Mouse models of lupus: what they tell us and what they don’t

Abstract

Lupus is a complex heterogeneous disease characterised by autoantibody production and immune complex deposition followed by damage to target tissues. Animal models of human diseases are an invaluable tool for defining pathogenic mechanisms and testing of novel therapeutic agents. There are perhaps more applicable murine models of lupus than any other human disease. There are spontaneous models of lupus, inducible models of lupus, transgenic-induced lupus, gene knockout induced lupus and humanised mouse models of lupus. These mouse models of lupus have contributed significantly to our knowledge of the pathogenesis of lupus and served as valuable preclinical models for proof of concept for new therapies. Despite their utility, mouse models of lupus have their distinct limitations. Although similar, mouse and human immune systems are different and thus one cannot assume a mechanism for disease in one is translatable to the other. Efficacy and toxicity of compounds can vary significantly between humans and mice, also limiting direct translation. Finally, the heterogeneous aspects of human lupus, both in clinical presentation, underlying pathogenesis and genetics, are not completely represented in current mouse models. Thus, proving a therapy or mechanism of disease in one mouse model is similar to proving a mechanism/therapy in a limited subset of human lupus. These limitations, however, do not marginalise the importance of animal models nor the significant contributions they have made to our understanding of lupus.

Dysregulation of T Follicular Helper Cells in Lupus

“…However, the significance of these mislocalized GCs in Fas mutant mice is unclear because the splenic architecture is greatly disrupted by hyperplasia of abnormal CD4 2 CD8 2 B220 + T cells (37)(38)(39)(40). Furthermore, SLE is a complex, multigenetic disease that is not well represented by single gene mutant Fas lpr/lpr , FasL gld/gld , BXSB-Yaa, or Ptpn6 me mice, which are prominent in the literature primarily because generation of transgenic or knockout mice bearing these single mutations is straightforward (41)(42)(43). GC development and architecture has been studied in two multigenetic strains of mice, the BXD2 (44)(45)(46)(47)(48)(49) and the NZB/W and related models, which are congenic at loci containing the NZB/W gene defects (50)(51)(52).…”

Tolerogenic dendritic cell transfer ameliorates systemic lupus erythematosus in mice

“…). Cutaneous lesions (considered within the clinical score) are more evident in MRL‐Fas lpr mice than the NZM2410 mice, which develop dermatitis only in advanced stages of the disease . In consequence, the improvement of the clinical score in MRL‐Fas lpr is more evident than that in NZM2410 mice at the evaluated periods.…”

B Cell ADAM10 Controls Murine Lupus Progression through Regulation of the ICOS:ICOS Ligand Axis

“…We next turned to a more severe model where overstimulation of the immune response is seen, the Fas lpr model (24). By appropriate backcrossing, B6 lpr mice that lacked ADAM10 on their B cells (A10B lpr ) were generated.…”

“…By appropriate backcrossing, B6 lpr mice that lacked ADAM10 on their B cells (A10B lpr ) were generated. The B6 strain has a delayed onset compared with the MRL, with 6 mo of age being the common onset of disease (24). Thus, our initial studies were performed at this age.…”