Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis
Tanuja Chitnis, … , Mohamed H. Sayegh, Samia J. Khoury
Tanuja Chitnis, … , Mohamed H. Sayegh, Samia J. Khoury
Published September 1, 2001
Citation Information: J Clin Invest. 2001;108(5):739-747. https://doi.org/10.1172/JCI12563.
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Article

Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is mediated by myelin-specific CD4+ T cells secreting Th1 cytokines, while recovery from disease is associated with expression of Th2 cytokines. Investigations into the role of individual cytokines in disease induction have yielded contradictory results. Here we used animals with targeted deletion of the STAT4 or STAT6 genes to determine the role of these signaling molecules in EAE. The STAT4 pathway controls the differentiation of cells into a Th1 phenotype, while the STAT6 pathway controls the differentiation of cells into a Th2 phenotype. We found that mice deficient in STAT4 are resistant to the induction of EAE, with minimal inflammatory infiltrates in the central nervous system. In contrast, STAT6-deficient mice, which have a predominantly Th1 phenotype, experience a more severe clinical course of EAE as compared with wild-type or STAT4 knockout mice. In addition, adoptive transfer studies confirm the regulatory functions of a Th2 environment in vivo. These novel data indicate that STAT4 and STAT6 genes play a critical role in regulating the autoimmune response in EAE.

Authors

Tanuja Chitnis, Nader Najafian, Christina Benou, Alan D. Salama, Michael J. Grusby, Mohamed H. Sayegh, Samia J. Khoury

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Quantitation of inflammatory cell infiltrates in the CNS of wild-type (W...
Quantitation of inflammatory cell infiltrates in the CNS of wild-type (WT), STAT4–/– (STAT4KO), and STAT6–/– (STAT6KO) mice. Quantitation of immunohistochemically stained spinal cord sections for CD4 and CD8 T cells and macrophages from C57BL/6 wild-type mice, STAT4–/– mice, and STAT6–/– mice. Spinal cord sections from three mice from each group were harvested on day 16 (a) and day 50 (b) and stained for CD4 (white bars), CD8 (dark gray bars), macrophages (black bars), and granulocytes (light gray bars). At least three sections from different levels of the cord were evaluated. Number of cells staining positive for the given marker were counted in 10 high-power fields (×40) per section. The results for one section were totaled, and the results between sections were averaged. Error bars represent standard deviation (SD). Statistical analysis was done using the Student’s t test. Results from a, day 16, show sections from STAT4–/– mice displayed significantly less CD4+ (P = 0.05) and CD8+ cells (P = 0.0005), macrophages (P = 0.02), and granulocytes (P = 0.004) than did wild-type mice. Sections from STAT6–/– mice consistently displayed more inflammatory cells than wild-type mice (however the P value was not significant), and significantly more than STAT4–/– mice (P < 0.05). Results from b, day 50, show significantly lower numbers of CD4+ cells in the STAT4–/– group compared with wild-type (P = 0.0024). There were no significant differences in inflammatory infiltrates between the STAT6–/– and wild-type mice at day 50.