Background/Purpose: Spleen tyrosine kinase (SYK) is a driver of B cell receptor and Fc receptor signaling pathways, which have central roles in initiating and driving pathogenesis of systemic lupus erythematosus (SLE). NZB/W F1 mice develop spontaneous lupus-like disease and are a model system for testing potential targeted therapies in SLE. Treatment of NZB/W F1 mice with SYK inhibitors has been previously reported to ameliorate symptoms of progressive disease (Bahjat et al, Arth & Rheum 2008). Since key pathological manifestations in studies using NZB/W F1 mice correlate with human SLE, we examined the immune cell populations that are affected in this model in order to translate to human SLE phenotypes. We compared splenic populations of healthy and diseased NZB/W F1 mice treated with a highly selective SYK inhibitor, SYKi-A, to PBMCs of healthy donors and SLE patients experiencing flares.

Methods: Spleens were harvested from NZB/W F1 mice without disease symptoms (16 weeks old, control), with progressive disease (40 weeks old), or from SYKi-A treated mice (40 weeks old with treatment initiated at 28 weeks). Splenic cells were analyzed by flow cytometry to identify B and T cell subpopulations modulated by disease and SYKi-A treatment. PBMCs isolated from blood of non-SLE and SLE patients were analyzed by flow cytometry to assess disease-mediated changes in disease-relevant lymphocyte populations.

Results: Treatment of NZB/W F1 mice with SYKi-A increased overall survival, reduced proteinuria, prevented renal inflammation, and preserved glomerular structure in the kidney. Immune cell populations were examined in the NZB/W F1 mouse cohorts. Splenic B cells from both control mice and SYKi-A treated mice showed a more naïve B cell phenotype than untreated mice with progressive disease as measured by the ratio of transitional B cells (IgM⁺IgD^±) to class switched cells (IgM^–IgD^–) (p<0.0001 and p=0.007, respectively). In human PBMCs, non-SLE individuals showed a more naïve B cell phenotype as measured by the ratio of transitional B cells (CD24⁺CD38⁺) to class switched cells (CD27⁺IgD^–IgM^–) compared to SLE subjects (p = 0.034). Additionally, splenic T cells from both control mice and SYKi-A treated mice showed a more naïve phenotype than untreated mice with progressive disease as measured by the ratio of naïve (CD44^–CD62L⁺) to memory (CD44⁺CD62L^±) T cells (CD4⁺: p=0.015 and p=0.002, respectively; CD8⁺: p=0.0003 and p=0.0003, respectively). In human PBMCs, non-SLE individuals showed a more naïve CD8⁺ T cell phenotype as measured by the ratio of naïve (CD45RA⁺CCR7⁺CD27⁺) to memory (CD45RO⁺CCR7^±) CD8⁺ T cells compared to SLE subjects (p=0.042).

Conclusion: SYK inhibition following disease onset shifts the balance of lymphocyte subsets to a more naïve phenotype identified in pre-disease NZB/W F1 mice. T and B cell subsets identified in PBMCs from SLE subjects reflect a similar phenotype to those observed in NZB/W F1 diseased mice.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/spleen-tyrosine-kinase-inhibition-reveals-immune-cell-subsets-of-diseased-nzbw-f1-mice-that-are-reflected-in-systemic-lupus-erythematosus-patient-peripheral-blood-mononuclear-cells/