Q J Med 2003; 96: 691-692
© 2003 Association of Physicians
Biologic |
Decus et Tutamen
It is a truism to say that most of our interaction with the environment depend on surface contacts of one kind or another. The nature of many of the interactions of any individual with his or her environment depend on the skin, and thus we come to a critical argument against adopting the Euro.
The amount of nickel is regulated in products that come into prolonged or repeated contact with the skin, because of the contact allergies produced. One- and two-euro coins induce positive skin-test reactions in sensitive individuals, and remarkably, release 240–320 times more nickel than is allowed in the European Union Nickel Directive.1 The electrode potential between the two metals that form the coins is an important part of the sweat-related galvanic release of nickel that occurs. The authors of this study (from Switzerland)1 point out that the effect is not seen with the Swiss franc, which contains 25% nickel but which is, of course, a more dependable currency.
The law of unintended consequences has played an important part in a number of discoveries (notably with many valuable side-effects of drugs) and is one of the most potent arguments to be deployed against the use of the Precautionary Principle in regulation. What is self-evident on the basis of limited data often turns out to be wrong: it was evident to all that air bags in cars would save lives but, alas, only clear after a number of deaths in children, that the argument could not be universally deployed. It is an understanding of the mechanisms leading to effects or events that offers the best protection against errors of this sort. The Paneth cell had no function when I was a boy; it was supposed that it did something ‘trophic’ for the crypts, much as the thymus was thought to ‘support’ lymphocytes until 1960. By 1964 I was doing neonatal thymectomies as part of an MD thesis on opportunistic infection. When things move they often happen fast in our discipline, but in the field of non-specific immune functions, things have hung fire a bit. However, important pieces of information are coming together.
Most infectious agents enter the body by crossing an epithelial surface, most commonly those of the skin, or the respiratory or alimentary tracts. Like most cells in organized tissue, the cells that make up these surfaces are polarized, with apical and basal domains that have different capabilities. The cells in these surfaces are linked by tight junctions that surround the cells like rings on a piston, and which may themselves be specialized in some sites (e.g. the urinary bladder). Their role in maintaining the integrity of the epithelium and in preventing penetration of the surface by macromolecules or organisms is an important one, and is calcium-dependent. That the maintenance of the integrity of these surfaces is important is a point clearly understood by any one who waits for to wounds heal or by those who work in burns units, for example. How is it done? By a surprisingly simple mechanism, only recently elucidated.
When a surface of this kind is breached it is erbB2 (a receptor in the plasma membrane that promotes cell proliferation) that becomes critical. Binding of a ligand to the extracellular portion of the receptor activates the intracellular part (a tyrosine kinase), and this sets off a signalling cascade leading to cell division. Vermeer et al.2 have shown that the ligand that is bound is heregulin, and that it is produced by epithelial cells themselves, with a potential for setting off self-stimulation of cell proliferation. What stops this from happening all the time is the polarization described above; heregulin is normally anchored to the outer surface of the cell membrane. With intact tight junctions, none of that small amount of the ligand that is released in to the respiratory tract, say, will reach the erbB2 on the non-surface aspects of the cell, and cell division is suppressed. Once the surface is breached, ligand and receptor interact. Vermeer and colleagues have found that specific antibodies to heregulin or the receptor prevent this response. The calcium-dependent nature of the tight junction capability is demonstrated by the observation that calcium removal may mimic the diffuse epithelial injury seen in smoking-related bronchitis.
However, this is not the whole story in terms of the intrinsic defence mechanisms of epithelial surfaces. In the gut, defensins, a family of structurally related antimicrobial peptides, are an important part of this local shield against the establishment of systemic infection. Paneth cells, most abundant in the jejunum and ileum, produce a number of defensins, and help to maintain the relative sterility of the small bowel when compared with the colon. In a series of experiments, Salzman et al.3 have shown that transgenic mice who make human defensin in their Paneth cells are resistant to infection by S. typhimurium. Human defensins are much more effective against the organism than those produced by mouse Paneth cells. This is a local effect; there is evidence of a thousand-fold reduction in bacterial numbers within 6–12 h after infection by the oral route, but there is no protective effect if organisms are injected intra-peritoneally.
In other studies, mice who were made deficient in their capacity to produce CRAMP (cathelin-related anti microbial peptide) were found to be more susceptible to skin infections by group A streptococci. Mice defective in the metalloprotinase matrilysin (an enzyme involved in the production of defensins in the gut) are also susceptible to Salmonella. Defensins are also found in neutrophils in man: they are secreted in the urine, made in infected skin and together with well-studied agents such as lysozyme and secretory phospholipase A, are an important part of what is sometimes called innate immunity.
Ganz4 has suggested that differences between particular species in terms of their susceptibility to particular infectious agents may depend on this type of immune function (as is well demonstrated in the S. typhimurium example). This has generated an interest in the use of these defence-related peptides in the therapy of human disease. What we need to find is the animal that has an effective anti-SARS mechanism in the respiratory tract—it will probably be a lot easier than finding a pan-antiviral agent or a reliable vaccine.
References
1. Nestle FO, Speidel H, Speidel MO. Metallurgy: high nickel release from 1- and 2-euro coins. Nature 2002; 419:132.[Medline]
2. Vermeer PD, Einwalter LA, et al. Segregation of receptor and ligand regulates activation of epithelial growth factor receptor. Nature 2003; 422:322–6.[CrossRef][Medline]
3. Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL. Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin. Nature 2003; 422:522–6.[CrossRef][Medline]
4. Ganz T. Gut defence. Nature 2003; 422:478–9.[CrossRef][Medline]
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