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Cellular and molecular pathogenesis of systemic lupus erythematosus: lessons from animal models

DOI: 10.1186/ar3465

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Our understanding of the pathogenesis mechanisms leading to lupus has been augmented by the analysis of several different murine models over the past four decades. Various mouse models of spontaneous lupus have been employed in an effort to understand the cellular and genetic mechanisms behind induction of systemic lupus erythematosus (SLE). The classic models of spontaneous lupus include the F1 hybrid of the New Zealand Black (NZB) and New Zealand White (NZW) strains, called NZB/W F1, and its derivatives, such as NZM2328 and NZM2410, and the MRL/lpr and BXSB/Yaa strains. The goal of this review is to discuss the systemic and local immune responses - as learned from the studies employing various mouse model systems - that lead to the development of lupus. The cellular and molecular mechanisms that contribute to the pathogenesis of lupus are discussed in the following sections and are illustrated in Figure 1.The presence of high titers of autoantibodies against nuclear antigens is the hallmark of SLE. Whereas there is little evidence to indicate whether self-antigens in SLE are aberrant in sequence or structure, there is evidence that the aberrant handling of self-antigens could facilitate lupus pathogenesis. Although apoptotic bodies are normally rapidly cleared with the help of the complement and other systems, defects in this clearance system could lead to the accumulation of apoptotic bodies and their prevalence in serum [1]. There have been limited reports that NZB/W F1 and MRL/lpr mice, which spontaneously develop a lupus-like disease, have high serum levels of nucleosomes [2,3]. Non-autoimmune C3H, BALB/c, and C57BL/6 mouse strains, when injected with apoptotic bodies, developed serum autoantibodies similar to those seen in SLE [4]. Although these studies warrant independent confirmation, they support the notion that apoptotic cells could harbor the immunogens responsible for antinuclear antibody formation. Moreover, mice with defects in genes that play an imp


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