Autoantibody-mediated neuroinflammation: Pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model

Mondal, Tapan Kumar; Saha, Sam K.; Miller, Veronica M.; Seegal, Richard F.; Lawrence, David A.

doi:10.1016/j.bbi.2008.01.013

Cited by 33 publications

(17 citation statements)

References 60 publications

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“…In addition, when the platform was removed at day 5, the control groups of mice spent more time and effort in the quadrant where the previous platform placed, as opposed to the INA+LPS group thus suggesting a significant memory impairment (Figure 4D). This impairment in learning and memory function is consistent with the neuropsychiatric studies of lupus-prone murine models which demonstrate poor performance in spatial memory tasks [53]–[57]. Other profound neurological dysfunction, such as exploratory behavior and motor coordination, was also observed in INA+LPS mice in open field activity and beam walking tasks (Figure S2).…”

Section: Resultssupporting

confidence: 87%

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Chen

Huang

et al. 2010

PLoS ONE

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BackgroundNeuropsychiatric systemic lupus erythematosus (NPSLE) is a major complication for lupus patients, which often leads to cognitive disturbances and memory loss and contributes to a significant patient morbidity and mortality. The presence of anti-neuronal autoantibodies (aAbs) has been identified; as examples, anti-NMDA receptors and anti-Ribsomal P aAbs have been linked to certain pathophysiological features of NPSLE.Methods and FindingsIn the current study, we used a proteomic approach to identify an intermediate neurofilament alpha-internexin (INA) as a pathogenetically relevant autoantigen in NPSLE. The significance of this finding was then validated in an expanded of a cohort of NPSLE patients (n = 67) and controls (n = 270) by demonstrating that high titers of anti-INA aAb was found in both the serum and cerebrospinal fluid (CSF) of ∼50% NPSLE. Subsequently, a murine model was developed by INA immunization that resulted in pronounced cognitive dysfunction that mimicked features of NPSLE. Histopathology in affected animals displayed cortical and hippocampal neuron apoptosis. In vitro studies further demonstrated that anti-INA Ab mediated neuronal damage via inhibiting axonal elongation and eventually driving the cells to apoptosis.ConclusionsTaken together, this study identified a novel anti-neurofilament aAb in NPSLE, and established a hitherto undescribed mechanism of aAb-mediated neuron damage that could have relevance to the pathophysiology of NPSLE.

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Section: Resultssupporting

confidence: 87%

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Chen

Huang

et al. 2010

PLoS ONE

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“…Presence of brain-reactive IgG in mice sera was determined as follows [72]. SCID mouse whole brain or brain regional proteins were coated (10 µg/well) in the 96-well plate overnight at 4°C, and after 3× washing, the plate was blocked with 5% BSA-PBS for 2 h. SCID brains were used so as to ensure the absence of IgG in the brain homogenates.…”

Section: Methodsmentioning

confidence: 99%

Aberrant Immune Responses in a Mouse with Behavioral Disorders

et al. 2011

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BTBR T+tf/J (BTBR) mice have recently been reported to have behaviors that resemble those of autistic individuals, in that this strain has impairments in social interactions and a restricted repetitive and stereotyped pattern of behaviors. Since immune responses, including autoimmune responses, are known to affect behavior, and individuals with autism have aberrant immune activities, we evaluated the immune system of BTBR mice, and compared their immunity and degree of neuroinflammation with that of C57BL/6 (B6) mice, a highly social control strain, and with F1 offspring. Mice were assessed at postnatal day (pnd) 21 and after behavioral analysis at pnd70. BTBR mice had significantly higher amounts of serum IgG and IgE, of IgG anti-brain antibodies (Abs), and of IgG and IgE deposited in the brain, elevated expression of cytokines, especially IL-33 IL-18, and IL-1β in the brain, and an increased proportion of MHC class II-expressing microglia compared to B6 mice. The F1 mice had intermediate levels of Abs and cytokines as well as social activity. The high Ab levels of BTBR mice are in agreement with their increased numbers of CD40hi/I-Ahi B cells and IgG-secreting B cells. Upon immunization with KLH, the BTBR mice produced 2–3 times more anti-KLH Abs than B6 mice. In contrast to humoral immunity, BTBR mice are significantly more susceptible to listeriosis than B6 or BALB/c mice. The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors, as has been suggested for some humans with autism.

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“…Although these correlations suggest a link between BRAA and behavioral alterations, they do not prove a causal connection. Other researchers have supplemented this by using passive or active BRAA transfer to specific antigens (Kowal et al , 2004; Lawrence et al, 2007; Mondal et al, 2008). Given the diversity of behavioral manifestations in NP-SLE and AABS, as well as the results of our current study, it is expected that a variety of BRAA account for deficits in different domains of behavior.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Kowal and colleagues have focused on the cross-reactivity between anti-DNA autoantibodies and the NMDA receptor, providing evidence for their role in neurobehavioral changes (Kowal et al , 2004). Similarly, using the autoimmune NZM strain, Lawrence and colleagues produced a monoclonal autoantibody that was directed against mouse dynamin-1 (Lawrence et al , 2007; Mondal et al , 2008). More importantly, when the antibody was injected intravenously into non-autoimmune Balb/C mice, they developed behavioral manifestations similar to those seen in the NZM mice.…”

Section: Discussionmentioning

confidence: 99%

Circulating brain-reactive autoantibodies and behavioral deficits in the MRL model of CNS lupus

Williams

Šakić

Hoffman

2010

Journal of Neuroimmunology

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Brain reactive autoantibodies (BRAA) are hypothesized to play a role in the neuropsychiatric manifestations that accompany systemic lupus erythematosus (SLE). The present study tests the proposed relation between circulating BRAA and behavioral deficits in lupus-prone MRL/lpr mice. Two age-matched cohorts born at different times were used to test the relationship in the context of altered disease severity. Significant correlations between autoimmunity and behavior were detected in both cohorts. These results are the first to report correlations between behavior and autoantibodies to integral membrane proteins of brain, supporting the hypothesis that BRAA contribute to the behavioral dysfunction seen in lupus.

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Autoantibody-mediated neuroinflammation: Pathogenesis of neuropsychiatric systemic lupus erythematosus in the NZM88 murine model

Cited by 33 publications

References 60 publications

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Anti-α-Internexin Autoantibody from Neuropsychiatric Lupus Induce Cognitive Damage via Inhibiting Axonal Elongation and Promote Neuron Apoptosis

Aberrant Immune Responses in a Mouse with Behavioral Disorders

Circulating brain-reactive autoantibodies and behavioral deficits in the MRL model of CNS lupus

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