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.
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.
Wen
Xiangshu
X
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Zhang
Danqing
D
Kikuchi
Yuji
Y
Jiang
Yi
Y
Nakamura
Kazuhiro
K
Xiu
Yan
Y
Tsurui
Hiromichi
H
Takahashi
Kazuko
K
Abe
Masaaki
M
Ohtsuji
Mareki
M
Nishimura
Hiroyuki
H
Takatsu
Kiyoshi
K
Shirai
Toshikazu
T
Hirose
Sachiko
S
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
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015848:Interleukin-5