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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
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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
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6. Cookson WOCM, Sharp P, Faux J, Hopkin J. - Linkage
between immunoglobulin-E responses underlying asthma and
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7. Agosli JM, Sprenger ID, Lum LG, et al. - Transfer of
allergen-specific IgE-mediated hypersensitivity with allogenic
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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,
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10. Beasley R, Roche WR, Roberts JA, Holgate ST. - Cellular
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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,
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