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

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. 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: Comparing rates of death from asthma to tuberculosis in 10 countries where asthma prevalence has been documented by ISAAC ( 1 )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.