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.