genotype was associated with suboptimal response to treatment and with worse clinical outcomes in patients with proliferative lupus nephritis.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>The SLE‐associated <jats:italic>STAT4</jats:italic> haplotype correlates with an abnormal IL‐12–mediated <jats:italic>STAT4</jats:italic> transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4+ proinflammatory capacities that, in the context of SLE, contribute to more severe disease. R/R patients may benefit from blockade of the IL‐12/STAT4 pathway.</jats:p><jats:p><jats:boxed-text content-type="graphic" position="anchor"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" mimetype="image/png" position="anchor" specific-use="enlarged-web-image" xlink:href="graphic/art42435-toc-0001-m.png"><jats:alt-text>image</jats:alt-text></jats:graphic></jats:boxed-text></jats:p></jats:sec>

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