Session Type: Poster Session (Monday)
Session Time: 9:00AM-11:00AM
Background/Purpose: Many systemic lupus erythematosus patients display a type I interferon (IFN) signature, and IFNα levels and gene signatures have been positively correlated with disease severity. Previous studies blocking the type I IFN pathway systemically in lupus models have seen some beneficial effects in attenuating both systemic and renal disease. However, its effects on the neuropsychiatric manifestations have yet to be assessed, even though therapeutic administration of IFNα has been associated with induction of depression, a common manifestation in NPSLE patients. Our aim was to investigate whether disrupting the type I IFN pathway systemically would attenuate the development of murine neuropsychiatric lupus.
Methods: Female MRL/lpr mice were administered an anti-IFNAR antibody (MAR1-5A3; MedImmune, Gaithersburg, MD) or an IgG isotype control antibody (1A7, IgG1) intraperitoneally 3 times weekly for 12 weeks starting at 4-5 weeks of age. Depression-like behavior was assessed at 8-9 weeks of age using the Porsolt swim test. Cognitive dysfunction was assessed at the end of treatment at 16-17 weeks of age, using the object placement (OP) and object recognition (OR) tests, which evaluates spatial and recognition memory, respectively. Brain tissue was analyzed by histology and by immunofluorescent staining for B220+ and CD3+ cells, as well as albumin and IgG deposition in the brain parenchyma to determine brain barrier integrity.
Results: No significant differences were seen between the anti-IFNAR and control treated mice when assessing for depression-like behavior (p=0.32) or cognitive dysfunction (OP: x2(1) = 0.54, p = 0.46; OR: x2(1) = 0.002, p = 0.96). Anti-IFNAR treatment also did not significantly improve cellular infiltration, as evident by hematoxylin and eosin staining and infiltrate composition comparing B220+ and CD3+ cell counts. Staining for albumin and IgG leakage in the brain parenchyma also showed similar brain barrier integrity between the groups. RNA expression level of CXCL10, a known interferon-stimulated gene, were significantly different in the spleen (p = 0.023) and the choroid plexus (p = 0.0088), suggesting that the pathway was inhibited in the choroid plexus with systemic delivery of the antibody.
Conclusion: Surprisingly, our results showed no improvement in neuropsychiatric disease in the MRL/lpr mouse model and suggest that the role of IFNAR signaling in the pathogenesis of neuropsychiatric lupus continues to need to be carefully assessed.
To cite this abstract in AMA style:Huang M, Stock A, Mike E, Kolbeck R, Putterman C. Anti-IFNAR Treatment Does Not Reverse Neuropsychiatric Disease in MRL/lpr Lupus Mice [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/anti-ifnar-treatment-does-not-reverse-neuropsychiatric-disease-in-mrl-lpr-lupus-mice/. Accessed November 28, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-ifnar-treatment-does-not-reverse-neuropsychiatric-disease-in-mrl-lpr-lupus-mice/