Dendritic cells are ideally suited to orchestrate the innate and adaptive immune responses to infection, but we know little about how these cells respond to infection with common respiratory viruses. Paramyxoviral infections are the most frequent cause of serious respiratory illness in childhood and are associated with an increased risk of asthma. We therefore used a high-fidelity mouse model of paramyxoviral respiratory infection triggered by Sendai virus to examine the response of conventional and plasmacytoid dendritic cells (cDCs and pDCs, respectively) in the lung. We found that pDCs are scarce at baseline but become the predominant population of lung dendritic cells during infection. This recruitment allows for a source of IFN-α locally at the site of infection. In contrast, cDCs rapidly differentiate into myeloid cDCs and begin to migrate from the lung to draining lymph nodes within 2 h after viral inoculation. These events cause the number of lung cDCs to decrease rapidly and remain decreased at the site of viral infection. Maturation and migration of lung cDCs depends on Ccl5 and Ccr5 signals because these events are significantly impaired in Ccl5−/− and Ccr5−/− mice. cDCs failure to migrate to draining lymph nodes in Ccl5−/− or Ccr5−/− mice is associated with impaired up-regulation of CCR7 that would normally direct this process. Our results indicate that pDCs and cDCs respond distinctly to respiratory paramyxoviral infection with patterns of movement that should serve to coordinate the innate and adaptive immune responses, respectively.

Fibrous dysplasia of bone (FD) is a mosaic disease caused by mutations in GNAS. Constitutive activation of the a-subunit of the G s stimulatory protein (Gas) leads to dysregulated proliferation of bone marrow stromal cells (BMSCs), generating expansile lesions of fibrotic tissue and abnormal bone. Local bone remodeling regulation by BMSCs is also altered, and FD tissue is characterized by abundant osteoclast-like cells that may be essential for lesion expansion. Animal models show local expression of RANKL in bone lesions, and treatment with the RANKL neutralizing antibody denosumab decreased lesion expansion rate in a patient with aggressive FD. However, the role of RANKL/osteoprotegerin (OPG) in FD pathophysiology is not yet understood. We measured serum levels of RANKL, OPG, and inactive RANKL-OPG complexes in FD patients of known disease burden and in healthy volunteers (HVs). RANK, RANKL, and Ki67 immunohistochemistry were assessed in FD tissue. Cultured FD and HV BMSCs were stimulated with prostaglandin E 2 (PGE 2 ) and 1,25 vitamin D 3 to increase RANKL expression, and media levels of RANKL and OPG were measured. Osteoclastogenic induction by FD or HV BMSCs was assessed in co-cultures with HV peripheral monocytes. FD patients showed a 16fold increase in serum RANKL compared to HVs. OPG was moderately increased (24%), although RANKL/OPG ratio was 12-fold higher in FD patients than in HVs. These measurements were positively correlated with the skeletal burden score (SBS), a validated marker of overall FD burden. No differences in serum inactive RANKL-OPG complexes were observed. In FD tissue, RANKLþ and Ki67þ fibroblastic cells were observed near RANKþ osteoclasts. High levels of RANKL were released by FD BMSCs cultures, but were undetectable in HV cultures. FD BMSC released less OPG than HV BMSCs. FD, but not HV BMSCs, induced osteoclastogenesis in monocyte co-cultures, which was prevented by denosumab addition. These data are consistent with the role of RANKL as a driver in FD-induced osteoclastogenesis.

Background: Tissue expansion is used for soft-tissue reconstruction in pediatric patients. The expansion process can be complicated by infection and extrusion, leading to premature expander removal. The aim of this study was to identify risk factors associated with premature expander removal caused by infection or extrusion in pediatric patients. Methods: A retrospective study of pediatric patients who underwent tissue expansion performed by the senior author (R.J.R.) over a 12-year period was performed. Predictor variables included age, sex, race, indication, anatomical location, number of expanders, serial expansion, and expander size. Bivariate and multivariate analyses were performed to identify risk factors for premature expander removal. Results: A total of 139 patients with 472 expanders were included in this study. Complications occurred with 78 expanders (16.5 percent). Premature expander removal caused by infection or exposure occurred with 51 expanders (10.8 percent). In terms of location, the highest rates of premature removal occurred in the lower extremity (20.0 percent) and scalp (16.3 percent). Multivariate analysis identified younger age (0 to 6 years compared with 13 to 17 years; OR, 3.98; 95 percent CI, 1.13 to 14.08; p = 0.03), greater number of expanders (OR, 1.45; 95 percent CI, 1.03 to 2.03; p = 0.03), and lower extremity location (OR, 4.27; 95 percent CI, 1.45 to 12.53; p = 0.008) were associated with an increased odds of premature expander removal. Conclusions: Expander removal occurred in approximately 10 percent of tissue expanders. Odds of premature removal is increased with younger age, greater number of expanders, and lower extremity location. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Further studies are needed to determine the safety of denosumab on the growing skeleton. However, in this child there was continued epiphyseal activity both during and after treatment and reversal of bone turnover suppression after treatment discontinuation, suggesting that denosumab did not have significant adverse effects on growth.