Skip Navigation LinksHome > May/June 2002 - Volume 34 - Issue > The Cause of Th2 to Th1 Imbalance in Asthma: A Function of E...
Journal of Pediatric Gastroenterology & Nutrition:
Article

The Cause of Th2 to Th1 Imbalance in Asthma: A Function of Exposure to Typhoid and Tuberculosis?

Jones, Peter D.

Free Access
Article Outline
Collapse Box

Author Information

Senior Lecturer in Pediatrics and Child Health, University of Newcastle, John Hunter Children's Hospital, New South Wales, Australia

University of Newcastle, John Hunter Children's Hospital, Locked Bag 1, Hunter Region Mail Centre, NSW 2310, New South Wales, Australia (e-mail: pjones@mail.newcastle.edu.au).

The prevalence of asthma varies from country to country, from a low of 2% to a high of 30% (1). The reasons for this extreme variation in asthma prevalence are unclear. Investigation of exposure to environmental triggers such as allergens and air pollution (2) yields inconsistent and confusing results. Paradoxically, in Mexico and Eastern Europe, which have an increased level of air pollution, the prevalence of asthma is very low. However, in the South Island of New Zealand, the air quality is good and asthma prevalence is very high. In this article, we will review some current concepts in asthma and use global epidemiologic information available through the World Health (WHO) to propose a theory to explain these phenomena.

Atopic asthma is now recognized as an inflammatory disease of the airways driven by a Th2-lymphocyte response, interleukin-4 and interleukin-5 secretion, and consequent eosinophilic infiltration (3). This contrasts with normal airways in which, despite exposure to allergens, a Th1-lymphocyte response predominates, with the release of interferon-γ that down-regulates the Th2 response (4). Maintaining pregnancy and early fetal and infant life requires a predominantly Th2-lymphocyte response (5). For the majority of the world's population, ex-utero exposure and maturation is associated with a switch to a Th1-lymphocyte response (6). Alterations in the Th2 to Th1 switch during early infancy may explain the marked geographic variations in asthma prevalence. Either exposures in countries with high asthma prevalence encourage the persistence of the Th2 response or exposures in countries with low asthma prevalence promote the development of a Th1 response.

If the current theory is correct, in countries in which asthma is uncommon, the majority of the population would have a predominance of Th1 lymphocytes. What are the possible advantages of a Th1 response? A Th1-lymphocyte response would be advantageous in controlling tuberculosis, typhoid, and enteric infections (7). Interferon-γ released by Th1 lymphocytes is vital in localizing primary tuberculosis.

Evidence for this comes from the experience of patients in whom disseminated tuberculosis develops after exposure to oral steroids. Steroids suppress the activity of Th1 lymphocytes, which in the presence of primary tuberculosis leads to disseminated disease. A Th1 response probably is vital in the cell-mediated immune response to typhoid and enteric infections (7). Furthermore, in developing countries, children are exposed to repeated enteric infections during infancy (8), and this may be responsible for the switch from a Th2-lymphocyte response to a Th1 response. A Th2-type response in an environment of repeated gut infection may cause the nonspecific enteropathy seen in children with chronic diarrhea and malnutrition in the developing world.

A Th1 response in such an environment would lead to less intestinal damage from repeated exposure to enteric pathogens, an advantage in a community with either a high prevalence of enteric infections or tuberculosis. In such communities, we should see a low prevalence of asthma.

Back to Top | Article Outline

THE WORLD HEALTH ORGANIZATION AND ISAAC

The evidence to support this hypothesis can be found by reviewing the WHO statistics on causes of death (9), the results of the ISAAC (1) study, and the WHO guidelines on travel and vaccination requirements (10). Table 1 (11) shows the ratio of deaths from asthma compared with deaths from tuberculosis in 10 countries with recent information about the prevalence of asthma, documented by ISAAC. In countries with a high prevalence of asthma, the ratio of asthma deaths compared with tuberculosis deaths increases 5- to 10-fold. Typhoid fever is an important infection and is endemic in each of the countries in which asthma prevalence is low. Vaccination against typhoid is recommended in countries with a low prevalence of asthma.

Table 1
Table 1
Image Tools

This means efforts to decrease the disease burden of asthma will be most effective if the immune system can be guided to respond in a Th1 manner. At this stage, there is some research into the potential benefits of BCG vaccine (4). Exposure to other attenuated enteric infections such as typhoid also may be a potential avenue of researching triggers that determine the way lymphocytes respond.

In developed countries with very low rates of infection such as typhoid and tuberculosis, there may be no survival advantage of lymphocytes switching to a Th1 response. In the WHO guidelines (12), travelers from outside of Oceania should not be concerned about an increased risk of infection. The relatively infection-free environment may be responsible for Australia and New Zealand's dubious honor of having the highest prevalence of asthma in the world. In the future, decreasing the burden of atopic disease in the developed world may involve developing “vaccines” that would allow for a series of controlled infections to occur throughout infancy to promote a Th1-predominant response. This in turn would then lead to a decreased burden of atopic diseases and asthma in the developed world.

Back to Top | Article Outline

REFERENCES

1. Beasley R, Mutius EV, Pearce N. Worldwide variation in the prevalence of symptoms of asthma, allergic conjunctivitis, and atopic asthma: ISAAC. Lancet 1998; 351:1225–32.

2. Rennick GJ, Jarman FC. Are children with asthma affected by smog? Med J Aust 1992; 156:837–9.

3. Sur S, Gleich GJ, Swanson MC, et al. Eosinophilic inflammation is associated with the elevation of interleukin-5 in the airways of patients with spontaneous symptomatic asthma. J Allergy Clin Immunol 1995; 96:661–8.

4. Holt PG, Sly PD. Breaking the nexus between asthma and atopy. Med J Aust 1998; 169:354–5.

5. Wegmenn TG, Lin H, Guilbert L, et al. Bi-directional cytokine interactions the maternal-fetal relationship: is successful pregnancy a Th2 phenomenon? Immunol Today 1993; 14;353–6.

6. Holt PG. Primary allergic sensitisation to environmental antigens: perinatal T-cell priming as a determinant of responder type in adulthood. J Exp Med 1996; 183:1297–301.

7. Mandal BK. Salmonella Infections in Manson's Tropical Diseases. 12th ed. Cook GC, ed, WB Saunders; 1996:849–63.

8. Wharton BA. Gastroenterological problems in developing countries. In: Anderson CM, Burke V, eds. Paediatric Gastroenterology, Oxford: Blackwell; 1975

9. Walker-Smith JA. Intractable Diarrhoea. In Walker-Smith JA, ed. Diseases of the Small Intestine of Childhood. 3rd ed. Butterworth; 1988:390–414.

10. World Health Organization. World Health Annual Statistics. Geneva: World Health Organisation; 1994.

11. Jones PD, Gibson PG, Henry RL. The prevalence of asthma appears to be inversely related to the incidence of typhoid and tuberculosis. An hypothesis to explain the variation in asthma prevalence around the world. J Med Hypoth 2000; 55:40–42.

12. World Health Organization. International Travel and Health. Vaccination Requirements and Health Advice, World Health Organisation. Geneva: World Health Organization; 1996.

© 2002 Lippincott Williams & Wilkins, Inc.

Login

Article Tools

Images

Share

Connect With Us

 

 

Twitter

twitter.com/JPGNonline

 

Visit JPGN.org on your smartphone. Scan this code (QR reader app required) with your phone and be taken directly to the site.