The germless theory of allergic disease: revisiting the hygiene hypothesis


Rising rates of allergic disease accompany the healthier benefits of a contemporary westernized lifestyle, such as low infant mortality. It is likely that these twinned phenomena are causally related. The hygiene hypothesis states that allergy and increased longevity are both consequences of reducing infectious stressors during early childhood. Mechanistic explanations for the hygiene hypothesis have typically invoked the T-helper-type 1/2 (TH1/TH2) model. Here, we discuss why we favour a broader 'counter-regulatory' model — one that might also explain the increasing incidence of autoimmune disease in westernized countries.

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Figure 1: Allergy: genes and environment.
Figure 2: Regulators and effectors of TH2 responses.
Figure 3: Schematic view of the counter-regulation hypothesis.


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M.W.-K. and C.L.K. are supported, in part, by grants from the NIH. The authors thank A. Sher for many stimulating discussions.

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Correspondence to Marsha Wills-Karp.

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IL-1 receptor antagonist







Atopic dermatits



Airborne allergens; important in allergic asthma.


An environmental antigen that typcially elicits allergic responses in susceptible individuals.


Clinically evident reactions to ubiquitous allergens reflecting acquired immune responses that are marked, phenotypically, by the presence of allergen-specific IgE, along with mast cell and eosinophil recruitment and/or activation. CD4+ T cells that produce a TH2 profile of cytokines (IL-4, IL-5 and IL-13) are thought to be central to the development of allergic responses.


A chronic disease of the lung, marked by airway hyper-responsiveness and inflammation. The most common form of the disease, allergic asthma, results from inappropriate immune responses to common allergens in genetically susceptible individuals. Allergic asthma is characterized by infiltration of the airway wall with mast cells, lymphocytes and eosinophils. CD4+ T cells producing TH2 cytokines are thought to have a pivotal role in orchestrating the recruitment and activation of these effector cells of the allergic response.


The propensity for developing allergic diseases, such as asthma, atopic dermatitis, food allergy or hay fever, defined operationally by elevations in serum levels of IgE reactive with allergens or by skin-test reactivity to allergens.


(DTH). A T-cell-mediated immune response marked by monocyte/macrophage infiltration and activation. DTH skin tests have classically been used for the diagnosis of infection with intracellular pathogens such as M. tuberculosis, and as a measure of the vigour of the cellular immune system. Classical DTH responses to intracellular pathogens are thought to depend on CD4+ T cells producing a TH1 profile of cytokines (IFN-γ and TNF-β).


Viable bacteria used therapeutically or prophylactically to colonize the intestine for the purpose of modifying the intestinal microflora in ways presumed to be beneficial to the host.

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Wills-Karp, M., Santeliz, J. & Karp, C. The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 1, 69–75 (2001).

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