Neuropsychiatric SLE: from animal model to human

R, Pikman; Kivity, Shaye; Levy, Yair; Mt, Arango; Chapman, Joab; Yonath, Hagith; Shoenfeld, Yehuda; Sg, Gofrit

doi:10.1177/0961203317694261

Cited by 14 publications

(15 citation statements)

References 59 publications

(73 reference statements)

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“…Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multisystemic involvement presenting with numerous clinical manifestations (Kaul et al, 2016;Rahman and Isenberg, 2008). Neuropsychiatric systemic lupus erythematosus (NPSLE) involves neurologic manifestations seen in the central, peripheral, and autonomic nervous systems as well as psychiatric disorders in patients with SLE in which other causes have been excluded (Monahan et al, 2017;Pikman et al, 2017;Unterman et al, 2011;Zirkzee et al, 2014). Extensive research into the pathogenesis of NPSLE has been conducted, with the identification of many potential contributing factors, including autoantibodies (such as anti-NMDA receptors, anti-GABA receptors, anti-ribosomal P and anti-U1 RNP et.…”

Section: Introductionmentioning

confidence: 99%

Intracerebroventricular administration of lupus serum induces microglia activation and leukocyte adhesion in the cerebromicrovasculature of mice

Wang

et al. 2019

Journal of Neuroimmunology

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Background: Central nervous system (CNS) involvement is commonly seen in the patients with system lupus erythematosus (SLE). Mechanisms underlying CNS damage in SLE remain largely unknown. Accumulating evidence suggest that activation of microglia in CNS plays an important role in the inflammatory responses in neurological diseases. The aim of this study is to examine the involvement of microglia in the CNS inflammatory responses induced by circulating serum of SLE patients. Methods: We performed intracerebroventricular (ICV) injection of serums collected from SLE patients or healthy controls to mice, and examined phenotypic changes of microglia, the levels of cytokines, chemokine and adhesion molecules in the brain. Intravital microscopy was used to observe leukocyte rolling and adhesion in the cerebromicrovasculature. We further examined whether minocycline can block inflammatory responses induced by SLE serum. In vitro experiments were conducted to examine whether IgGs from the sera of SLE patients or healthy control can activate the primary cultured microglia. Results: We found that ICV injection of SLE serum increases morphological activation of microglia in the cortex and hippocampus. Inflammatory mediators including pro-inflammatory cytokines (IL-1, IL-6 and TNF-α), chemokine (CCL2 and CCL5) and adhesion molecules (P-selectin and ICAM-1) were significantly elevated in the brains of SLE-serum-treated mice. Using intravital microscopy, we demonstrated that SLE serum promotes leukocyte rolling and adhesion. Furthermore, suppression of microglia activation by systemically using minocycline could decrease the levels of inflammatory molecular, and prevent leukocyte rolling and adhesion. The in vitro experiments revealed that IgG from SLE sera could be engulfed by microglia and stimulated the microglia to secret pro-inflammatory cytokines. Conclusion: Our data suggest that the activation of microglia, which promotes leukocyte adhesion to the brain microvasculature, is an important pathological mechanism of CNS involvement in SLE.

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Section: Introductionmentioning

confidence: 99%

Intracerebroventricular administration of lupus serum induces microglia activation and leukocyte adhesion in the cerebromicrovasculature of mice

Wang

et al. 2019

Journal of Neuroimmunology

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“…Polyclonal B cell activation and autoantibody production seem to play a major role in the pathogenesis of SLE; however, the initial events leading to this activation and deregulation remain undetermined [2]. Still, overwhelming evidence supports a pathogenic role for autoantibodies as will be discussed further below.…”

Section: Understanding Of Npsle-like Pathogenesismentioning

confidence: 97%

“…The MRL/lpr model carries a spontaneously occurring mutation in the lymphoproliferative (lpr) gene on the MRL inbred background. The lpr mutation is linked to Neuropsychiatric SLE: From Immune Mechanisms to Clinical Management DOI: http://dx.doi.org /10.5772/intechopen.82183 a variation in the fas gene that causes failure of lymphocytes to undergo apoptosis [2]. The result of this mutation is the accumulation of CD4, CD8, and CD3 T cells in lymphoid tissue [3].…”

Section: Mrl/lpr Micementioning

confidence: 99%

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Neuropsychiatric SLE: From Immune Mechanisms to Clinical Management

Zhang¹,

Jørgensen²

2020

Lupus - New Advances and Challenges

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In this chapter, we will describe neuropsychiatric lupus (NPSLE) as it develops and is treated in lupus patients, as well as means to study the disease using animal models. Based on mouse studies, we will discuss the correlation between inflammatory mediators, such as cytokines and autoantibodies, and the development of neurological symptoms with specific emphasis on the evidence for systemic versus local effects. We will describe specifically the effect of these mediators on the blood-brain barrier, microglia cell function, and the immune system. In addition, we will summarize signs and symptoms in NPSLE patients, especially with respect to primary versus drug-induced neurological issues and current treatment strategies. The chapter will offer a comprehensive review of old and new studies in animal models and patient populations and offer insight into how these results align with current treatment strategies offered to patients.

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“…In 1999, the ACR established a standard nomenclature with case definitions for 19 neuropsychiatric conditions, 12 related to central nervous system (CNS) manifestations (mainly seizures, headache, stroke, depression, cognitive dysfunction, and psychosis) [3, 4]. Clinical studies estimate an NPSLE prevalence in a range from 17 to 80%, these variations can be attributed to diagnostic criteria, patient selection and assessment methods for autoantibodies detections [3, 5–7]. The etiopathogenesis of NPSLE is still unknown, however, several studies suggest that the presence of autoantibodies against to N-methyl-D-aspartate (NMDA) receptors in serum and cerebrospinal fluid (CF), the production of intrathecal proinflammatory cytokines/chemokines and vasculitis are associated to neuropsychiatric manifestations such as cognitive dysfunction [2, 3].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of hippocampal NR2A/2B subunits related to cognitive impairment in a pristane-induced lupus BALB/c mice

Luciano-Jaramillo

Sandoval-García

Mercado

et al. 2019

Preprint

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Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe complication associated with the neurotoxic effects of circulating autoantibodies in the central nervous system (CNS) manifested frequently as a learning and memory deficit. Pristane-induced lupus in BALB/c female mice is an experimental model that resembles some clinical and immunological SLE pathogenesis associated with environmental factors. Nevertheless, there is no experimental evidence that relate pristane-induced lupus with cognitive dysfunction associated with autoantibodies production.ObjectiveTo evaluate cognitive impairment related to memory deficits in a pristane-induced lupus BALB/c female mice related to mRNA expression levels of NR2A/2B hippocampal subunits in short and long-term memory task at 7 and 12 weeks after LPS exposition (7wLPS and 12wLPS) in a behavioral test with the employment of Barnes maze.MethodsFifty-four female BALB/c mice of 8-12 weeks old were included in 2 experimental groups: 7 and 12 weeks after lypopolissacharide (LPS) exposure and classified in subgroups (control, pristane and pristane+LPS). To determine cognitive dysfunction, mice were tested in a Barnes maze. Serum anti-Sm antibodies and relative expression of hippocampal NR2A/NR2B subunits were quantified.ResultsPristane and pristane+LPS mice showed a prolonged escape latency at 7wLPS than at 12wLPS in short-term memory. Downregulation of hippocampal NR2A subunit was more evident than NR2B in pristane and pristane+LPS at 7wLPS and 12wLPS. The anti-Sm autoantibodies levels correlate with the relative expression of NR2A.ConclusionDownregulation of hippocampal NR2A/2B subunits in the pristane-model of lupus in BALB/c mice may be related to anti-Sm autoantibodies production with the consequence of cognitive impairment in early stages of autoimmune disease.

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Neuropsychiatric SLE: from animal model to human

Cited by 14 publications

References 59 publications

Intracerebroventricular administration of lupus serum induces microglia activation and leukocyte adhesion in the cerebromicrovasculature of mice

Intracerebroventricular administration of lupus serum induces microglia activation and leukocyte adhesion in the cerebromicrovasculature of mice

Neuropsychiatric SLE: From Immune Mechanisms to Clinical Management

Downregulation of hippocampal NR2A/2B subunits related to cognitive impairment in a pristane-induced lupus BALB/c mice

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