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.


CONCLUSIONS
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 1β.
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University. aweldon@llu.edu.
Abby Jones
AJ
Weldon
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Ioana
I
Moldovan
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Marven G
MG
Cabling
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Elvin A
EA
Hernandez
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Sheri
S
Hsu
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Jennifer
J
Gonzalez
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Andrea
A
Parra
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Abigail
A
Benitez
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Nasim
N
Daoud
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Keith
K
Colburn
From the Center for Health Disparities and Molecular Medicine, Department of Microbiology and Molecular Genetics, Department of Medicine, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda; Division of Rheumatology, Beaver Medical Group, Redlands, California, USA.A.J. Weldon, MS; A. Benitez, PhD, Center for Health Disparities and Molecular Medicine, and Department of Microbiology and Molecular Genetics, Loma Linda University; I. Moldovan, MD, Department of Medicine, Loma Linda University, and Division of Rheumatology, Beaver Medical Group; M.G. Cabling, MD; S. Hsu, MD; N. Daoud, MD; K. Colburn, MD, Department of Medicine, Loma Linda University; E.A. Hernandez, PhD, Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, Loma Linda University; J. Gonzalez, BS; A. Parra, BS, Center for Health Disparities and Molecular Medicine, Loma Linda University; K.J. Payne, PhD, Center for Health Disparities and Molecular Medicine, and Department of Pathology and Human Anatomy, Loma Linda University.
Kimberly J
KJ
Payne
D000368:Aged; D001172:Arthritis, Rheumatoid / Q000175:diagnosis / Q000378:metabolism*; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D012720:Severity of Illness Index; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D053583:Interleukin-1beta; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D014409:Tumor Necrosis Factor-alpha
APRIL; AUTOIMMUNITY; INFLAMMATION; MONOCYTES; RHEUMATOID ARTHRITIS; TNFSF13