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

Loheswaran, Genane; Stanojcic, Mile; Xu, Li; Šakić, Boris

doi:10.1111/j.1759-1961.2010.00014.x

Cited by 12 publications

(5 citation statements)

References 47 publications

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“…A point of interest is the potential role of the hypothalamus–pituitary–adrenal (HPA) axis in development of the MRL/lpr NPSLE phenotype. Previous studies have shown increased HPA axis activity in this strain, evidenced by increased serum corticosterone levels as well as adrenal hyperplasia [ 57 , 58 ]. Furthermore, treatment with immunosuppression normalized expression of neuroendocrine mediators in MRL/lpr mice, suggesting that neuroendocrine dysregulation is consequent to autoimmunity [ 59 ].…”

Section: Discussionmentioning

confidence: 81%

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

Stock

Wen

Doerner

et al. 2015

J Neuroinflammation

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BackgroundSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease marked by both B and T cell hyperactivity which commonly affects the joints, skin, kidneys, and brain. Neuropsychiatric disease affects about 40 % of SLE patients, most frequently manifesting as depression, memory deficits, and general cognitive decline. One important and yet unresolved question is whether neuropsychiatric SLE (NPSLE) is a complication of systemic autoimmunity or whether it is primarily driven by brain-intrinsic factors.MethodsTo dissect the relative contributions of the central nervous system from those of the hematopoietic compartment, we generated bone marrow chimeras between healthy control (MRL/+) and lupus-prone MRL/Tnfrsf6lpr/lpr mice (MRL/+ → MRL/lpr), as well as control chimeras. After bone marrow reconstitution, mice underwent extensive behavioral testing, analysis of brain tissue, and histological assessment.ResultsDespite transfer of healthy MRL/+ bone marrow and marked attenuation of systemic disease, we found that MRL/+ → MRL/lpr mice had a behavioral phenotype consisting of depressive-like behavior and visuospatial memory deficits, comparable to MRL/lpr → MRL/lpr control transplanted mice and the behavioral profile previously established in MRL/lpr mice. Moreover, MRL/+ → MRL/lpr chimeric mice displayed increased brain RANTES expression, neurodegeneration, and cellular infiltration in the choroid plexus, as well as blood brain barrier disruption, all in the absence of significant systemic autoimmunity.ConclusionsChimeric MRL/+ → MRL/lpr mice displayed no attenuation of the behavioral phenotype found in MRL/lpr mice, despite normalized serum autoantibodies and conserved renal function. Therefore, neuropsychiatric disease in the MRL/lpr lupus-prone strain of mice can occur absent any major contributions from systemic autoimmunity.

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Section: Discussionmentioning

confidence: 81%

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

Stock

Wen

Doerner

et al. 2015

J Neuroinflammation

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“…The line was eventually reconstituted and again manifests rapid development of the typical severe autoimmune profile ( http://jaxmice.jax.org/ : re-coding of stock #485-attenuated disease to stock #6825-reconstituted severe line). This serendipitous circumstance permits the differentiation between negative behavioral outcomes that may result from gross peripheral pathology and specific CNS-mediated behaviors [ 14 , 143 ].…”

Section: Introductionmentioning

confidence: 99%

“…Given that there is no evidence of kidney pathology in the disease-attenuated mice, these data confirm the robustness of emotional dysfunction and provide further support that such outcomes are likely a primary manifestation of autoimmunity rather than arising from nonspecific illness and peripheral organ pathology. Finally, the presence of two MRL/lpr strains that share a mutated Fas yet which differ in their autoantibody profile and neurobehavioral manifestations [ 14 , 143 ] is strong evidence that the CNS manifestations in these mice are primarily immunologically mediated, rather than resulting from possible effects of abnormal Fas-mediated apoptosis on brain development or glial function.…”

Section: Introductionmentioning

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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“…In support of this hypothesis, inbreeding has been shown to have significant detrimental effects on the survivorship of mice reintroduced into a natural habitat [38] , offspring survival and reproductive success [39] . Indeed, the effects of laboratory inbreeding can be exemplified by the gradual decline in the autoimmune phenotype ( http://jaxmice.jax.org/strain/006825.html ) and severity of behavioral deficits in the MRL/ lpr substrain [40] , [41] .…”

Section: Discussionmentioning

confidence: 99%

Zoopharmacognosy in Diseased Laboratory Mice: Conflicting Evidence

Kapadia

Zhao

et al. 2014

PLoS ONE

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Zoopharmacognosy denotes a constellation of learned ingestive responses that promote healing and survival of infected or poisoned animals. A similar self-medication phenomenon was reported in diseased laboratory rodents. In particular, a series of studies revealed that autoimmune MRL/lpr mice readily consume solutions paired or laced with cyclophosphamide (CY), an immunosuppressive drug that prevents inflammatory damage to internal organs. However, due to design limitations, it could not be elucidated whether such a response reflects the learned therapeutic effect of CY, or a deficit in sensory input. We presently assess the behavioural effects of prolonged consumption of CY-laced, 16% sucrose solution in a continuous choice paradigm, with tap water available ad lib. Contrary to overall expectation, MRL/lpr mice did not increase their intake of CY with disease progression. Moreover, they ingested lower doses of CY and preferred less CY-laced sucrose solution than age-matched controls. The results obtained could not confirm zoopharmacognosy in diseased MRL/lpr mice, likely due to impaired responsiveness to palatable stimulation, or attenuated survival mechanisms after prolonged inbreeding in captivity. However, by revealing the effectiveness of unrestricted drinking of drug-laced sucrose solution on behavior and immunity, the current study supports broader use of such an administration route in behavioural studies sensitive to external stressors.

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

Cited by 12 publications

References 47 publications

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

Neuropsychiatric systemic lupus erythematosus persists despite attenuation of systemic disease in MRL/lpr mice

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

Zoopharmacognosy in Diseased Laboratory Mice: Conflicting Evidence

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