Alterations in Hypothalamic–Pituitary–Adrenal Function Correlated with the Onset of Murine SLE in MRL +/+ and lpr/lpr Mice

Shanks, NM; Moore, P A; Perks, PA; Lightman, Stafford L.

doi:10.1006/brbi.1998.0535

Cited by 38 publications

(25 citation statements)

References 33 publications

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“…Some reports indicate that young lpr/lpr (MRL background) mice have higher basal corticosterone levels but no differences in corticosterone-binding globulin (28) and disturbances of corticosterone circadian rhythm (29). Other groups have reported decreased hypothalamic corticotropin-releasing hormone and increased arginine vasopressin mRNA expression, increased circulating levels of corticosterone and a trend for levels of corticosterone-binding globulin to be decreased (30,31). We have neither detected significant differences between B6 and B6 lpr/lpr mice in basal corticosterone levels in the blood of the same 9-, 18-, and 40-wk-old mice used for the studies reported here, nor observed significant differences in blood corticosterone levels in a small group of adult lpr/lpr female mice denervated at birth with 6-OH-DA, compared with aged-and sex-matched, vehicle-injected lpr/lpr mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The Role of Noradrenergic Nerves in the Development of the Lymphoproliferative Disease in Fas-Deficient, lpr/lpr Mice

Rey¹,

Roggero²,

Kabiersch

et al. 2006

The Journal of Immunology

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Lpr/lpr mice develop a lymphoproliferative, autoimmune, lupus-like disease. These mice lack functional Fas (CD95) expression and are resistant to Fas ligand (CD178)-mediated apoptosis, a critical mechanism for the maintenance of peripheral tolerance. In this study, we show that noradrenaline (NA), the main sympathetic neurotransmitter, can induce apoptosis of lymphoid cells independently of functional Fas. Based on this finding, we used lpr/lpr mice as model to study the role of noradrenergic nerves in the expression of a lymphoproliferative disease. Early in ontogeny, the concentration of NA was significantly increased in the spleen of lpr/lpr mice, compared with normal littermates. However, splenic sympathetic innervation gradually declined as the disease progressed, and IgM blood levels and splenic NA concentration inversely correlated when the disease was overtly manifested. When the loss of noradrenergic fibers that occurred naturally during adult life in lpr/lpr mice was experimentally advanced by neonatal sympathectomy, the concentration of IgM and IgG2a in blood was markedly higher than that of control lpr/lpr mice, and the appearance of lymphadenopathy was accelerated. Furthermore, although neonatal denervation did not affect the life span of normal animals, it shortened significantly the survival time of lpr/lpr mice. These data show that, in addition to defects in the Fas pathway, an altered sympathetic innervation in lpr/lpr mice also contributes to the pathogenesis of the autoimmune disease, and strongly support the hypothesis that the sympathetic nervous system can modulate the expression of lymphoproliferative diseases.

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Section: Discussionmentioning

confidence: 99%

The Role of Noradrenergic Nerves in the Development of the Lymphoproliferative Disease in Fas-Deficient, lpr/lpr Mice

Rey¹,

Roggero²,

Kabiersch

et al. 2006

The Journal of Immunology

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“…Sustained binding of CORT to its central receptors renders neurons vulnerable to various metabolic insults (Uno et al 1994;Sapolsky 2000). This neurotoxic mechanism is based on the evidence that onset of autoimmune disease in MRL-lpr mice is accompanied by alterations in the endocrine system, including increased plasma levels of CORT and melatonin (Hu et al 1993;Lechner et al 1996;Lechner et al 2000), imbalanced expression of corticotropin releasing factor (CRF) and arginine vasopressin (AVP) mRNA in the paraventricular nucleus and amygdala (Shanks et al 1997;Shanks et al 1999;Sakic et al 1999), and reduced serum levels of testosterone (Sakic et al 1998a). Both castration and estrogen treatment exacerbate the disease in MRL-lpr mice, while testosterone treatment improves it (Melez et al 1978;Shear et al 1983;Carlsten et al 1989;Carlsten et al 1990).…”

Section: Discussionmentioning

confidence: 99%

Behavioral heterogeneity in an animal model of neuropsychiatric lupus

Šakić¹,

Hanna²,

Millward³

2005

Biological Psychiatry

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Background-Various psychiatric manifestations of unknown etiology are common in systemic autoimmune disease lupus erythematosus (SLE). Profound heterogeneity at clinical and neuropathological levels suggests distinct subpopulations of SLE patients and multiple mechanisms in the pathogenesis of aberrant behavior. Using inbred mice prone to SLE-like condition, we presently examine whether subpopulations of diseased mice can be identified on the basis of their behavioral performance.

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“…Similar to the effects of chronic stress, NP-lupus mice show brain atrophy and deficits in cognition at the onset of disease (Sakic et al, 1993b(Sakic et al, , 1998bBallok et al, 2004b). In addition to the peripheral dysregulation of glucocorticoids, studies have also revealed a dysfunctional hypothalamic-pituitary axis in these animals (Shanks et al, 1999;Sakic et al, 1999). Although an imbalanced neuro-immuno-endocrine network is proposed to play a key role in the etiology of brain damage, it is still not clear whether central neurons are initially damaged by an autoimmune-driven upregulation in corticosterone production.…”

Section: Corticosteroids: the Permissive Factor For Cell Death?mentioning

confidence: 99%

“…This may ultimately contribute to the neurodegeneration and neurological dysfunction seen in NP lupus ( Fig. 1) (Svenungsson et al, 2001;Jongen et al, 1990;Hafler and Weiner, 1989;Brey et al, 1997a;Shanks et al, 1999;Sakic et al, 1999;Ballok et al, 2003;Kyttaris et al, 2005). The precise regulatory mechanisms of cytokines in this dynamic autoimmune disease, however, remain unresolved.…”

Section: Prelude To Cns Damage: Disruption Of the Blood-brain Barriermentioning

confidence: 99%

Neuroimmunopathology in a murine model of neuropsychiatric lupus

Ballok

2007

Brain Research Reviews

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Animal models are extremely useful tools in defining pathogenesis and treatment of human disease. For many years researchers believed that structural damage to the brain of neuropsychiatric (NP) patients lead to abnormal mental function, but this possibility was not extensively explored until recently. Imaging studies of NP-systemic lupus erythematosus (SLE) support the notion that brain cell death accounts for the emergence of neurologic and psychiatric symptoms, and evidence suggests that it is an autoimmunity-induced brain disorder characterized by profound metabolic alterations and progressive neuronal loss. While there are a number of murine models of SLE, this article reviews recent literature on the immunological connections to neurodegeneration and behavioral dysfunction in the Fas-deficient MRL model of NP-SLE. Probable links between spontaneous peripheral immune activation, the subsequent central autoimmune/inflammatory responses in MRL/MpJ-Tnfrsf6 lpr (MRL-lpr) mice and the sequential mode of events leading to Fas-independent neurodegenerative autoimmune-induced encephalitis will be reviewed. The role of hormones, alternative mechanisms of cell death, the impact of central dopaminergic degeneration on behavior, and germinal layer lesions on developmental/regenerative capacity of MRL-lpr brains will also be explored. This model can provide direction for future therapeutic interventions in patients with this complex neuroimmunological syndrome.

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Alterations in Hypothalamic–Pituitary–Adrenal Function Correlated with the Onset of Murine SLE in MRL +/+ and lpr/lpr Mice

Cited by 38 publications

References 33 publications

The Role of Noradrenergic Nerves in the Development of the Lymphoproliferative Disease in Fas-Deficient, lpr/lpr Mice

The Role of Noradrenergic Nerves in the Development of the Lymphoproliferative Disease in Fas-Deficient, lpr/lpr Mice

Behavioral heterogeneity in an animal model of neuropsychiatric lupus

Neuroimmunopathology in a murine model of neuropsychiatric lupus

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