Intrathecal antibodies and brain damage in autoimmune MRL mice

Stanojcic, Mile; Loheswaran, Genane; Xu, Li; Hoffman, Steven A.; Šakić, Boris

doi:10.1016/j.bbi.2009.10.009

Cited by 25 publications

(17 citation statements)

References 74 publications

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“…Experimental studies support this last hypothesis in MRL-lpr model [79]. Intrathecally-generated Abs are of the IgG isotype [95] and their levels correlate with increased immobility in the forced-swim test [122]. These authors proposed that intrathecal brain-reactive Abs predict depressive-like response while anxiety-like behavior and "anhedonic" response are rather associated with circulating Abs [111].…”

Section: Evidence Of Pathogenic Absmentioning

confidence: 90%

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

Jeltsch-David

Muller

2014

Autoimmunity Reviews

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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.

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Section: Evidence Of Pathogenic Absmentioning

confidence: 90%

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

Jeltsch-David

Muller

2014

Autoimmunity Reviews

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“…There is also evidence that some of these serum autoantibodies react with brain antigens [160, 161] and occur in serum of as early as 2-3 months old in MRL/lpr mice [61] and in CSF as early as 4-5 months [162]. Nevertheless, as further discussed below, the fact that behavioral deficits are present before major rises in serum autoantibody titers or detectable breaches in the blood-brain barrier indicates that serum antibodies alone are clearly not the sole important pathogenic factor in NP-SLE, at least early in the disease.…”

Section: Cns Mechanisms and Pathologymentioning

confidence: 99%

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Gulinello

Putterman

2011

Journal of Biomedicine and Biotechnology

115

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To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.

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“…As discussed earlier, 28 significant relationships between behavioral and neuropathological measures further supported (yet did not prove) the notion of structural damage as a basis of aberrant behavior. 29 To obtain 100 ng of brain proteins, approximately 30 immunoprecipitations were required using serum and approximately 5 immunoprecipitations using CSF samples. This discrepancy was evident by comparing protein yields in the first three immunoprecipitations; pooled sera yielded between 0.14 and 0.52 ng, whereas pooled CSF samples extracted at least threefold more protein (0.52 ng and 1.86 ng).…”

Section: Resultsmentioning

confidence: 99%

“…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%

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

Loheswaran

Stanojcic

et al. 2010

Clinical & Exp Neuroim

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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)

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Intrathecal antibodies and brain damage in autoimmune MRL mice

Cited by 25 publications

References 74 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

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

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

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