Mast cells in inflammatory arthritis

Abstract

Mast cells are present in limited numbers in normal human synovium, but in rheumatoid arthritis and other inflammatory joint diseases this population can expand to constitute 5% or more of all synovial cells. Recent investigations in a murine model have demonstrated that mast cells can have a critical role in the generation of inflammation within the joint. This finding highlights the results of more than 20 years of research indicating that mast cells are frequent participants in non-allergic immune responses as well as in allergy. Equipped with a diversity of surface receptors and effector capabilities, mast cells are sentinels of the immune system, detecting and delivering a first response to invading bacteria and other insults. Accumulating within inflamed tissues, mast cells produce cytokines and other mediators that may contribute vitally to ongoing inflammation. Here we review some of the non-allergic functions of mast cells and focus on the potential role of these cells in murine and human inflammatory arthritis.

Figure 1

Mast cells within the rheumatoid synovium. Shown is fixed, paraffin-embedded synovial tissue obtained during arthroplasty from a patient with chronic rheumatoid arthritis. This tissue was stained with safranin-O, which labels mast cell granule proteoglycans red, and counterstained with hematoxylin. Note the frequent safranin-O-positive mast cells present within the synovial sublining (several indicated with arrows). A fold of thickened synovial lining is seen at the bottom left of the image (outlined with a dotted line) and a blood vessel (BV) is visible in the middle of the field, with erythrocytes staining blue. (Section 5 μm thick; original magnification ×400.)

Figure 2

Mast cells constitute a critical pathogenic link in K/BxN serum transfer arthritis. Compared with wild-type controls, mast-cell-deficient W/W^v mice injected with K/BxN arthritogenic serum are resistant to the development of arthritis. After reconstitution with cultured wild-type mast cells, but not sham reconstitution, normal susceptibility is restored. Error bars = SEM. (Adapted from reference [1], with permission.)

Figure 3

Candidate proinflammatory functions of mast cells in synovitis. Mast cell effector functions suggest their participation in diverse pathogenic pathways in inflammatory arthritis, including leukocyte recruitment and activation, synovial fibroblast activation and hyperplasia, angiogenesis, and cartilage and bone destruction. Activated mast cells elaborate mediators potently capable of enhancing vasopermeability, inducing endothelial expression of adhesion molecules, recruiting circulating leukocytes, and activating infiltrating leukocytes as well as resident macrophages, thereby contributing to the early phases of inflammatory arthritis. In chronic synovitis, mast cells synthesize mitogens and cytokines that activate synovial fibroblasts, recruit macrophages, and promote the growth of new blood vessels, implicating them in synovial lining hyperplasia and pannus formation. Further, mast cells may participate in joint destruction by the induction of matrix metalloproteinases (MMPs) from fibroblasts, by activation of chondrocytes, and by direct and indirect promotion of osteoclast differentiation and activation. Because activated synovial fibroblasts demonstrate enhanced stem cell factor (SCF) expression, a potentially important positive feedback loop is established in which SCF promotes mast cell survival and proliferation, leading to the mastocytosis described in inflamed synovium. Note that the importance of these candidate pathways in vivo remains to be established. See text for details and references. bFGF, basic fibroblast growth factor; IFN, interferon; IL, interleukin; MCP, monocyte chemoattractant protein; M-CSF, macrophage colony-stimulating factor; MIP, macrophage inflammatory protein; PDGF, platelet-derived growth factor; PMN, polymorphonuclear cell; RANK-L, receptor activator of NF-κB ligand; TNF, tumor necrosis factor. (Graphic design by Steve Moskowitz.)