title: Pathogenic Th2-type follicular helper T cells contribute to the development of lupus in Fas-deficient mice.
abstract: Fas mutant mice are well recognized as autoimmune mouse models, which develop symptoms similar to human systemic lupus erythematosus. Although disease severity in Fas mutant mice is greatly affected by the genetic background, the mechanisms affecting pathological heterogeneity among different strains of Fas mutant mice are poorly understood. In this study, we examined the phenotypic differences between Fas-deficient (Fas (-/-)) mice on the BALB/c and C57BL/6 backgrounds to gain insight into the etiological and pathological heterogeneity of monogenic autoimmune diseases. Fas (-/-) mice on the BALB/c background (BALB/c-Fas (-/-)) developed more severe autoimmune disease with high serum auto-antibodies and renal disease compared with those on the C57BL/6 background (C57BL/6-Fas (-/-)). Splenic B cells were highly activated, and germinal center formation was enhanced in BALB/c-Fas (-/-) but not in C57BL/6-Fas (-/-) mice. Follicular helper T (Tfh) cells were equally abundant in the spleens from both strains of Fas (-/-) mice. However, Tfh cells from BALB/c-Fas (-/-) mice produced much higher amounts of B-cell-activating cytokines, including IL-4 and IL-10, a phenotype reminiscent of Th2-type Tfh cells described in human studies. Our results revealed a qualitative difference in Tfh cells between the two strains of Fas (-/-) mice. We propose that the pathogenic Th2-type Tfh cells in BALB/c-Fas (-/-) mice contribute to the excessive activation of B cells, resulting in high serum immunoglobulin levels and the severe lupus phenotype, which may account for the differential outcomes of human monogenic autoimmune diseases.
authors.affiliation: Laboratory of Allergic Diseases, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Shizue
authors.initials: S
authors.lastname: Futatsugi-Yumikura
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Matsushita
authors.forename: Ayumi
authors.initials: A
authors.lastname: Fukuoka
authors.forename: Suzuka
authors.initials: S
authors.lastname: Takahashi
authors.forename: Nayu
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Shin
authors.initials: S
authors.lastname: Yonehara
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshimoto
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D018418:Th2 Cells / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics
chemical_list: D001323:Autoantibodies; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4
keywords: CD95; IL-4; Th2-type follicular helper T cell; auto-antibody; germinal center