Article

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

Juntendo University, Edo, Tōkyō, Japan
European Journal of Immunology (Impact Factor: 4.52). 10/2004; 34(10):2740-9. DOI: 10.1002/eji.200425267
Source: PubMed

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.

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Available from: Xiangshu Wen, Aug 30, 2015
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    • "IL-5 is a critical growth factor for B1 cells present in the peritoneal cavity and plays an important role in innate-type immune responses by producing natural antibodies [97–99]. Wen et al. [100] reported that deregulated, 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 of aberrant expansion of B1 cells, giving rise to B-cell chronic lymphocytic leukaemia (B-CLL). Moreover, despite no correlation with SLEDAI, our results indicate that Th17-(IL-1β, IL-6), Th0-(IL-2), Th1-(IFN-γ, TNF-α), Th2-(IL-13), and IL-10 plasma cytokines are positively correlated with the inflammation mediator CRP. "
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    ABSTRACT: Kinases have been implicated in the immunopathological mechanisms of Systemic Lupus Erythematosus (SLE). v-akt murine-thymoma viral-oncogene-homolog 1 (AKT1) and mitogen-activated-protein-kinase 1 (MAPK1) gene expressions in peripheral mononuclear cells from thirteen SLE patients with inactive or mild disease were evaluated using quantitative real-time reverse-transcription polymerase-chain-reaction and analyzed whether there was any correlation with T-helper (Th) transcription factors (TF) gene expression, cytokines, and S100A8/S100A9-(Calprotectin). Age- and gender-matched thirteen healthy controls were examined. AKT1 and MAPK1 expressions were upregulated in SLE patients and correlated with Th17-(Retinoic acid-related orphan receptor (ROR)-C), T-regulatory-(Treg)-(Transforming Growth Factor Beta (TGFB)-2), and Th2-(interleukin (IL)-5)-related genes. MAPK1 expression correlated with Th1-(IL-12A, T-box TF-(T-bet)), Th2-(GATA binding protein-(GATA)-3), and IL-10 expressions. IL-10 expression was increased and correlated with plasma Tumor Necrosis Factor (TNF)-α and Th0-(IL-2), Th1-(IL-12A, T-bet), GATA3, Treg-(Forkhead/winged-helix transcription factor- (FOXP)-3), and IL-6 expressions. FOXP3 expression, FOXP3/RORC, and FOXP3/GATA3 expression ratios were increased. Plasma IL-1β, IL-12(p70), Interferon-(IFN)-γ, and IL-6 cytokines were augmented. Plasma IL-1β, IL-6, IL-2, IFN-γ, TNF-α, IL-10, and IL-13 correlated with C-reactive protein, respectively. Increased Calprotectin correlated with neutrophils. Conclusion, SLE patients presented a systemic immunoinflammatory activity, augmented AKT1 and MAPK1 expressions, proinflammatory cytokines, and Calprotectin, together with increased expression of Treg-related genes, suggesting a regulatory feedback opposing the inflammatory activity.
    Mediators of Inflammation 10/2012; 2012:495934. DOI:10.1155/2012/495934 · 3.24 Impact Factor
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    • "Indeed, in vitro activation of (NZBxNZW)F1 B-1 cells with IL-5 results in B-1 cells differentiation to Mott cells (Jiang et al., 1997) and IgM overproduction (Herron et al., 1988; Kanno et al., 1992; Umland et al., 1989), strongly suggesting that IL-5 overproduction might exacerbate the disease. To prove the role of IL-5 in SLE, Wen and coworkers (Wen et al., 2004) generated (NZBxNZW)F1 congenic for an IL-5 transgene. Contrary to expectations, these mice showed a significant amelioration of SLE symptoms but increased incidence of B cell malignancy. "
    Chronic Lymphocytic Leukemia, 02/2012; , ISBN: 978-953-307-881-6
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    • "IL-5 preferentially activates B1 cells to produce natural antibodies cross-reactive to self antigens [75]. Wen et al. [76] have reported that B/WF1 mice congenic for IL-5 transgene (TG-F1) reduced the incidence of lupus nephritis with decreased anti-DNA antibodies and those produced by splenic B cells in vitro. As TG-F1 mice aged, frequencies of peripheral B1 cells progressively increased, and the mice frequently developed B-cell chronic lymphocytic leukemia (B-CLL). "
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    ABSTRACT: Systemic lupus erythematosus (SLE: lupus) is a chronic complicated autoimmune disease and pathogenesis is still unclear. However, key cytokines have been recognized. Interferon (IFN)-γ and also IFNalpha/beta are of particular importance. Depending on the concept that lupus is a helper T(Th)1 disease and that dendritic cells (DCs) determine the direction of lupus, balance shift of Th1/Th2 and immunogenic/tolerogenic DCs is reviewed for therapy. (IFN)-gamma- and IFN-alpha/beta-targeted (gene) therapies are introduced. These consist of Th1/Th2 balance shift and elimination of IFN-gamma and IFN-gamma-related cytokines such as (interleukin)IL-12 and IL-18. Other approaches include suppression of immunocompetent cells, normalization of abnormal T-cell function, costimulation blockade, B lymphocyte stimulator (Blys) blockade, and suppression of nephritic kidney inflammation. Moreover, balance shift of IFN-alpha/beta and tumor necrosis factor (TNF)-alpha together with regulatory T(Treg) cells are briefly introduced. Clinical application will be discussed.
    BioMed Research International 08/2010; 2010(144). DOI:10.1155/2010/461641 · 2.71 Impact Factor
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