title: Interleukin 6 Accelerates Mortality by Promoting the Progression of the Systemic Lupus Erythematosus-Like Disease of BXSB.Yaa Mice.
abstract: IL6 is a multifunctional cytokine that drives terminal B cell differentiation and secretion of immunoglobulins. IL6 also cooperates with IL21 to promote differentiation of CD4+ T follicular helper cells (TFH). Elevated serum levels of IL6 correlate with disease flares in patients with systemic lupus erythematosus (SLE). We previously reported that IL21 produced by TFH plays a critical role in the development of the SLE-like disease of BXSB.Yaa mice. To examine the possible contributions of IL6 to disease, we compared disease parameters in IL6-deficient and IL6-competent BXSB.Yaa mice. We report that survival of IL6-deficient BXSB.Yaa mice was significantly prolonged in association with significant reductions in a variety of autoimmune manifestations. Moreover, B cells stimulated by co-engagement of TLR7 and B cell receptor (BCR) produced high levels of IL6 that was further augmented by stimulation with Type I interferon (IFN1). Importantly, the frequencies of TFH and serum levels of IL21 were significantly reduced in IL6-deficient mice. These findings suggest that high-level production of IL6 by B cells induced by integrated signaling from the IFN1 receptor, TLR7 and BCR promotes the differentiation of IL21-secreting TFH in a signaling sequence that drives the lethal autoimmune disease of BXSB.Yaa mice.
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States of America.
authors.forename: Shweta
authors.initials: S
authors.lastname: Jain
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States of America.|Hematology Research Unit, University of Helsinki, Helsinki University Central Hospital Cancer Center, Biomedicum Helsinki 1, Haartmaninkatu, Helsinki, Finland.
authors.forename: Giljun
authors.initials: G
authors.lastname: Park
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Sproule
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States of America.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Christianson
authors.affiliation: Department of Animal and Poultry Sciences, College of Agriculture and Life Sciences, Virginia Tech, Blacksburg, VA, United States of America.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Leeth
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States of America.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States of America.
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
authors.affiliation: Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States of America.
authors.forename: Herbert C
authors.initials: HC
authors.lastname: Morse
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000401:mortality* / Q000503:physiopathology; D008297:Male; D051379:Mice; D015398:Signal Transduction
chemical_list: D015850:Interleukin-6