Circulating brain-reactive autoantibodies and behavioral deficits in the MRL model of CNS lupus

Williams, Simon; Šakić, Boris; Hoffman, Steven A.

doi:10.1016/j.jneuroim.2009.10.008

Cited by 20 publications

(19 citation statements)

References 68 publications

(105 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MRL-lpr mice significantly differ from the other lupus models by the development in certain mice colonies of a rheumatoid arthritis-like polyarthritis, with a high incidence and titer of RF in their serum, and high levels of circulating immune complexes and cryoglobulins. It is important to know that over the past decade, MRL-lpr mice displayed "accidental" lessening of symptoms of unexplained origin [76] and that the MRL-lpr original stock was re-established in 2008 (http://jaxmice.jax.org/strain/006825.html). This event has been recounted in detail elsewhere [16,77].…”

Section: The Mrl-lpr Mouse Modelmentioning

confidence: 99%

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

Jeltsch-David

Muller

2014

Autoimmunity Reviews

View full text Add to dashboard Cite

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.

show abstract

Section: The Mrl-lpr Mouse Modelmentioning

confidence: 99%

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

Jeltsch-David

Muller

2014

Autoimmunity Reviews

View full text Add to dashboard Cite

show abstract

“…Numerous significant correlations with immune markers are consistent with our recent studies, pointing to the multifactorial nature of brain pathology and behavioral dysfunction. 13,29 One of the principal culprits appears to be the IgG BRA in CSF. The evidence that CSF antibodies from MRL ⁄ lpr mice are cytotoxic in vitro to mature and immature neurons 23,31 directly supports a cause-effect relationship.…”

Section: Discussionmentioning

confidence: 99%

“…This phenomenon of unknown origin was also accompanied by a gradual decline in the number and severity of behavioral deficits. 13 In 2007, the supplier (The Jackson Laboratories) announced phenotype loss in the stock 485 and reassigned it into stock 6825 (MRL ⁄ MpJ-Fas lpr ⁄ 2J), which still carried the FasR deficiency (http:// jaxmice.jax.org/strain/006825.html). Because embryos of the original stock 485 were cryopreserved in 1993, this stock was re-established in the summer of 2008.…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity as a principal pathogenic factor in the refined model of neuropsychiatric lupus

Loheswaran

Stanojcic

et al. 2010

Clinical & Exp Neuroim

View full text Add to dashboard Cite

Objectives: Over the past decades, the MRL mouse model had shown significant validity in elucidating the pathogenesis of neuropsychiatric lupus erythematosus (NP SLE). However, the possibility that the inherited Fas receptor deficiency (and not autoimmunity) accounts for central nervous system (CNS) damage in the original stock 485 of MRL/MpJ‐Faslpr mice could not be rejected. The aim of the present study was to examine the consequences of autoimmune disease on behavior and brain morphology, while controlling for the genetic deficiency with a new, less symptomatic 6825 stock.Methods: Spleen mass, serum autoantibody and cytokine levels, immunoglobulins in cerebrospinal fluid (CSF), and brain planimetry were used to assess disease severity and CNS involvement in 5‐month‐old mice from stocks 6825 and 485. Their behavioral profiles were compared in a standard battery of tasks. The 2D‐DIGE and mass spectrometry examined brain antigens targeted by autoantibodies from serum and CSF.Results: The 6825 mice had smaller spleens, lower antibody and cytokine levels, and less IgG in the CSF. They were more active and showed better performance in tasks reflective of anxiety and motivated behavior. Signs of brain pathology were less profound and their CSF autoantibodies showed reduced affinity for brain antigens, largely characterized as highly‐conserved cytoskeletal proteins.Conclusions: The constellation of differences between the two MRL/MpJ‐Faslpr stocks confirms that the lpr mutation per se does not account for the brain pathology and altered behavior in the 485 stock. Together with significant correlations between immunological and behavioral measures, this observation suggests that soluble immune factors play a key role in pathogenesis of NP SLE. (Clin. Exp. Neuroimmunol. doi: 10.1111/j.1759‐1961.2010.00014.x, September 2010)

show abstract

“…The immunohistochemistry technique used was previously described [2]. The slides were observed using a Leitz Laborlux 12 microscope and pictures were taken using a Nikon camera at 4× and 250× magnification.…”

Section: Methodsmentioning

confidence: 99%

Diagnosis and early detection of CNS-SLE in MRL/lpr mice using peptide microarrays

2014

View full text Add to dashboard Cite

BackgroundAn accurate method that can diagnose and predict lupus and its neuropsychiatric manifestations is essential since currently there are no reliable methods. Autoantibodies to a varied panel of antigens in the body are characteristic of lupus. In this study we investigated whether serum autoantibody binding patterns on random-sequence peptide microarrays (immunosignaturing) can be used for diagnosing and predicting the onset of lupus and its central nervous system (CNS) manifestations. We also tested the techniques for identifying potentially pathogenic autoantibodies in CNS-Lupus. We used the well-characterized MRL/lpr lupus animal model in two studies as a first step to develop and evaluate future studies in humans.ResultsIn study one we identified possible diagnostic peptides for both lupus and altered behavior in the forced swim test. When comparing the results of study one to that of study two (carried out in a similar manner), we further identified potential peptides that may be diagnostic and predictive of both lupus and altered behavior in the forced swim test. We also characterized five potentially pathogenic brain-reactive autoantibodies, as well as suggested possible brain targets.ConclusionsThese results indicate that immunosignaturing could predict and diagnose lupus and its CNS manifestations. It can also be used to characterize pathogenic autoantibodies, which may help to better understand the underlying mechanisms of CNS-Lupus.

show abstract

Circulating brain-reactive autoantibodies and behavioral deficits in the MRL model of CNS lupus

Cited by 20 publications

References 68 publications

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

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

Autoimmunity as a principal pathogenic factor in the refined model of neuropsychiatric lupus

Diagnosis and early detection of CNS-SLE in MRL/lpr mice using peptide microarrays

Contact Info

Product

Resources

About