Session Title: Systemic Lupus Erythematosus - Animal Models
Session Type: Abstract Submissions (ACR)
Autoantibodies contribute to the pathogenesis of the autoimmune disease Systemic Lupus Erythematosus (SLE) by stimulating the immune response. Further, deposits of immune complexes in the kidneys can lead to severe nephritis. The autoantibodies are secreted by short- and long-lived plasma cells located in the bone marrow and in the spleen. In NZB/W mice – a mouse model for SLE – both parental strains New Zealand Black (NZB) and New Zealand White (NZW) contribute different sle-loci to the formation of SLE. The NZB strain passes the sle2c locus in which the gene for the Thrombopoietin (TPO)-receptor (c-mpl) is located.
According to the relevance of megakaryocytes for the plasma cell niche and the correlation between plasma cell and megakaryocyte numbers, we wanted to elucidate whether c-Mpl and/ or megakaryopoiesis is altered in auto-immune mice.
Therefore, we examined in wild type, NZB and NZW mice the amount of megakaryocytes and plasma cells in spleen and bone marrow, the occurrence of genetic variations for c-mpl and the degree of megakaryopoiesis upon TPO stimulation by histological survey, flow-cytometric and genetic analysis and by in vitrostudies.
We found, that in the spleen of NZB mice the number of long-lived plasma cells and megakaryocytes are 10-times higher than in wild type while in NZW mice the numbers are equal. We detected a missense mutation in the c-mpl gene of NZB mice leading to an amino acid replacement within the essential TPO-binding site. Upon TPO stimulation of splenocyte and bone marrow cultures NZB cultures responded significantly stronger resulting in the double amount of megakaryocytes compared to NZW cultures.
In summary, our data indicate that the mutated c-mpl gene located within the sle2c-locus is leading to an augmented megakaryopoiesis which enables the accumulation of a greater number of autoreactive plasma cells and thus is contributing to the development of SLE.
R. A. Manz,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/numbers-of-splenic-long-lived-plasma-cells-in-autoimmune-and-pre-autoimmune-lupus-mice-are-linked-to-a-hyper-responsive-variant-of-the-thrombopoietin-receptor-and-enhanced-megakaryopoiesis/