Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

Abstract

Mouse models of autoimmunity, such as (NZB×NZW)F1, MRL/MpJ-Fas(lpr) (MRL-lpr) and BXSB mice, spontaneously develop systemic lupus erythematosus (SLE)-like syndromes with heterogeneity and complexity that characterize human SLE. Despite their inherent limitations, such models have highly contributed to our current understanding of the pathogenesis of SLE as they provide powerful tools to approach the human disease at the genetic, cellular, molecular and environmental levels. They also allow novel treatment strategies to be evaluated in a complex integrated system, a favorable context knowing that very few murine models that adequately mimic human autoimmune diseases exist. As we move forward with more efficient medications to treat lupus patients, certain forms of the disease that requires to be better understood at the mechanistic level emerge. This is the case of neuropsychiatric (NP) events that affect 50-60% at SLE onset or within the first year after SLE diagnosis. Intense research performed at deciphering NP features in lupus mouse models has been undertaken. It is central to develop the first lead molecules aimed at specifically treating NPSLE. Here we discuss how mouse models, and most particularly MRL-lpr female mice, can be used for studying the pathogenesis of NPSLE in an animal setting, what are the NP symptoms that develop, and how they compare with human SLE, and, with a critical view, what are the neurobehavioral tests that are pertinent for evaluating the degree of altered functions and the progresses resulting from potentially active therapeutics.

Neuropsychiatric lupus: a mosaic of clinical presentations

“…Genetically prone strains are characterized by varying proportions by autoantibody production, circulating immune complexes, complement consumption, and clinical manifestations such as glomerulonephritis. These strains include the NZB / NZWF1, MRL/lpr, NZM2410, and BXSB mice [29]. The most extensively studied strains are the MRL/lpr and NZB/NZW F1.…”

“…Anti-depressants, and more interestingly, immunosuppressants were found to reduce depression-like behavior as well as the other SLE symptoms of this model [31]. However, there is less consistency regarding anxiety and cognitive impairment in the MRL/lpr mice [29,31]. MRL/lpr mice produce several autoantibodies (anti-ribosomal, anti-phospholipid, and anti-nucleosome) and cytokines in the serum or CSF that may correlate with neuropsychiatric symptoms [31].…”

Modelling clinical systemic lupus erythematosus: similarities, differences and success stories

“…Lymphadenopathy and splenomegaly are attributable to expansion of an unusual double-negative CD4 − CD8 − CD3 + B220 + T cell population [11]. Aside from examining the mechanisms of autoantibody production and renal failure, MRL/ lpr mice are also used to examine cutaneous and neurological aspects of lupus, in contrast with other strains [12, 13]. …”

The role of B cells and autoantibodies in neuropsychiatric lupus

“…The disease phenotype in this strain is caused by a mutation in the Fas (CD95) gene, compromising Fas-FasL signaling and resulting in defective lymphocyte apoptosis and lymphoproliferation [15]. Importantly, this strain has been validated as a useful model for studying NPSLE [7,16]. MRL/lpr mice exhibit robust depression-like behavior as early as 5 weeks of age [12], and cognitive dysfunction, such as spatial memory deficits, at 16 weeks of age, a phenotype consistent with human NPSLE [17].…”