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World Allergy Organization
WAO's mission: To be a global resource and advocate in the field of allergy, advancing excellence in clinical care through education, research and training as a world-wide alliance of allergy and clinical immunology societies.

World Allergy Forum: The Epithelium as a Modulator of the Allergic Response

Sensitisation and Tolerance Through the Lung: Regulation of Th-cell Responses to Inhaled Allergen by Airway Intraepithelial Dendritic Cells (DC)

Patrick G. Holt

Recent studies suggest that airway intraepithelial DC play a key role in both the induction and expression of allergic disease, via control of primary and secondary Th-cell responses to aeroallergens.

Two major networks of DC have recently been identified, respectively within the interstitium of the peripheral lung and the epithelium of the conducting airways. These DC, in particular the airway subset, sample inhaled antigen by receptor mediated endocytosis, and process and store this material as peptides within intracellular vesicles. The lack the capacity to efficiently presents these peptides to T-cells until they undergo a GM-CSF mediated maturation step, which usually does not occur until they migrate to regional lymph nodes (RLN). This strict compartmentalisation of functions is believed to be a protective mechanism to limit damage to the delicate airway epithelium which would result from cytokine release during T-cell activation, in particular if this occurred continuously in response to the myriad of antigens/allergens presents in normal ambient air.

In healthy lung airway tissue, the intraepithelial DC population turns over every 48hrs, resident cells migrating (with internalised antigen) to RLN, and being replaced by incoming precursor DC from the blood. During inflammatory challenge, additional DC are rapidly recruited with kinetics equivalent to neutrophils, markedly increasing the efficiency of local antigen surveillance; this occurs regardless of the nature of the challenge (bacterial, viral, protein antigen/allergen, chemical irritant), underscoring the importance of these cells in host defense.

An important aspect of the function of these cells is to set the Th1/Th2 balance in immune responses to inhaled antigens. Recent studies indicate that their "default" function in the steady state is to prime for weak Th2 immunity, and they require a GM-CSF maturation signal (especially if accompanied by TNFa or CD40L) to initiate the switch to Th1 immunity.

It is hypothesised that hyperactivity of the airway DC network, in particular insitu upregulation of APC function, may be an important component of the chronic phase of atopic asthma, and accordingly these cells are now acknowledged as prime targets for development of new anti-inflammatory drugs. It is also likely that they play a significant role in the establishment of Th1/Th2 memory against inhalant allergens during early childhood, and the kinetics of their functional maturation during infancy may be a major determinant of susceptibility to allergic sensitisation (i.e. development of Th-polarised memory). The rapid responsiveness of this network to microbial challenge suggests that they may also constitute a pathway for modulation of the allergic sensitisation process by respiratory infection.

References

  1. Holt PG, Oliver J, Bilyk N, McMenamin C, McMenamin PG, Kraal G, Thepen T. Downregulation of the antigen presenting cell function(s) of pulmonary dendritic cells in vivo by resident alveolar macrophages. J Exp Med. 1993;177:397-407.
  2. McWilliam AS, Napoli S, Marsh AM, Pemper FL, Nelson DJ, Pimm CL, Stumbles PA, Wells TNC, Holt PG. Dendritic Cells are recruited into the airway epithelium during the inflammatory response to a broad spectrum of stimuli. J Exp Med. 1996;184:2429-32.
  3. Nelson DJ, Holt PG. Defective regional immunity in the respiratory tract of neonates is attributable to hyporesponsiveness of local Dendritic Cells to activation signals. J Immunol. 1995;155:3517-3524.
  4. Lambrecht BN, Salomon B, Klatzmann D, Pauwels RA. Dendritic Cells are required for the development of chronic eosinophilic airway inflammation in response to inhaled antigen in sensitized mice. J Immunol. 1998;160:4090-4097.
  5. Stumbles PA, Thomas JA, Pimm CL, Lee PT, Venaille TJ, Proksch S, Holt PG. Resting respiratory tract Dendritic Cells preferentially stimulate Th2 responses and require obligatory cytokine signals for induction of Th1 immunity. J Exp Med. 1998;188:2019-2031.

 

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