title: Transgene-mediated hyper-expression of IL-5 inhibits autoimmune disease but increases the risk of B cell chronic lymphocytic leukemia in a model of murine lupus.
abstract: IL-5 preferentially activates B1 cells to produce natural antibodies cross-reactive to self antigens. To determine the role of IL-5 in antibody-mediated autoimmune disease, we generated systemic lupus erythematosus (SLE)-prone (NZB x NZW)F1 mice congenic for IL-5 transgene (TG-F1). The transgene unexpectedly reduced the incidence of lupus nephritis. Anti-DNA antibodies in sera and those produced by splenic B cells in vitro were markedly decreased in TG-F1 mice, while total polyclonal Ig levels were comparable to those in IL-5 transgene-negative (NZB x NZW)F1 (non-TG-F1) littermates. Flow cytometry-sorted splenic B1 cells showed a significant reduction of anti-DNA antibody synthesis in response to IL-5, while proliferative responses to IL-5 did not significantly differ between TG-F1 and non-TG-F1 mice. As TG-F1 mice aged, frequencies of peripheral B1 cells progressively increased, and the mice frequently developed B cell chronic lymphocytic leukemia (B-CLL). Our results suggest that dysregulated, continuous high expression of IL-5 in SLE-prone mice may directly or indirectly mediate a skewed signaling of proliferation/differentiation of self-antigen-activated B1 cells, leading to suppression of autoimmune disease, but instead to aberrant expansion of B1 cells, giving rise to B-CLL. Thus, this model may provide a clue to the pathogenesis of both SLE and B-CLL.
authors.affiliation: Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Wen
authors.forename: Danqing
authors.initials: D
authors.lastname: Zhang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiu
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tsurui
authors.forename: Kazuko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Abe
authors.forename: Mareki
authors.initials: M
authors.lastname: Ohtsuji
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishimura
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Shirai
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirose
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015139:Blotting, Southern; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D015848:Interleukin-5 / Q000235:genetics* / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology* / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008181:Lupus Nephritis / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019076:Transgenes
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015848:Interleukin-5