Session Type: Abstract Submissions (ACR)
Background/Purpose: Neuropsychiatric lupus (NPSLE) is one of the earliest clinical manifestations in human lupus. However, its mechanisms are not fully understood. In lupus, a compromised blood brain barrier may allow for the passage of circulating autoantibodies into the brain, where they can induce neuropsychiatric abnormalities. Autoantibody titers can correlate with the severity of depressive-like behavior, and injection of anti-ribsomal P or anti-NMDA receptor antibodies into the brain induces neuronal damage and memory deficits. Since antibodies play an important role in lupus pathogenesis, B-cell depletion has been proposed as a targeted treatment approach. To determine if indeed B-cells and/or autoantibodies are instrumental in the pathogenesis of murine NPSLE, we evaluated neuropsychiatric disease in constitutively B cell deficient (JhD/MRL/lpr) and conditionally B-cell deficient mice (Cre-human CD20 MRL/lpr x Rosa26-Flox-STOP-DTA MRL/lpr, referred to as hCD20-DTA MRL/lpr, inducible by tamoxifen), as compared to MRL/lpr lupus mice.
Methods: hCD20-DTA MRL/lpr mice were B cell depleted at 13-14 weeks of age with tamoxifen treatment for 5 days. Blood and cerebrospinal fluid (CSF) were collected from JhD/MRL/lpr, hCD20-DTA MRL/lpr, MRL/lpr (positive controls) and MRL/MPJ (negative controls) at 18 weeks of age. Total IgG and IgG anti-dsDNA antibody concentrations in the serum and CSF were measured by ELISA. Comprehensive neurobehavioral testing including forced swim, anhedonia, open field, object recognition, object placement, and social preference were employed to evaluate the neuropsychiatric manifestations in the B cell sufficient and deficient MRL/lpr strains.
Results: Autoantibody levels were negligible (JhD/MRL/lpr) or significantly reduced (hCD20-DTA MRL/lpr) in the serum and CSF of B cell deficient mice. Nevertheless, we found that in the forced swim test, both JhD/MRL/lpr and hCD20-DTA MRL/lpr mice showed profound depressive-like behavior, which was no different from MRL/lpr mice. However, JhD/MRL/lpr mice displayed an increase in both total track length and number of rears (standing on the hind feet) in open field. Additionally, hCD20-DTA MRL/lpr mice exhibited an increased trend in preference score in object placement. No significant differences were observed in anhedonia, object recognition and social preference tests among all three strains. Interestingly, hCD20-DTA MRL/lpr mice demonstrated a significantly reduction in cellular infiltrates in the choroid plexus compared to MRL/lpr mice.
Conclusion: We found that B-cell depleted MRL/lpr mice surprisingly had no significant attenuation of key features of neuropsychiatric disease, including depressive-like behavior and cognitive dysfunction. However, increased motor activity was observed in JhD/MRL/lpr mice. Additionally, a trend toward improved visual memory was found in hCD20-DTA MRL/lpr mice. Finally, the decreased cellular infiltrates in the brain of hCD20-DTA MRL/lpr mice indicate that B cells play an important role in facilitating the immune cell entry into the choroid plexus.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neuropsychiatric-lupus-is-substantially-unaffected-by-b-cell-deficiency/