Macrophage migration and maturation within rheumatoid nodules

Abstract

In long-established rheumatoid nodules, monocytes continue to be recruited and to migrate from the outer vascular zone toward the palisade and central necrotic area. Maturation of these cells is shown to take place during tissue migration. We found that the great majority of palisade cells express exclusive mononuclear phagocyte phenotypes. Among this mononuclear phagocyte population are many cells that bear the receptor for iC3b (CR3), but few that bear the receptor for C3b (CR1). HLA-D region molecule expression is intense and widespread.The pathogenesis of the subcutaneous rheumatoid nodule is not understood. These nodules develop in about 20% of patients with rheumatoid arthritis (RA) and are associated with circulating rheumatoid factors and with more severe erosive disease (1). Such lesions are necrotizing granulomas with a characteristic orderly arrangement of cells.Although the majority of patients with RA never develop nodules, lesions that appear to be identical to rheumatoid nodules are sometimes seen in otherwise healthy people, children in particular, in the absence of joint involvement (2). The relationship between the intimal cell hyperplasia and chronic inflammatory cell infiltrate, which characterize the synovium of joints affected with RA, and the granulomatous nodule is unclear.The general histologic characteristics of the subcutaneous nodule have been accepted for some 50 years (3), but the nature of the cellular infiltrate itself has been open to debate. The radially arranged palisade of cells which surrounds the necrotic center has been said to consist of fibroblasts (4), macrophage-like cells (3, or both of these cell forms (6). The controversy has not been settled by recent studies in which monoclonal antibodies were used. Hedfors et a1 (7) found that the palisading cells expressed HLA-D region antigens and the macrophage phenotype OKM 1 (8); moreover, these cells expressed the T helper cell markers Leu-3a and OKT4, which as others have found, are also expressed by macrophages (9). Thus, none of these markers are expressed exclusively by macrophages. Duke et a1 (10) confirmed that the palisade cells were HLA-D region-positive and that a further macrophage phenotype, FMC-17, was frequently expressed. However, the monoclonal antibody FMC-17 also shows weak reactivity with cells other than mononuclear phagocytes (1 1).We have extended these earlier observations by studying the distribution of cells that bear epitopes which not only specifically identify mononuclear phagocytes, but also reflect their maturational stage. In addition, we have demonstrated that the complement receptor for iC3b, but not that for C3b, is expressed by these cells.

The rheumatoid nodule

“…Hedfors et al first reported that these cells stained positively with anti-HLA-DR and OKMl antibodies, in the manner of macrophages (9). Similar results have since been obtained in 3 other laboratories, using other monocyte/macrophage-specific monoclonal antibodies and anti-HLA-DR antibody (7,8,10,11).…”

“…Palmer et a1 have observed that the majority of these large mononuclear cells carry a monocyte marker (7) and acquire a macrophage marker in the immediate vicinity of the palisaded layer (8). Almost all of these monocyte/macrophage-staining cells are also HLA-DR+ (8-1 1).…”

Changes in the phenotype of monocytes/macrophages and expression of cytokine mRNA in peripheral blood and synovial fluid of patients with rheumatoid arthritis

“…In rheumatoid nodules macrophages migrate towards a central necrotic focus [1]. Altered expression of macrophage surface molecules [1,2] and production of angiotensin converting enzyme (ACE) [3] and IL-l^S [4] provide evidence of macrophage activation.…”

“…In rheumatoid nodules macrophages migrate towards a central necrotic focus [1]. Altered expression of macrophage surface molecules [1,2] and production of angiotensin converting enzyme (ACE) [3] and IL-l^S [4] provide evidence of macrophage activation. The earliest foci of necrosis occur within small collections of macrophages characterized by sustained expression of the p8,14 molecule [5], a calcium binding dimer of unknown function [6].…”

From Pathology to Diagnosis: A Symptom-Free Patient with a Rheumatoid Nodule in the Foot

“…[8] Histologically, the RN is a granuloma in which activated macrophages are prominent. [9][10][11] Although RNs are not frequently encountered in RA patients, their existence strongly indicates RA diagnosis. In fact, Gossec et al [12] reported their diagnostic sensitivity as 2.4% and their specificity as 100%, and this is also true in cases of early RA.…”