Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple end organs including the brain. Despite a prevalence of over 50% in SLE patients depending on the attribution model, neuropsychiatric symptoms of SLE (NPSLE) are among the least understood complications. Notwithstanding the paucity of data examining underlying mechanisms, accumulating evidence points to microglia, a brain-resident innate immune cell population, as a driver of disease. Our group was the first to show that microglial expression of disease-associated genes correlates with the severity of behavioral deficits in a NPSLE model prior to overt systemic disease. Previous data suggest NPSLE-like disease persists in bone marrow (BM) chimeric MRL^lpr/lpr mice (MRL BMMRL^lpr/lpr) despite mitigation of systemic disease, suggesting a brain-intrinsic mechanism. However, these findings do not negate the contribution of circulating mediators of SLE-like disease at subclinical levels (antibodies, proteins, immune cells) to brain dysfunction. Indeed, the reciprocal chimera (MRL^lpr/lpr BMMRL) was not evaluated. Further, radiation impacts microglial function and recipient mice from this study were not head-shielded.

Methods: Young female CD45.1 (Jackson 033076) and SLE-prone B6.Sle1Sle2Sle3 (B6.TC; Jackson 007228) mice were used to generate head-shielded reciprocal BM chimeric mice with busulfan treatment to clear remaining BM (CD45.1 BMCD45.1; B6.TC BMCD45.1; CD45.1 BMB6.TC; B6.TC BMB6.TC). Mice underwent a behavioral tasks and PET imaging of activated microglia 10 weeks post-transfer. Perfused brains were extracted, meninges were removed and live CD45⁺ cells were FACSorted from pooled cell suspensions (n=3/group to account for biological variability) for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq; 10X Genomics 3′ v3.1).

Results: Introduction of B6.TC BM into CD45.1 hosts yields 95% reconstitution and induces systemic inflammation indicative of SLE-like disease. Conversely, B6.TC hosts receiving CD45.1 BM showed a trend towards dampened SLE-like disease resulting from only 50% reconstitution. Optimization (increased busulfan, transfer of double CD45.1 BM cells) was unsuccessful following head-shielded irradiation of B6.TC mice, suggesting that the minor fraction of B6.TC host-derived progenitors remaining will still outcompete CD45.1 donor progenitors. Similar to NPSLE patients, B6.TC mice exhibit heightened anxiety. Anxiety persists in chimeric mice of B6.TC, but not CD45.1, host origin, suggesting that brain-intrinsic defects in B6.TC mice are required for this behavior. However, impaired motor learning in B6.TC mice is recapitulated by both brain-intrinsic and hematopoietic-derived defects in B6.TC mice. Analysis of PET tracer uptake and CITE-seq data are pending and will provide critical insight into the activation status of microglia and other immune cell subsets.

Conclusion: We find that NPSLE manifestations diverge in mechanistic origin within the same organism. Further understanding this specificity of brain-intrinsic and/or hematopoietic-derived mechanisms mediating NPSLE will be critical for developing treatment strategies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/specificity-of-brain-intrinsic-and-hematopoietic-derived-mechanisms-in-mediating-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/