Background/Purpose: Despite the many lupus patients affected by neuropsychiatric signs and symptoms, the pathogenesis of neuropsychiatric disease in SLE remains unclear. MRL-lpr/lpr mice, a classic mouse model of SLE, presents with neuropsychiatric abnormalities similar to those seen in human disease including cognitive abnormalities and affective deficits. We recently found that MRL-lpr/lpr mice develop tertiary lymphoid structures (a.k.a. ectopic germinal centers) in the brain choroid plexus. Structurally and functionally, tertiary lymphoid structures resemble lymph nodes forming at the site of chronic inflammation to create more localized and specialized immune responses, which may however be detrimental in autoimmune disease. CXCL13 is a key chemokine that drives the formation of lymphoid structures. We studied whether antibody blockade of CXCL13 would prevent brain tertiary lymphoid structure formation and attenuate neuropsychiatric SLE.

Methods: Female MRL-lpr/lpr mice received intraperitoneal injections of a monoclonal anti-CXCL13 antibody, an IgG isotype control antibody, or PBS 3 times weekly for 12 weeks starting at 6-8 weeks of age. During the last week of treatment at 18-20 weeks of age, mice were assessed for cognitive dysfunction (object placement and object recognition tests), and affective deficits (Porsolt forced swim test). Brain tissues were analyzed by histology and immunofluorescent staining.

Results: Anti-CXCL13 mAb treated MRL/lpr mice displayed significant improvement in depression-like behavior as compared to the two control groups, as shown by increased mobility during the forced swim assessment (p=0.004). However, cognitive function assessment showed no significant improvements in visuospatial or recognition memory. Preliminary analysis of brain tissue histology showed less choroid plexus lymphocytic infiltration in anti-CXCL13 treated mice. However, there were no apparent differences in systemic disease, as spleen-to-body weight and lymph node-to-body weight ratios, as well as serum IgG anti-double stranded DNA antibody titers, were similar among the groups.

Conclusion: Preventing choroid plexus tertiary lymphoid structure formation by neutralizing CXCL13 attenuates depression-like behavior but not cognitive dysfunction in MRL-lpr/lpr mice. Our results suggest that brain tertiary lymphoid structures play an important role in the pathophysiology of affective deficits, although whether this effect of treatment was limited to the brain remains to be determined. Furthermore, CXCL13 neutralization may be a potential therapeutic strategy to target neuropsychiatric lupus.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neutralizing-cxcl13-attenuates-neuropsychiatric-disease-in-lupus-prone-mice/