Scientific rationale for the Finnish Allergy Programme 2008-2018: emphasis on prevention and endorsing tolerance.

In similarity to many other western countries, the burden of allergic diseases in Finland is high. Studies worldwide have shown that an environment rich in microbes in early life reduces the subsequent risk of developing allergic diseases. Along with urbanization, such exposure has dramatically reduced, both in terms of diversity and quantity. Continuous stimulation of the immune system by environmental saprophytes via the skin, respiratory tract and gut appears to be necessary for activation of the regulatory network including regulatory T-cells and dendritic cells. Substantial evidence now shows that the balance between allergy and tolerance is dependent on regulatory T-cells. Tolerance induced by allergen-specific regulatory T-cells appears to be the normal immunological response to allergens in non atopic healthy individuals. Healthy subjects have an intact functional allergen-specific regulatory T-cell response, which in allergic subjects is impaired. Evidence on this exists with respect to atopic dermatitis, contact dermatitis, allergic rhinitis and asthma. Restoration of impaired allergen-specific regulatory T-cell response and tolerance induction has furthermore been demonstrated during allergen-specific subcutaneous and sublingual immunotherapy and is crucial for good therapeutic outcome. However, tolerance can also be strengthened unspecifically by simple means, e.g. by consuming farm milk and spending time in nature. Results so far obtained from animal models indicate that it is possible to restore tolerance by administering the allergen in certain circumstances both locally and systemically. It has become increasingly clear that continuous exposure to microbial antigens as well as allergens in foodstuffs and the environment is decisive, and excessive antigen avoidance can be harmful and weaken or even prevent the development of regulatory mechanisms. Success in the Finnish Asthma Programme was an encouraging example of how it is possible to reduce both the costs and morbidity of asthma. The time, in the wake of the Asthma Programme, is now opportune for a national allergy programme, particularly as in the past few years, fundamentally more essential data on tolerance and its mechanisms have been published. In this review, the scientific rationale for the Finnish Allergy Programme 2008-2018 is outlined. The focus is on tolerance and how to endorse tolerance at the population level.

Asthma and atopy - the price of affluence?

Irrespective of improved knowledge of many aspects of atopic diseases, the unfavorable trends in their prevalence particularly among children could not have been reversed. A growing body of evidence suggests that something may lack from our societal affluence that has the capacity to provide protection against the development of atopic diseases. Much attention during the last years has been devoted to the hygiene hypothesis. This review outlines the impact of environment and lifestyle, particularly from the perspective of the East-West gradient, on the development of atopic diseases, with a special emphasis on the hygiene hypothesis in its broadest sense.

Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae.

Conventional risk factors have been unable to explain most of the substantial increase in the prevalence of asthma observed in many countries during the last few decades. Much attention has been directed at the "hygiene hypothesis", the apparent inverse relationship between intense systemic childhood infections and the subsequent development of asthma and atopy. However, it is not only the absence or scarcity of infections, but the prolonged presence of certain microorganisms in the lungs that may be involved in the development of asthma. Accumulating evidence suggests that Chlamydia pneumoniae, an intracellular ubiquitous pathogen with an innate propensity to persist and cause chronic infections, may be associated with asthma. This microorganism can achieve a state of "latency" in which it is viable but dormant and does not multiply. During this state, however, chlamydia continues to synthesize the "stress" protein, a 60-kDa heat shock protein (hsp60). This protein is able to elicit a strong host inflammatory response at sites of its production and appears to be involved in tissue injury and scarring processes. As inflammation has been found to be present in almost all asthmatics, whatever the severity and aetiology of the disease, inhaled glucocorticoids now have an established position in the treatment of early stages. However, corticosteroids negatively affect many aspects of cell-mediated immunity and favour the shift from a T-helper-1-type response towards a T-helper-2-type response. Corticosteroids may thus severely deteriorate the host's ability to eradicate an intracellular pathogen, such as Chlamydia pneumoniae, which requires a properly functioning cell-mediated (T-helper-1-type) immune response to be cleared. These drugs are also able to reactivate persistent Chlamydia to an active growth phase, which, by increasing the production of pro-inflammatory cytokines at the site of infection, can further amplify inflammation in the airways of patients with asthma.

Puzzling associations between childhood infections and the later occurrence of asthma and atopy.

The current unfavourable trends in asthma and atopy prevalences have raised great concern and have challenged investigators to accelerate search for new risk factors for atopic diseases. The lack or scarcity of intense, systemic infections in early life has been postulated to increase susceptibility of becoming sensitized to otherwise harmless allergens in later life. This hygiene hypothesis is considered one of the most plausible explanations for the current trends in atopic diseases to date. There are data to suggest that measles, hepatitis A, and Mycobacterium tuberculosis infection in early life may prevent the subsequent development of atopic diseases. The hypothesis is based on the concept that certain viral and bacterial infections, which induce a strongly polarized T helper (Th)-1 type response and a long-lasting memory immunity, are in early life able to reverse or prevent the biased Th1/Th2 balance in individuals prone to atopy and asthma. Evidence for the ability of mycobacterial infections to alter the Th1/Th2 balance has also been obtained from murine models. In humans, the critical time period during which immunomodulation with long-lasting effects is considered most successful is within the first two years of life. Possibly also nonpathogenic residents of the intestinal mucosa are involved in the proper maturation of the immune system. The use of antibiotics has been shown to be positively associated with the development of asthma and atopy. The mechanisms underlying these associations remain largely unknown.

Chlamydia pneumoniae and its role in chronic obstructive pulmonary disease.

The diverging of T-helper (Th) cells into predominantly Th1 and Th2 subsets on the basis of their cytokine profiles has decisively improved our understanding of the pathogenesis of many chronic infectious diseases. Recent data suggest that the presence of interferon-gamma and the subsequent suppression of interleukin-4 production leads to a Th1-type response that is required for the resolution of infections caused by intracellular pathogens. The ability of the macrophages to respond aggressively during early antigen contact seems to be one crucial factor in the development of an appropriate Th-cell response. Several host-related factors can affect macrophage function and the polarization of T-cell responses, ie the shift from a Th1 response to a Th2 one, and thus dramatically deteriorate the resolution of infections caused by intracellular agents such as Chlamydia pneumoniae. Chronic C. pneumoniae infection has been associated with several common chronic diseases, quite recently with chronic obstructive pulmonary disease. Chronic C. pneumoniae infection may amplify smoking-associated inflammation in the bronchi and may be a contributory factor in the development of irreversible pathological changes.