Category: Autoimmune rheumatologic diseases
Spontaneous murine models of lupus-like disease are used to study the pathogenesis of SLE, but require extended observation. Some accelerants, (i.e. Type I IFN) are used to trigger earlier disease onset. We used a TLR 7/8 agonist, previously reported to induce lupus-like disease in WT mice within weeks, as an accelerant in lupus prone mice. C57BL/6J mice (n=29) and pre-disease NZM2410 (n=31) were treated with topical R848 for 8 wks. Compared to vehicle-treated mice, R848-treated B6 and NZM mice had profoundly enlarged spleens, and survival was significantly reduced (p<0.009 and p<0.001). Treated B6 mice trended towards a higher ANA (p=0.059), but not anti-dsDNA, while treated NZM mice had higher levels of ANA (p=0.07) and dsDNA (p=0.004). Albuminuria and renal pathology in treated NZM mice indicated acceleration of nephritis, but not sufficient to cause death. Treated mice had significantly reduced splenic B cells (4% vs. 40%) and T cells (8% vs. 31%) compared with vehicle. CD11b+ cells were significantly expanded (66% vs. 45%) in BM from treated mice. Spleen IHC and histopathology revealed a massive expansion of F4/80+ cells, extramedullary hematopoiesis and changes consistent with histiocytic sarcoma. In summary, topical TLR7/8 agonist treatment induced mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice. Both had a severe immunophenotype and early death most consistent with malignant histiocytosis. Care should be taken in using TLR7/8 as a disease accelerant in NZM2410 mice as data suggest that death is accelerated by myeloproliferative disease rather than nephritis.
Jena Wirth– MUSC
Ivan Molano– MUSC
Gary Gilkeson– Distinguished University Professor, Medicine, Medical University of South Carolina
Phillip Ruiz– University of Miami
Sheryl Coutermarsh-Ott– Virginia Tech
Melissa Cunningham– Asst Professor, Medical University of South Carolina