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 (NZBÂNZW)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 (NZBÂNZW)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-antigenactivated 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.

Genetic Dissection of the Murine Lupus Susceptibility LocusSle2: Contributions to Increased Peritoneal B-1a Cells and Lupus Nephritis Map to Different Loci

“…Supporting this latter hypothesis, it has been shown that B-1a cells do not contribute to autoantibody production in FAS-deficient mice (18). Furthermore, transgenic overexpression of IL-5 in the BWF 1 model greatly increased the number of B-1a cells, but, surprisingly, significantly reduced anti-dsDNA Ab production and incidence of nephritis (19). Finally, the NZB-derived Nba2 locus was shown to induce disease when crossed to NZW without affecting the size of the B-1 cell compartment (20), and the same observation was made for Sle1 (L. Morel, unpublished observations).…”

T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

“…In SLE patients with severe skin involvement, IFN-γ and IL-5 were the most commonly overexpressed cytokines in skin lesions, implying that both Th1 and Th2 subsets may be involved in the pathophysiology of SLE inflammation 92 . However, an earlier report suggests that IL-5 may play a protective role as overexpression of IL-5 in SLE-prone mice suppresses the disease 93 .…”

Contributions of B cells to lupus pathogenesis

“…Accordingly, the removal of peritoneal B-1 cells from NZB/W F1 mice correlated with disease attenuation (Mihara et al, 1988), and osteopontin-induced B-1 cell expansion paralleled an increased anti-dsDNA Ab titers (Iizuka et al, 1998). On the other hand, B-1a cells are not responsible for autoAb production in Fas-deficient mice (Reap et al, 1993), and IL-5 induced expansion of B-1a cells in NZB/W F1 was associated with disease protection (Wen et al, 2004). …”