Background/Purpose:

Neuropsychiatric disease is one of the earliest clinical manifestations in systemic lupus erythematosus (SLE). However, the mechanisms leading to neuropsychiatric SLE (NPSLE) are not fully understood, and the optimal treatment yet to be defined. In lupus, a compromised blood brain barrier may allow for the passage of circulating autoantibodies into the brain, where they can then induce neuropsychiatric abnormalities. Previous studies have reported that autoantibody titers correlate with the severity of depressive-like behavior, and that injection of anti-ribsomal P and 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 B-cell depleted (JhD/MRL/lpr) and wild type MRL/lpr lupus mice, the latter which are known to develop several cardinal features of human NPSLE.

Methods:

Blood and cerebrospinal fluid (CSF) were collected from female JhD/MRL/lpr and MRL/lpr mice at 20 weeks of age. To confirm B cell depletion in JhD/MRL/lpr mice, PBMC were stained with CD19 and analyzed by FACS. Total IgG and IgG anti-DNA 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 JhD/MRL/lpr as compared to MRL/lpr mice.

Results:

We confirmed that peripheral B-cells were substantially depleted in JhD/MRL/lpr mice, and that autoantibody levels were negligible in the serum and CSF. Nevertheless, we found that in the forced swim test, JhD/MRL/lpr mice showed dramatic depressive-like behavior (as indicated by increased floating time), which was no different than MRL/lpr mice (JhD/MRL/lpr: 56.2%+1.2%, n=7; MRL/lpr: 61.8%+6.9%, n=5; MRL/+: 19.9%+4.7%, n=5). Additionally, JhD/MRL/lpr mice displayed cognitive dysfunction in the object placement (OP) test, as demonstrated by the OP preference score (JhD/MRL/lpr: 40.8%+8%, n=5; MRL/lpr: 50.9%+12.5%, n=5; MRL/+: 66.0%+3.8%, n=5). Furthermore, there were no differences in object recognition and social preference between these two mice strains. However, in the open field test, an increased number of rears were observed in JhD/MRL/lpr mice.

Conclusion:

B-cell depleted MRL/lpr mice surprisingly had no attenuation of key features of neuropsychiatric disease, including depressive-like behavior and cognitive dysfunction, despite negligible serum and CSF IgG concentrations. However, an increased number of rears were observed in JhD/MRL/lpr mice, indicating higher motor activity. Thus, constitutive depletion of B-cells was not sufficient to ameliorate lupus-associated neuropsychiatric disease, at least in the MRL/lpr strain. Whether conditional B-cell ablation later on in life will have the same effect remains to be determined.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/hold-the-rituximab-neuropsychiatric-disease-in-murine-lupus-is-not-b-cell-dependent/