Extract from New Study on Mast Cells

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This is fascinating stuff. Here, in my opinion, is what's behind CPPS in men and women. Yes, the nerves may be setting them off; yes, allergens or stress or exercise or chemicals may be activating them; but the Mighty Mast Cell is looking like the big player in the game. If we can get the nerves to stop activating them, the pain will disappear.

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Figure 1. The Mighty Mast Cell. (warning to dialup users: big graphic - 140Kb!!)

Extract from
The Mast Cell in Inflammatory Arthritis
David E. Woolley, Ph.D., D.Sc.

Rheumatoid arthritis is a chronic destructive disease of joints, characterized by inflammation, synovial hyperplasia, and abnormal cellular and humoral immune responses. Although several types of cells have been proposed to trigger synovial inflammation, the etiologic process and pathogenesis of the disease remain controversial. But, as indicated by a recent study by Lee et al., the mast cell is emerging as a key player in the erosive and inflammatory events leading to joint destruction (Fig. 1). The inflammatory processes that result in rheumatoid arthritis are multifactorial, involving complex interactions among the cytokine network, autoantibodies, and the complement cascade. Various mediators are purported to act on both immune and stromal cells, but the mast cell, on activation, releases an exceptionally broad range of potent effectors, including histamine, heparin, proteinases, cytokines, prostaglandins, and growth factors. The release of these effectors probably brings about changes in the microenvironment, such as the catabolic actions of neighboring cells. Work from my laboratory has demonstrated accumulations of mast cells in rheumatoid synovial tissues and has provided evidence of their activation and degradation, associated with proinflammatory cytokines and chondrolytic enzymes, at sites of cartilage erosion.

Lee et al. reported that mice that lack mast cells are resistant to inflammatory and erosive arthritis induced by arthritogenic serum, in contrast to control mice and formerly deficient mice that are engrafted with mast cells. They therefore proposed that the mast cell is a cellular link among autoantibodies, the complement network, and inflammatory mediators that give rise to erosive arthritis. If, as now seems likely, the activation of mast cells makes a pivotal contribution to inflammatory arthritis, how best to counter its activities? Four approaches would seem to hold promise: stabilization of mast cells, which involves raising the threshold for activation and degranulation; the use of antihistamines; the inhibition of mast-cell proteinases; and the use of agents that counter tumor necrosis factor a (TNF- a ).

Effective stabilization of synovial mast cells in vivo is problematic, since there is little information on the use of antiallergic drugs such as cromolyn sodium, ketotifen, and albuterol in rheumatoid arthritis. With respect to stability and other features, mast cells show marked heterogeneity from tissue to tissue, and yet little research has been conducted on mast cells from specific tissues. Pharmaceutical companies have mainly focused their efforts on mast cells derived from rats and mice, resulting in compounds that are ineffective in humans. And little is known of the effect on synovial mast cells of the drugs that are commonly used in the management of rheumatoid arthritis, such as corticosteroids and nonsteroidal antiinflammatory drugs. Although we have a poor understanding of how to control mastcell activation in vivo, an agent that achieves this remains a potential strategy for treating arthritis.

All mast cells express histidine decarboxylase -- the enzyme essential for histamine production -- and recent studies in my laboratory have demonstrated that in humans, articular chondrocytes produce both histidine decarboxylase and histamine, suggesting that cartilage-derived histamine, as well as that from mast cells, could contribute to the inflammatory processes in rheumatoid arthritis. Although mast-cell histamine is a recognized feature of various allergic conditions, resulting in numerous antihistamine compounds that antagonize histamine receptors, their use has not yet been seriously considered in arthritic disorders. In addition to attempts to counter the effects of histamine, pharmacologists are also researching ways of inhibiting the mast-cell proteinases tryptase and chymase.

Whether such an approach could counteract the effects of these enzymes in a specific microenvironment remains to be determined.

The realization that TNF- a has an important role in the inflammatory cytokine cascade led to the development of an anti--TNF- a antibody to treat rheumatoid arthritis. 4

Originally, it was thought that activated macrophages were probably the chief source of TNF- a in situ, but given the effectiveness of anti--TNF- a therapy in rheumatoid arthritis, it may also target the TNF- a derived from activated mast cells. Perhaps a similar immunotherapeutic approach targeting stem cell factor (also known as c-kit) or its receptor, which regulates the recruitment and maturation of mast cells, would be effective.

The biologic consequences of the activation and degranulation of mast cells in rheumatoid synovial tissue are extremely complex and depend on the release of various combinations of soluble and granular factors. At the moment, we have a poor understanding of the hierarchy of the agents released by the mast cell, but the rapid release of histamine will almost certainly induce localized tissue edema and disrupt the stromal matrix. The subsequent solubilization and release of factors from exocytosed granules would provide a temporally regulated supply of specific signals (such as those triggered by the cytokines TNF- a and interleukin-1) within the vicinity of the activated mast cell, leading to the erosion of cartilage. 5

It therefore seems likely that activated mast cells are a driving force in propagating microenvironmental inflammatory cycles, by recruiting other types of cells and inducing local proteolytic and cytokine activity. And so despite the fact that its ability to mediate inflammation was neglected for years, the mast cell and its products are now recognized as prime targets of therapy for rheumatoid arthritis.

From the University Department of Medicine, Manchester Royal Infirmary, Manchester, United Kingdom.

1. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002;297:1689-92.

2. Tetlow LC, Woolley DE. Mast cells, cytokines and metalloproteinases at the rheumatoid lesion: dual immunolocalisation studies. Ann Rheum Dis 1995;54:896-903.

3. He S, Gaca MDA, Walls AF. The activation of synovial mast cells: modulation of histamine release by tryptase and chymase and their inhibitors. Eur J Pharmacol 2001;412:223-9.

4. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nat Rev Immunol 2002;2:364-71.

5. Woolley DE, Tetlow LC. Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res 2000;2:65-74.