Mast cells in the pathogenesis of rheumatic diseases and as potential targets for anti‐rheumatic therapy

Abstract

Increasing evidence suggests that mast cells (MCs), in addition to acute allergic reactions, are involved in the pathogenesis of chronic inflammatory diseases and in particular in rheumatoid arthritis (RA). MCs reside in connective tissues and in synovial tissue of joints. They produce an array of proinflammatory mediators, tissue destructive proteases, and cytokines, most prominently tumor necrosis factor-alpha, which is one of the key cytokines in the pathogenesis of RA. MCs may also participate in the development of secondary or amyloid A amyloidosis, as the partial degradation of the serum amyloid A (SAA) protein by MCs leads to the generation of a highly amyloidogenic N-terminal fragment of SAA. MCs may contribute to the pathogenesis of connective tissue diseases, scleroderma, vasculitic syndromes, and systemic lupus erythematosus, although the data available are limited. Inhibition of the most important growth factor receptor of human MCs, c-Kit, by the selective tyrosine kinase inhibitor imatinib mesylate, induces apoptosis of synovial tissue MCs. As MCs are long-lived cells, induction of their apoptosis could be a feasible approach to inhibit their functions. Preliminary findings suggest that a drug that inhibits c-Kit could have anti-rheumatic activity in the treatment of patients with RA and spondyloarthropathies.

JNK1 controls mast cell degranulation and IL-1β production in inflammatory arthritis

“…Consistent with their activation in the context of arthritis, granule exocytosis was documented in less than 1% of MCs from normal joint tissue, but was seen in 10-15% of MCs in RA synovium (15). These data are consistent with presence of the contents of MC granules, including tumor necrosis factor (TNF) and IL-17A, in synovial fluid (14,18). The triggers of synovial MC activation in human arthritis remain speculative, but one plausible mechanism is engagement of receptors for IgG Fcγ receptors (FcγRs), given the prevalence of circulating IgG autoantibodies in RA and their presence in synovial immune complexes (14,15,19).…”

“…In addition to type A and B synoviocytes, mast cells (MCs) are present in both the normal and inflamed synovial tissue of joints in relatively high numbers (14,15). Although found throughout synovial tissue, MCs are often located in the vicinity of nerves and around blood vessels, where they are positioned to initiate inflammatory reactions, activate endothelial cells, and recruit other immune and inflammatory cells to the joint.…”

Interleukin‐17–positive mast cells contribute to synovial inflammation in spondylarthritis

“…[12][13][14]. Analysis of tissue specimens obtained during joint replacement surgery indicated a 6-25-fold increase in the number of mast cells in RA patients as compared to patients with osteoarthritis.…”

“…It has been established that synovial mast cells degranulate to a limited extent in RA synovitis (12)(13)(14), as histamine and tryptase are readily detectable in the synovial fluid. The synovial fluid levels of these mediators were not increased in patients with SpA compared to patients with RA, suggesting that, if anything, the degree of degranulation would, rather, be decreased in SpA.…”

The mouse mast cell–restricted tetramer‐forming tryptases mouse mast cell protease 6 and mouse mast cell protease 7 are critical mediators in inflammatory arthritis

“…Numerous cellular participants of innate and adaptive immunity contribute to the pronounced inflammatory processes seen in rheumatoid synovitis. Our group (1)(2)(3)(4) and many other investigators (5)(6)(7)(8)(9)(10)(11)(12)(13)(14) have obtained data implicating a prominent involvement of mast cells (MCs) and their mediators in RA and some animal models of this autoimmune disorder. On a weight basis, tetramer-forming ␤ tryptases (15)(16)(17)(18)(19) are the most abundant proteins present in the secretory granules of human MCs.…”