Inflammatory central nervous system disease in lupus-prone MRL/lpr mice: comparative histologic and immunohistochemical findings

Vogelweid, Catherine M.; Johnson, Gayle C.; Besch‐Williford, Cynthia; Basler, Joe; Walker, Sara E.

doi:10.1016/0165-5728(91)90164-3

Cited by 93 publications

(74 citation statements)

References 27 publications

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“…The CNS and choroid plexus pathology in the MRL-lpr strain has been reported extensively (Alexander et al, 1983;Vogelweid et al, 1991;Hess et al, 1993;Farrell et al, 1997;Sakic et al, 2000b). Similarly, clinical reports point to the possibility that the choroid plexus is a site for immune complex and leukocyte deposition (Atkins et al, 1972;Gershwin et al, 1975;Peress et al, 1981;Duprez et al, 2001).…”

Section: Discussionmentioning

confidence: 92%

“…First, a direct pathway may involve increased permeability of the blood-brain barrier and infiltration of circulating immune factors into the CNS. The choroid plexus appears to be the primary site of immune complex deposition (Lampert and Oldstone, 1973;Vogelweid et al, 1991), which facilitates increased entry of soluble immune factors, monocytes and lymphocytes into the parenchyma (Hess et al, 1993;Farrell et al, 1997) and hippocampal regions of lupus-prone mice (Kier, 1990). Subsequent leukocyte clustering may lead to the dissemination of autoreactive clones into the CSF (Sakic et al, 2000b).…”

Section: Discussionmentioning

confidence: 99%

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Hippocampal damage in mouse and human forms of systemic autoimmune disease

Ballok¹,

Woulfe

Sur

et al. 2004

Hippocampus

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Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJBpositive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Ballok¹,

Woulfe

Sur

et al. 2004

Hippocampus

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“…Older NZBIWF, mice had significant increases in BUN, anti-DNA, and anticardiolipin levels, but showed cognitive deficits only in comparison to young NZB/WF, mice. The NZB and NZB/WF, mice utilized in these studies differed from the MRLflpr mice, in that they did not have CNS inflammation (34). Rather, NZB mice have structural abnormalities: they develop ectopic collections of neurons and cortical dysplasia (39, and as the mice mature, the caudate-putamen complex and globus pallidus have decreased volume growth (36).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of memory, learning ability, and clinical neurologic function in pathogen‐free mice with systemic lupus erythematosus

Vogelweid

Wright

Johnson

et al. 1994

Arthritis & Rheumatism

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Objective. To determine if neurologic impairment is related to progressive autoimmune disease in 3 murine models of systemic lupus erythematosus (SLE): MRLl lpr, NZB, and NZBIWF,.Methods. Sensorimotor function, learning, and memory were tested within strains at specific ages, before and after the appearance of SLE. These parameters were also compared between strains for young and older lupus mice and their congenic controls with reduced autoimmune disease (MRL/lpr versus MRL/+ ; NZB versus NZB/xid).Results. Abnormal neurologic features were present at a much higher frequency in MRL/lpr mice than in age-matched MRL/+ control mice, and sensorimotor function deficits were also seen in NZB/WF, mice. Strains that develop lupus showed deficits on a waterescape, distal cue discrimination task and on a foodrewarded, proximal cue discrimination task, but the cognitive impairments were not global.Conclusion. MRL/lpr, NZB, and NZB/WF, mice differed in terms of which behaviors were impaired as well as when those impairments appeared.Abnormalities of neurologic and cognitive function are second only to renal disease in producing

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“…Pathological abnormalities are also seen in the choroid plexus, a structure that synthesizes most of the cerebrospinal fluid (CSF) volume (Duprez et al, 2001;Schwartz and Roberts, 1983). Widespread damage of the blood-brain barrier in MRL-lpr mice is accompanied by lymphocyte and monocyte infiltration into the choroid plexus (Alexander et al, 1983;Farrell et al, 1997;Hess et al, 1993), in some cases as early as 8 weeks of age (Vogelweid et al, 1991). Areas around the third and lateral ventricles show enhanced neurodegeneration, as revealed by staining with Fluoro Jade B (Ballok et al, 2003), excessive DNA fragmentation (Sakic et al, 2000b) and expression of cell adhesion molecules (Zameer and Hoffman, 2003).…”

Section: Introductionmentioning

confidence: 99%

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

Šakić

Kirkham

Ballok

et al. 2005

Journal of Neuroimmunology

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Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented. AbbreviationsACA, anti-cardiolipin antibodiesx; Abbreviations, anti-nuclear antibodies; CSF, cerebrospinal fluid; FJB, Fluoro Jade B stain; NP-SLE, neuropsychiatric systemic lupus erythematosus; PBS, phosphate buffered saline

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Inflammatory central nervous system disease in lupus-prone MRL/lpr mice: comparative histologic and immunohistochemical findings

Cited by 93 publications

References 27 publications

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Evaluation of memory, learning ability, and clinical neurologic function in pathogen‐free mice with systemic lupus erythematosus

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease

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