Restricted expression of FcγRIII (CD16) in synovium and dermis: implications for tissue targeting in rheumatoid arthritis (RA)

Abstract

Interactions between immune complexes and immunoglobulin Fc receptors may contribute to inflammation in RA. Previous studies suggested that FcγRIII (CD16) may be preferentially expressed in diseased synovial intima. The distribution of immunoreactive FcγRIII was examined in normal fetal limb tissues, and both normal and selected abnormal samples of adult synovium and skin. In fetal limbs at 10–14 weeks gestation FcγRIII was restricted to synovial intima. In normal adult synovium FcγRIII was restricted to intimal cells. In inflamed synovia differential expression of FcγRIII in the intima was less consistent. In both fetal and adult synovium FcγRIII was largely restricted to cells expressing CD45 (leucocyte common antigen). Staining for FcγRIII was, however, occasionally associated with CD45− intimal cells in fetal synovium. In both fetal and adult tissues cell membrane FcγRIII was frequently closely associated with complement decay‐accelerating factor (DAF), which is present on intimal fibroblasts and extracellular matrix. FcγRIII expression was minimal in normal forearm dermis, but widespread on CD45+ cells in skin exposed to mechanical stress. In skin containing rheumatoid nodules, FcγRIII was preferentially expressed on palisading macrophages. These observations indicate that expression of FcγRIII on macrophages may be involved in the susceptibility of connective tissues to immune complex‐induced damage in RA. Colocalization of FcγRIII and DAF in synovium may indicate an unrecognized functional interrelationship.

The Role of FcγR Signaling in the K/B × N Serum Transfer Model of Arthritis

“…Various cells expressing FcRs are present in joints. Reports of FcR expression on fibroblast-like synoviocytes led us to examine the role of jointassociated Fc␥R expression in the serum transfer model (17)(18)(19)(20). The experiments with the chimeric mice show that the development of arthritis depends on the expression of Fc␥R by bone marrow-derived cells, which may include mesenchymal stem cells (33,34).…”

“…FcRs present on synovial fibroblasts and extracellular matrix have been described previously (17)(18)(19)(20). To evaluate whether joint inflammation is associated with bone marrow-derived elements or with other connective tissues, bone marrow chimeras were made by irradiating C57BL/6 and Fc␥R recipients and reconstituting them with Fc␥R and C57BL/6 donor bone marrow, respectively.…”

Studies on the association of Fcγ receptor IIA, IIB, IIIA and IIIB polymorphisms with rheumatoid arthritis in the Japanese: evidence for a genetic interaction between HLA-DRB1 and FCGR3A

“…The expression of FcgRIIIA on macrophage in the synovium and dermis was suggested to be involved in the immune complex-induced tissue damage in RA. 15 A major role for macrophage FcgRIIIA in the induction of tumor necrosis factor a following receptor ligation by small immune complex was shown in RA. 16 At this point, it is not clear how FcgRIIIA-176F protein, previously shown to be associated with lower affinity to IgG1, IgG3 and reduced signaling in NK cells, 1 is associated with the pathogenesis of RA.…”

Fcγ receptor type IIIA is associated with rheumatoid arthritis in two distinct ethnic groups

“…These circulating IgG-RF complexes do not fix complement well (35), allowing them to pass freely into the extravascular space (2), where they are not generally thought to mediate tissue damage (3). However, the extraarticular manifestations of RA appear to be restricted to sites where connective tissue macrophages express Fc␥RIIIA, such as in rheumatoid nodules, alveoli, liver, pericardium, lymphoid tissue, bone marrow, and salivary glands (36). The high-affinity Fc␥RIIIA-158V isoform on these connective tissue macrophages may be more likely to bind extravasated IgG-RF complexes, thereby initiating an enhanced inflammatory response.…”