Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Neuronal ceroid lipofuscinosis wikipedia , lookup
Polycomb Group Proteins and Cancer wikipedia , lookup
Gene therapy of the human retina wikipedia , lookup
Site-specific recombinase technology wikipedia , lookup
X-inactivation wikipedia , lookup
Designer baby wikipedia , lookup
Vectors in gene therapy wikipedia , lookup
EDITORIAL Eur Respir J 1989, 2, 921-922 Asthma: an inherited dysfunction of bone marrow cells? ·r . Higenbottam, The pathogenic mechanisms in bronchial asthma are complex, and the many inflammatory mediator cascades [1-4] fail to explain all the characteristics of the disease. Notably, they do not encompass familial inheritance, development of immediate hypersensitivity and airway inflammation. However, over the last year detailed epidemiological, genetic and molecular biological studies have begun to point to a unitary hypothesis which involves immunoglobulin E (JgE) hyperresponsiveness. Using skin tests and radioallergosorbent tests (RAST) for specific IgE to define atopy, CooKSON and HoPKIN [5] demonstrated that atopic status is an autosomally dominant inherited trait. Ninety percent of atopic asthmatics had at least one atopic parent. By use of modem genetic linkage analysis, these workers [6) identified a gene locus on chromosome llq in individuals who have decisive IgE hyperresponsiveness. Thus, 85% of those with this gene had symptoms of atopy, 60% had wheeze and 20% had been diagnosed as asthmatic. To provide a clue to the role of this gene, chromosome llq is known to carry a number of genes for cell surface antigens, some of which occur on T-lymphocytes. This tendency to lgE hyperrcsponsiveness and to asthma can be transmitted in bone marrow transplants. AaosTt et al. [7] showed that positive skin tests to specific allergens can be transmitted from donors to recipients of allogenic bone marrow transplants as can asthma itself. The effect extended beyond one year, suggesting that proliferating cells from the donor bone marrow were responsible for specific IgE hyperrcsponsiveness and asthma in the recipient. These observations on atopic asthma are important because it has recently been realized that there may be no distinction between extrinsic (atopic) and intrinsic asthma [8]. In a large scale epidemological study, BURRows et al. [8] showed that the tendency to asthma is correlated with a high IgE level, whilst rhinitis is associated with positive skin tests. They therefore questioned the need to distinguish between intrinsic and extrinsic asthma, arguing that both have a common mechanism associated with IgE hyperresponsiveness. IgE production by B-lymphocytes appears to be controlled by a cytokine (leucocyte regulatory peptide) called intcrlcukin-4 (IL-4), which may be elaborated and released by a subset of T-lymphocyte helper cells [9]. In • Dept of Respiratory Physiology, Papwonh Hospital, Cambridge Cl33 8RE, U.K . N. Varma addition to regulatory IgE production, IL-4 may play an important role in locating mast cells within the mucosa. The final element in this unitary hypothesis of asthma, is the role of the mast cell in regulating the development of airway inflammation. Inflammation is considered by many [10] to be important in causing the manifestation of airway narrowing and bronchial hyperresponsiveness. When the specific allergen reacts with its high affinity IgE receptor on a mast cell, a number of powerful haemopoietic growth factors are released. They include granulocyte/macrophage colony stimulatory factor (GMCSF) and IL-3 [11], which appear able to recruit, prime and activate inflammatory cells such as neutrophils, macrophagcs and eosinophils as well as to stimulate bone marrow production. From these observations, we can perhaps conclude that asthma may not specifically be a disease of the lungs. Instead, it could be a dysfunction of a bone marrow cell, probably of a lymphocyte subset. This dysfunction is an autosomally dominant inherited trait and can lead to IgE hypcrresponsiveness. Much still remains unexplained, but a unitary theory encompassing many of the important characteristics of asthma is now available. This could not only revolutionize our understanding, but could also lead to new therapeutic approaches which do not rely on antagonizing secondary mediators [12]. References 1. Cuss FM, Dixon CMS. Barnes PJ. - Effects of inhaled platelet activating factor on pulmonary function and bronchial responsiveness in man. Lancet, 1986, ii, 189- 192. 2. Ann JP, Spur BW, Lee TH. - The effects of inhaled leucotriene E4 on the airways responsiveness to histamine in asthmatics and normal subjects. J Allergy Clin lmmunol, 1988, 82, 654-660. 3. Hardy CC, Bradding P, Robinson C, et al. - The combined effects of two pairs of mediators. adenosine with methacholine and prostaglandin Dl...with histamine on airway calibre in asthma. Clin Sci, 1986, ll, 385- 392. 4. Said SI. - Vasoactive intestinal polypeptide and astluna. N Engl 1 Med, 1989, 320, 1271-1273. 5. Cookson WOCM, Hopkin JM. - Dominant inheritance of immunmoglobulin-E responsiveness. Lancet, 1988, i, 86-87. 6. Cookson WOCM, Sharp P, Faux J, Hopkin J. - Linkage between immunoglobulin-E responses underlying asthma and rhinitis and chromosome llq. Lancet, 1989, i, 1292-1294. 7. Agosli JM, Sprenger ID, Lum LG, et al. - Transfer of allergen-specific IgE-mediated hypersensitivity with allogenic 922 T. HIGENBOTTAM, N. VARMA bone marrow transplants. N Engl J Med, 1988,319, 1623-1628. 8. Burrows B, Martinez FD, Halonen M, et al. - Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med, 1989, 320, 27 1- 277. 9. Snapper CM, Finkelman FD, Paul WE. - Regulation of IgG and IgE production by intcrlcukin-4. lmmwwl Rev, 1988, 102, 49-75. 10. Beasley R, Roche WR, Roberts JA, Holgate ST. - Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis. 1989, 139, 806-817. 11., Wodnar-Filipowicz A, Heusscr CH, MoroniC.- Production of the haemopoietic growth factors GM -CSP and intcrleuk.in-3 by mast cells in response to lgE receptor mediated activation. Nature, 1989, 339, 150-152. 12. Editorial. - PAF antagonists in asthma. Lancet, 1989, i, 592-593.