CD14+,CD16+ blood monocytes and joint inflammation in rheumatoid arthritis

Abstract

Objective. CD14؉,CD16؉ monocytes, identified as a minor population of monocytes in human peripheral blood (PB), have been implicated in several inflammatory diseases. We undertook this study to investigate the relevance of this phenotype to joint inflammation in rheumatoid arthritis (RA).Methods Results. The mean ؎ SD frequency of CD14؉,CD16؉ blood monocytes was significantly increased in RA patients (11.7 ؎ 5.6%; n ‫؍‬ 105) compared with healthy controls (9.5 ؎ 2.2%; n ‫؍‬ 15) (P < 0.01), and the patient group with an increased frequency of CD16؉ monocytes (>13.9%) had active disease, as defined by increased counts of tender and swollen joints, levels of acute-phase reactants, and titers of rheumatoid factor. The response to drug therapy correlated with changes in the frequency of this phenotype. The expression of CD16 on SF monocytes from RA patients was markedly elevated compared with the expression on PB monocytes. CD16 expression on RA blood monocytes was augmented in vitro by IL-10, M-CSF, and TGF␤1. Plasma concentrations of these cytokines and of sCD14 were significantly higher in RA patients with high CD16؉ monocyte frequencies than in those with low CD16؉ monocyte frequencies or in healthy controls. CD14؉,CD16؉ monocytes expressed higher levels of CCR1, CCR5, and ICAM-1 than did regular CD14؉؉,CD16؊ monocytes, particularly in active RA.Conclusion. These results indicate that the maturation of blood monocytes into tissue-infiltrative CD16؉ cells before entry into the joint, induced by cytokine spillover from the inflamed joint, may contribute to the persistent joint inflammation of RA.In human peripheral blood (PB), two monocyte subpopulations with distinct functional properties have been defined by their expression of CD14 and CD16 molecules (1,2). CD14 is the receptor for complexes of lipopolysaccharide (LPS) and LPS-binding protein (3). CD16 is the low-affinity receptor for the Fc region of IgG (Fc␥ receptor type III [Fc␥RIII]) and plays an important role in the clearance of immune complexes (4). Significant expression of CD16 was originally found to be induced on blood monocytes during their differentiation to macrophages in culture, while expression of other Fc␥R decreased (5), but 2-color immunofluorescence analysis with antibodies against CD14 and CD16 has revealed the existence of CD16-expressing monocytes with weak CD14 staining in PB. These CD14ϩ,CD16ϩ cells show typical monocyte morphology with irregular nuclei and account for ϳ10% of circulating monocytes in healthy individuals (1,2,6).

Elevated CD16 expression by monocytes from patients with tumor necrosis factor receptor–associated periodic syndrome

“…Increased CD16 expression by monocytes has been reported in RA (9,11), which is consistent with the similarities observed between the inflammatory features of RA and TRAPS. In RA, however, the level of monocyte CD16 expression was shown to be increased only during active (as opposed to quiescent) disease (11).…”

The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases

“…However, the relevance of these changes to the increased numbers of macrophages in RA synovium discussed above remains to be established. Peripheral blood monocyte subsets have recently been identified (43)(44)(45) and, for reasons that are unclear, conflicting observations of their ratios have been reported in RA patients, with different studies showing an increased or reduced proportion of the CD14 low CD16ϩ subset (46,47). The potential significance of these subsets is detailed below.…”

“…In humans, 2 main monocyte populations have been delineated, namely, the major CD14ϩCD16Ϫ and the minor CD14 low CD16ϩ subsets (43). As mentioned above, there have been conflicting findings regarding the ratio of these subpopulations in the blood of RA patients (46,47). The CD14ϩCD16Ϫ subpopulation is considered to be the less mature, while the more mature CD14 low CD16ϩ monocytes have been called "inflammatory" monocytes (44,134), in part because their level may be elevated in blood in inflammatory conditions, such as RA (135), and in part because they produce TNF in response to LPS (44,134).…”

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

“…Some of the associations that we report here may exert their influence through the function of these cells. Patients with RA have an increase in the frequency of CD14 þ CD16 þ monocytes in the synovium and peripheral blood; 44 this was associated with increased TNF-a production following exposure to aggregated IgG. 44,45 DC are known to play an important role in the initiation of the immune response.…”