Saturday, June 10, 2023
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Chairman, Department of Pediatrics, National Jewish Medical and Research Center; Professor of Pediatrics and Immunology, University of Colorado, Denver, Colorado
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At a seminar during the 60th Anniversary Meeting of the American Academy of Allergy, Asthma and Immunology, Adnan Custovic, MD, PhD,[1] of Wythenshawe Hospital, North West Ling Centre, Manchester, United Kingdom, and Erika von Mutius, MD, MSc,[2] of Munich University Children's Hospital, Munich, Germany, discussed the pros and cons of the hygiene hypothesis for asthma.
Before approaching the controversy that surrounds the hygiene hypothesis for asthma, several factors must be considered. First, asthma prevalence has increased significantly, doubling each decade for the last 2 to 3 decades. Second, this increase appears to be relatively recent, beginning 3 to 4 decades ago. Third, the hygiene hypothesis must be distinguished in terms of whether one is addressing asthma or atopy. Although there are associations between asthma and atopy, they are not interchangeable. Fourth, the observed increases in this prevalence of asthma and atopy cannot be genetic in origin. Finally, lifestyles have changed in many ways, adding to the complexity of the associations.
It is thought that the hygiene hypothesis emerged from the early studies reporting an inverse association between family size and manifestations of atopy in early life to childhood.[3,4] These findings, coupled with changing patterns of microbial exposure, the decline in naturally occurring infectious diseases, or some vaccinations (eg, against tuberculosis), form the background for the hypothesis. Even with the reports of reduced atopy in large subships, there are considerable discrepancies between studies, and the strength of the relationships, if present, is with atopy and less so with asthma.
Exposure to microbes, through active infection or in the absence of infection, may initiate protective responses.[5] In the absence of infection, both viable and nonviable components or fragments of a broad range of micro-organisms found at different concentrations in different environments may be involved. These microbial derivatives, which are primarily recognized by the innate immune system (as opposed to T-cell-specific adaptive immunity), may drive protective responses, especially at the cytokine level. This exposure to microbial derivatives may play a critical role in the shaping of the immune response when encountered at important stages during the maturation of immune responses. This could result in the development of immune tolerance to potential allergens. A major basis for the hypothesis is that improved hygienic conditions in Western or developed countries results in less infection-driven or microbial pressure during early but critical time periods in early childhood. This change in pressure, in turn, results in an important failure to maintain an optimal balance between the 2 opposing T-helper cell responses when cytokine profiles are examined -- the Th1 and Th2 responses. Th1 responses are dominated by interferon (IFN)-gamma and interleukin (IL)-12 production, whereas Th2 responses are primarily associated with IL-4, IL-5, IL-13 (and IL-10) production. In association with reductions or altered exposures to infectious agents or their components, it is proposed that Th2 immunity, predominating from birth, dominates through critical childhood periods, resulting in the higher incidence of atopy and asthma. Several studies have advanced the theory that fecal contamination of the environment (and possibly infections such as hepatitis A), and unhygienic food handling may similarly protect against development of atopy. Intestinal microflora could also exert a continuous stimulation of the immune system, resulting in immune polarization -- the cleaner the intestine or the nature of colonization of the intestine, the more Th2-driven is the immune response.
Much of the hygiene hypothesis rests on the theory that atopy/asthma is Th2-driven and that there is an imbalance between Th1 and Th2 immunity. At one level, the data support this imbalance. Atopic individuals do show an increase in IL-4, IL-5, IL-13, immunoglobulin (Ig) E antibody responses, immediate skin test reactivity, and decreases in IFN-gamma. Whether atopy results from decreased bacteria exposure is unclear. It is also unclear if asthma is simply a Th2 disease or whether Th1 cells also play a role in the development of the disease, further distinguishing asthma from atopy. Surprisingly, parasitic infections in areas of the developing world have also appeared to exhibit protective effects, despite heightened Th2 immunity.
Lower prevalences of allergic diseases are described in rural areas of Africa and China. Similar urban-rural differences have not been seen in Europe or North America. Nonetheless, there are strong differences within rural areas showing clear differences in the incidence of atopy, asthma, and hay fever in children growing up on dairy farms compared with nonfarm children. Corroborative studies have emerged in Germany, Austria, Canada, and Australia. The source of the protective effects is not clear. Exposure to microbial substances in stables and unpasteurized (raw) milk inversely relate to development of atopy.[6] The role of bacterial products is under intense investigation. Initial enthusiasm focused on a major product from Gram-negative bacteria, lipopolysaccharide (LPS) or endotoxin, as levels were found to be much higher within the environment of farming families than in nonfarming surroundings.[7] Levels of LPS exposure were negatively related to the prevalence of atopy, hay fever, and even atopic asthma, although to a lower degree. LPS, interacting through CD14 and toll-like receptor (TLR) 4, is a major stimulus of Th1 immunity. In evaluating the role of endotoxin, the relationship between exposure and aggravation or protection from allergy and asthma is a very complex one. On one hand, the potential of Th1-inducers like endotoxin to reduce asthma and allergy is consistent with and provides support for the hygiene hypothesis. On the other hand, endotoxin exposure may play a central role in determining the severity in asthma as well.[7] For example, in occupational asthma, endotoxin exposure induces airflow obstruction and neutrophil inflammation, even in nonasthmatics. Asthmatics are hypersensitive to endotoxin exposure, and low levels can markedly augment the inflammatory response to allergen exposure in sensitized subjects. Higher house dust endotoxin levels are associated with increased wheezing in the first year of life.
To reconcile this apparent paradox between harmful and beneficial effects of endotoxin in the context of atopy and asthma, several theories have been offered. They focus on the importance of timing, dose, cofactors, and genetics in the determination of outcome. Rigorous studies are clearly required if we are to understand the role of endotoxin and harness its beneficial effects while avoiding potential harmful consequences.
A recent study has carefully evaluated environmental exposure to endotoxin and attempted to determine its relationship to asthma in school children.[8] Data were available for 812 children, 319 from farming families and 493 from nonfarming families. Endotoxin exposure showed a strong inverse association with hay fever and atopic sensitization. An inverse relationship was also found between the levels of endotoxin exposure and the capacity of peripheral blood leukocytes to release inflammatory cytokines after LPS stimulation. As these studies proceeded, it appeared that these protective effects of endotoxin exposure were independent of the protective effects of early life exposure to stables, implying additional and as yet undefined factors contributing to protection. Whether these are bacterial products interacting with other TLRs or are the consequences of antigen-presentation in the context of adjuvant-like factors in the hay or stables remains to be determined.
The protective effects of a farming environment in childhood provide important evidence in favor of the hypothesis that environmental factors encountered in childhood could have a lifelong protective effect against the development of allergy. Since there are numerous reports of an increase in asthma in a number of settings -- for example, urban African towns and inner cities in the United States, it is not simply a clean vs dirty environment that may dictate outcome. The farming environments may be creating an immunologic setting, beyond endotoxin exposure, that directs the immune response along a particular pathway. Defining these important factors and pathways that appear to protect against allergic sensitization will have major therapeutic implications as we consider strategies for early intervention. It is not as simple as eating dirt!
