March 25, 2013
Fabian Salazar, MSc, Herb F. Sewell, MBChB, PhD, FRCP, FRCPath, Farouk Shakib, PhD, FRCPath, and Amir M. Ghaemmaghami, MD, PhD
Allergic diseases are a global public health issue affecting millions of persons around the world. However, full understanding of the molecular basis of this group of chronic inflammatory disorders remains rather elusive. Recently, the role of carbohydrates on allergens and their counterstructures on antigen-presenting cells (lectins) have been highlighted as crucial factors in allergen sensitization, which culminates in TH2 cell differentiation and the production of deleterious specific IgE antibodies.
Here we review recent progress on the role of different lectins in patients with type I hypersensitivity or allergy, their interplay with other determinants of allergenicity, and ways of developing therapeutic modalities against newly identified targets. (J Allergy Clin Immunol 2013;132:27-36.)
Key words: C-type lectin receptor, lectin, glycosylation, allergen, type-I hypersensitivity, asthma, house dust mite, mannose receptor, DC-SIGN, Toll-like receptor, dendritic cells, galactins
Type I hypersensitivity or allergy is an exacerbated immune response against specific antigens called allergens. The reexposure to those molecules by means of inhalation, ingestion, injection, or direct contact triggers the allergic reaction characterized by the synthesis of IgE.
In general terms the sequence of events starts with the recognition of an allergen by dendritic cells (DCs), followed by TH2 cell differentiation, IgE production, and mast cell (MC) sensitization and triggering. During re-exposure, the cross-linking of Fc receptor–bound IgE on MCs by allergens promotes the release of soluble mediators and onset of the allergic reaction.1
DCs have been shown to have a crucial role in the induction and re elicitation of TH2-mediated allergic diseases; however, the molecular processes underpinning these events are still unclear.2
Recognition and internalization of antigens by DCs is an important first step in the sequence of events that leads to the induction of the adaptive immune response. Immature DCs take up antigens in the periphery, process them into peptides, and then migrate to the lymph nodes, where, through expression of costimulatory molecules and cytokines, they can stimulate naive T cells or induce tolerance, depending on the nature of the antigen and other microenvironmental factors.3 DCs efficiently sample their milieu for foreign antigens by using pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), C-type lectin receptors (CLRs), or scavenger receptors, which increase their internalization efficiency and deliver information regarding the presence of danger signals.4
This review will focus on the role of different membrane associated CLRs, soluble lectins, and galectins in allergen recognition and downstream events leading to TH2 cell polarization. We will also discuss the interplay between lectins, PRRs, and other determinants of allergenicity, such as molecular mimicry and enzymatic activity, and how such interactions could collectively determine the outcome of the immune response to allergens.
CONCLUSIONS AND FUTURE PERSPECTIVES
As demonstrated here, lectins and carbohydrates play a key role in allergic responses (Fig 3).* Between them, they are able to exert synergistic or antagonistic effects. For instance, the MR and DC-SIGN both are able to recognize and internalize Der p 1; however, those interactions lead to TH214 and TH118 responses,respectively. In addition, Der p 1 can cleave DC-SIGN and downregulate its expression on DCs,29,30 whereas it does not have such effect on MR.29 Dectin-2 can recognize different extracts from HDM and induce the release of cysteinyl leukotriene.19 Furthermore, it is crucial in eosinophilic and neutrophilic pulmonary inflammation and TH2 cytokine production.41 Both SP-A and SP-D have been shown to bind HDM extracts and in that way block PBMC proliferation9; however, Der p 1 can degrade and inactivate both SP-A and SP-D, favoring an allergic response.44 Furthermore, SPs can reduce the proliferation of B cells and shift the response to a TH1 profile.9 Finally, galectins are involved in
epithelial cell–lymphocyte interactions63 and the blocking of asthmatic reaction driven by IgE.64
The general physiologic functions of sugar moieties and their receptors are highly diverse and include roles in cell trafficking105 and cellular signaling,106 among others. Moreover, the lectin repertoire, as well as the cellular glycosylation signatures, participate in diverse cellular mechanisms involving innate and adaptive immune responses,107 such as pathogen recognition,108 antigen presentation,109 immune tolerance,110 and cancer progression111 (Fig 4). In the case of galectins, they have been shown to be involved in different biological processes. In particular, they can regulate various mediators of cellular signaling through the
cross-linking of glycoproteins,106 mediate rolling and adhesion of eosinophils in cell trafficking,105 modulate cancer progression,111 and induce immune tolerance.110 In addition, DC-SIGN has been demonstrated to be involved in antigen presentation.109
Unlike nucleic acids and proteins, carbohydrates remain an enigmatic arm of biology. Although carbohydrates play as diverse a function in biology as proteins, they have been difficult to study because of the complexity of their synthetic pathways, unlike the template-driven synthesis of nucleic acids and proteins. Our new insights into the role of lectins in the initial recognition and uptake of allergens by DCs could also be exploited in designing new intervention strategies aimed at early events (ie, allergen uptake by DCs) at the interface of allergens and innate immune cells. For example, localized blocking of allergen receptors, such as the MR, is likely to impede allergic sensitization and the development of symptoms. Moreover, mannose seems to be the dominant type of sugar carried on a diverse range of allergens, such as bromelain, papain, Bla g 1, Ara h 1, Can f 1, Fel d 1, and Der p 1.70 Thus the development of different allergen glycoforms with immunemodulatory properties could be an alternative strategy for allergen-specific immunotherapy.112
In this review we propose that sugar moieties on allergens play an important role in allergen recognition. We suggest that their presence on allergens is crucial in the allergen sensitization process because they participate in the recognition, uptake, and presentation of different glycosylated allergens on antigenpresenting cells. We also suggest that lectins recognize glycoallergens from diverse sources and that this engagement elicits different intracellular and extracellular responses, which in some cases lead to opposing effects (eg, the MR vs DC-SIGN). Some of these interactions could form the basis for developing new strategies for immunotherapy of allergy. For instance, blocking allergen recognition and uptake by lectins, such as the MR, could be one strategy. On the other hand, DC-SIGN could be exploited in promoting antiallergic responses to switch the response to a protective TH1 profile
