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.
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ABSTRACT: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease of unknown etiological origin. CLL is the only B cell malignancy where a characteristic chromosomal translocation is not involved in cancer initiation. Therefore, the cause of tumorigenesis in CLL patients and the type of cell that is transformed are two questions that have intrigued researchers for decades. However, evidence suggests the CLL cell may be derived from B-1 cells. These B-1 cells, thought to develop during neonatal maturation as a link between innate and adaptive immunity, share multiple phenotypic and genetic patterns with CLL cases. These include signaling molecules sensitivity and expression patterns, B-cell receptor (BCR) specificity, and a unique immune-modulatory phenotype. Through understanding the biological relevance of B-1 cells in immune development and regulation, we may further understand the molecular mechanisms underlying the complexity of CLL. With this understanding, we can provide more optimal care to patients based on their unique diagnosis and pathologic disease course. In this review, based on our current understanding of CLL cells and B1 cells we hypothesize that CLL cells are originated from B1 cells. Following are some of our rationale in deriving this hypothesis.The Open Leukemia Journal 01/2010; 3:69-73.
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ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies. This review summarizes first the results obtained in the mouse that have revealed how B cell tolerance is breached in SLE. We then review the B cell subsets, in addition to the autoAb producing cells, which contribute to SLE pathogenesis, focusing on marginal zone B cells, B-1 cells and regulatory B cells. Finally, we review the interactions between B cells and other immune cells that have been implicated in SLE, such as dendritic cells, macrophages, neutrophils and T cells.Molecular Immunology 12/2013; 62(2). DOI:10.1016/j.molimm.2013.11.013 · 3.00 Impact Factor
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ABSTRACT: IL-10-producing B (Breg) cells regulate various immune responses. However, their phenotype remains unclear. CD40 expression was significantly increased in B cells by LPS, and the Breg cells were also enriched in CD40hiCD5+ B cells. Furthermore, CD40 expression on Breg cells was increased by IL-10, CD40 ligand, and B-cell activating factor, suggesting that CD40hi is a common phenotype of Breg cells. LPS-induced CD40 expression was largely suppressed by an anti-IL-10 receptor antibody and in IL-10-/-CD5+CD19+ B cells. The autocrine effect of IL-10 on the CD40 expression was largely suppressed by an inhibitor of JAK/STAT3. In vivo, the LPS treatment increased the population of CD40hiCD5+ Breg cells in mice. However, the population of CD40hiCD5+ B cells was minimal in IL-10-/- mice by LPS. Altogether, our findings show that Breg cells are largely enriched in CD40hiCD5+ B cells and the autocrine effect of IL-10 is critical to the formation of CD40hiCD5+ Breg cells.BMB reports 10/2014; 48(1). DOI:10.5483/BMBRep.2015.48.1.213 · 1.99 Impact Factor