Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis.

OBJECTIVE: To assess surface APRIL (a proliferation-inducing ligand; CD256) expression by circulating myeloid cells in rheumatoid arthritis (RA) and to determine its relationship to disease activity. METHODS: Peripheral blood mononuclear cells (PBMC) and plasma were obtained from patients with RA and healthy donors. PBMC were stained for flow cytometry to detect surface APRIL and blood cell markers to identify circulating myeloid cell subsets. Based on CD14 and CD16 phenotypes, monocyte subsets described as classical (CD14+CD16-), intermediate (CD14+CD16+), and nonclassical (CD14loCD16+) were identified. Levels of surface APRIL expression were measured by flow cytometry and median fluorescence intensity was used for comparisons. Levels of soluble APRIL in the plasma were determined by ELISA. Disease activity was measured by the Disease Activity Score in 28 joints. RESULTS: In patients with RA, total myeloid cells showed expression of surface APRIL that correlated with disease activity and with plasma APRIL levels observed in these patients. In healthy donors, classical monocytes were composed of > 80% of circulating monocytes. However, in patients with RA, the intermediate and nonclassical subsets were elevated and made up the majority of circulating monocytes. In contrast to healthy donors, where high levels of surface APRIL were only observed in nonclassical monocytes, patients with RA showed high levels of surface APRIL expression by all circulating monocyte subsets. CONCLUSION: Surface APRIL is elevated in circulating myeloid cells in patients with RA where it is highly correlated with disease activity. Patients with RA also showed skewing of monocytes toward subsets associated with secretion of tumor necrosis factor-α and/or interleukin 1ß.

Differences in mouse and human nonmemory B cell pools.

Identifying cross-species similarities and differences in immune development and function is critical for maximizing the translational potential of animal models. Coexpression of CD21 and CD24 distinguishes transitional and mature B cell subsets in mice. In this study, we validate these markers for identifying analogous subsets in humans and use them to compare the nonmemory B cell pools in mice and humans, across tissues, and during fetal/neonatal and adult life. Among human CD19(+)IgM(+) B cells, the CD21/CD24 schema identifies distinct populations that correspond to transitional 1 (T1), transitional 2 (T2), follicular mature, and marginal zone subsets identified in mice. Markers specific to human B cell development validate the identity of marginal zone cells and the maturation status of human CD21/CD24 nonmemory B cell subsets. A comparison of the nonmemory B cell pools in bone marrow, blood, and spleen in mice and humans shows that transitional B cells comprise a much smaller fraction in adult humans than mice. T1 cells are a major contributor to the nonmemory B cell pool in mouse bone marrow, in which their frequency is more than twice that in humans. Conversely, in spleen, the T1:T2 ratio shows that T2 cells are proportionally ∼ 8-fold higher in humans than in mice. Despite the relatively small contribution of transitional B cells to the human nonmemory pool, the number of naive follicular mature cells produced per transitional B cell is 3- to 6-fold higher across tissues than in mice. These data suggest differing dynamics or mechanisms produce the nonmemory B cell compartments in mice and humans.