The germless theory of allergic disease: revisiting the hygiene hypothesis

Wills‐Karp, Marsha; Santeliz, Joanna; Karp, Christopher

doi:10.1038/35095579

Cited by 702 publications

(496 citation statements)

References 83 publications

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“…The dysregulation of these tolerogenic processes plays an important role in the emergence of aberrant immune responses to harmless environmental or self Ags (23,24). Although the molecular basis underlying these mechanisms remains an area of intense investigation, comparatively little is known with respect to the extent by which immune tolerance is secured in diverse secondary lymphoid organs.…”

Section: Inhalation Tolerance Is Induced Selectively In Thoracic Lymphmentioning

confidence: 99%

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

Álvarez

Świrski

Yang

et al. 2006

The Journal of Immunology

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Under immunogenic conditions, both the site of initial Ag exposure and consequent T cell priming in specific draining lymph nodes (LNs) imprint the ensuing immune response with lasting tissue-selective tropism. With respect to immune tolerance, whether the site of tolerance induction leads to compartmentalized or, alternatively, pervasive tolerance has not been formally investigated. Using a murine model of inhalation tolerance, we investigated whether the induction of respiratory mucosal tolerance precludes the development of de novo Th2 sensitization upon subsequent exposure to the same Ag at distant mucosal (gut) and nonmucosal (cutaneous) sites. By tracking the proliferation of CFSE-labeled OVA-TCR transgenic CD4+ T cells upon OVA inhalation in vivo, we defined the site of tolerance induction to be restricted to the thoracic LNs. Expectedly, inhalation tolerance prevented de novo Th2 sensitization upon subsequent exposure to the same Ag at the same site. Importantly, although gut- and skin-draining LNs were not used during tolerance induction, de novo Ag-specific proliferation and Th2 differentiation in these LNs, as well as memory/effector Th2 responses in the gut (allergic diarrhea) and skin (late-phase cutaneous responses) were inhibited upon immunogenic challenge to the same Ag. Interestingly, this pervasive tolerogenic phenotype was not associated with the presence of suppressive activity throughout the lymphatics; indeed, potent suppressive activity was detected solely in the spleen. These data indicate that while inhalation tolerance is selectively induced in local thoracic LNs, its tolerogenic activity resides systemically and leads to pervasive immune tolerance in distant mucosal and nonmucosal sites.

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Section: Inhalation Tolerance Is Induced Selectively In Thoracic Lymphmentioning

confidence: 99%

Inhalation Tolerance Is Induced Selectively in Thoracic Lymph Nodes but Executed Pervasively at Distant Mucosal and Nonmucosal Tissues

Álvarez

Świrski

Yang

et al. 2006

The Journal of Immunology

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“…It is clear that the protective effect of helminth infection on the development of allergy cannot be explained simply in terms of the absence of Th1-inducing stimuli. This has led, recently, to a reworking of the hygiene hypothesis that emphasizes the counterregulatory mechanisms induced by all types of inflammatory responses (5)(6)(7). Prominent among these are regulatory T cells secreting immunosuppressive cytokines like IL-10 and TGF-␤.…”

mentioning

confidence: 99%

An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen

Bashir

Andersen

Fuss

et al. 2002

The Journal of Immunology

214

161

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Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE.

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“…Allergic and autoimmune diseases are united by the fact that they both represent poorly regulated and exaggerated immune responses. Thus, a balance between regulated and deregulated immune responses, rather than the involvement of a T helper 1 (Th1) -Th2 balance, might be important [6]. Clearly, Treg cells control immune reactions to commensal and pathogenic bacteria.…”

mentioning

confidence: 99%