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Background: Seasonal allergic rhinitis is a chronic inflammation in the nasal mucosa triggered by inhaled aeroallergens. The inflammatory reaction is controlled by allergen-specific T cells, but where and how these T cells become activated is not fully understood., Objectives: We wanted to determine whether allergen-specific T-helper (Th) 2 cells are residing in the nasal mucosa under steady-state conditions outside of the pollen season and, if so, whether these cells are activated locally in response to allergen challenge., Methods: Mucosal biopsies from the lower turbinate were obtained out of season from patients with either birch- or grass-pollen-allergic rhinitis and from healthy controls. Cultured explant samples were challenged with relevant pollen extract or with a mix of overlapping 20-mer peptides derived from the sequence of the major birch allergen, Betula verrucosa (Bet v) 1. After 24 h, culture medium was harvested for multiplex cytokine and tryptase analysis., Results: Significant amounts of interleukin (IL)-5 were secreted from resident cells in response to ex vivo allergen challenge in the allergic group only. No increase was observed for the other cytokines measured. Production of IL-5 in response to both extract and the Bet v1-derived peptide mix strongly suggested that T cells were a major source of IL-5., Conclusion: Our explant model indicated that local presentation of antigen to resident allergen-specific Th2 cells is the early event in the pathogenesis of allergic rhinitis. These findings identify possible cellular targets for anti-inflammatory treatment., (© 2015 John Wiley & Sons Ltd.)

Lymphocyte recruitment to peripheral tissues is fundamental for immune surveillance and homeostasis, but the chemokines and chemokine receptors responsible for tissue-specific homing of T cells to the upper airway mucosa have not been determined. To address this, we analyzed the chemokines expressed in the normal human nasal mucosa and found that CCL28 is preferentially expressed at a high level on the lumenal face of vascular endothelial cells in the mucosa. Analysis of the cognate chemokine receptors revealed that close to 50% of the CD4(+) T cells in the human nasal mucosa expressed the CCL28 receptor CCR3, whereas CCR3 was hardly detectable on T cells in the small intestine and skin. In the circulation, CCR3(+) T cells comprised a small subset that did not express homing receptors to the intestine or skin. Moreover, depletion of CCR3(+)CD4(+) T cells abrogated the proliferative response of human blood CD4(+) T cells against the opportunistic nasopharyngeal pathogen Haemophilus influenzae, indicating that the CCR3(+)CD4(+) T-cell subset in the circulation contains antigen specificities relevant for the upper airways. Together, these findings indicate that CCL28-CCR3 interactions are involved in the homeostatic trafficking of CD4(+) T cells to the upper airways.

CD123(hi) CD11c(-) dendritic cells (CD123(hi) DC) are a distinct subset of human DC present in bone marrow, blood, lymphoid organs, and peripheral tissues. Pathogen stimulation, cytokine, or CD40 ligation induces CD123(hi) DC maturation, involving a shift from their innate immune to cognate antigen-presenting functions. In this study, we revealed that blood CD123(hi) DC in the presence of cytokine (granulocyte macrophage-colony stimulating factor and interleukin-3) undergo progressive, step-wise maturation through an "early" stage, delineated by expression of the antigen detected by the new monoclonal antibody CMRF58 (CD123(hi)CMRF58(+)CD40(-)CD86(-)CD83(-)) to the "late" stage with costimulatory antigen expression (CD123(hi)CMRF58(+)CD40(+)CD86(+)CD83(+/-)). In this early stage, cytokine-maintained CD123(hi) DC do not display changes in their morphology, no longer produce interferon-alpha (IFN-alpha) in response to bacteria, and develop the capacity to induce proliferation and polarization of allogeneic T cells. CD123(hi)CMRF58(+) DC, phenotypically similar to in vitro cytokine-maintained CD123(hi) DC, were not detected in tonsil but are present in allergen-challenged nasal mucosa of allergic individuals. Thus, CD123(hi) DC in certain tissue environments such as allergen-challenged nasal mucosa share a common CD123(hi)CMRF58(+) phenotype with in vitro cytokine-maintained blood CD123(hi) DC characterized by lack of IFN-alpha production.

Recent evidence suggests that the previously enigmatic cell type designated plasmacytoid monocytes can function as dendritic cells and contribute substantially to both innate and adaptive immunity. This cell type has previously been described only in bone marrow, blood, and organized lymphoid tissue, but not at effector sites with direct Ag exposure such as the mucosae. Plasmacytoid dendritic cells (P-DCs) matured in vitro can induce T cells to produce allergy-promoting Th2 cytokines; therefore, their possible occurrence in nasal mucosa during experimentally elicited allergic rhinitis was examined. Patients with silent nasal allergy were challenged topically with relevant allergen daily for 7 days. Biopsy specimens as well as blood samples were obtained before and during such provocation, and P-DCs were identified by their high expression of CD123 (IL-3R alpha-chain), together with CD45RA. Our results showed that P-DCs were present in low and variable numbers in normal nasal mucosa but increased dramatically during the allergic reaction. This accumulation concurred with the expression of the L-selectin ligand peripheral lymph node addressin on the mucosal vascular endothelium. The latter observation was particularly interesting in view of the high levels of L-selectin on circulating P-DC precursors and of previous reports suggesting that these cells can enter organized lymphoid tissue via high endothelial venules (which express peripheral lymph node addressin constitutively). Together, our findings suggested that P-DCs are involved in the triggering of airway allergy and that they are directed to allergic lesions by adhesion molecules that normally mediate leukocyte extravasation in organized lymphoid tissue.

Phenotypic and functional studies are required to understand the immunoregulatory role of mucosal T cells. Information about T cells in the human upper respiratory tract is limited and conflicting. Therefore, we phenotyped T cells in nasal mucosa by means of multicolor in situ immunofluorescence. In normal mucosa, most CD3+ intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) (> 90%) expressed T-cell receptor (TCR)alpha/beta, and only approximately 5% expressed TCRgamma/delta. Although most IELs in the surface epithelium were CD8+ (64%), many expressed CD4 (30%) and the CD4 phenotype dominated (55%) only slightly in the lamina propria. This result was strikingly different from that obtained for comparable compartments in histologically normal jejunal mucosa, where IELs consisted of 83% CD8+ and LPLs of 73% CD4(+) T cells. Nasal CD3+ IELs and LPLs were mainly CD45RO+CD45RA- and usually expressed CD7. The integrin alphaEbeta7 was, as expected, more common on IELs than on LPLs (78 versus 20%). In conclusion, nasal T cells show several similarities to those of the normal jejunum but some notable differences exist, especially a relative increase in CD4+ T cells in the epithelium and a decrease in the lamina propria. It should be explored whether this disparity, together with an increased expression of epithelial adhesion molecules, might contribute to local immunological overstimulation and partly explain the relatively high frequency of airway allergy.

The specific defence of airway mucosae depends primarily on secretory immunity. The B cells involved are initially stimulated in organized mucosa-associated lymphoid tissue, apparently including the tonsils and adenoid. From these inductive sites, memory cells migrate to secretory effector sites where they differentiate terminally to immunoglobulin (Ig)-producing plasma cells. Locally produced Ig consists mainly of J chain-containing dimers and larger polymers of IgA (pIgA) that are selectively transported through glandular cells by an epithelial receptor called secretory component or the pIg receptor. IgG can participate in immune exclusion because it reaches the secretions by passive diffusion. However, its proinflammatory properties render IgG antibodies of local immunopathological importance when elimination of penetrating antigens is unsuccessful. T helper (Th) cells activated in this process may by a Th2 cytokine profile promote persistent inflammation with extravasation and priming of eosinophils. This development appears to be part of the late-phase allergic reaction, perhaps initially driven by interleukin-4 (IL-4) released from mast cells that are subjected to IgE-mediated activation, and subsequently also by Th2 cell activation. Eosinophils are potentially tissue-damaging, particularly after priming with IL-5. Various cytokines up-regulate adhesion molecules on endothelial and epithelial cells, thereby enhancing migration of eosinophils into the mucosa, and perhaps in addition causing aberrant immune regulation within the epithelium. Soluble antigens bombarding the epithelial surfaces normally seem to induce several immunosuppressive mechanisms, but mucosal homeostasis appears less patent in the airways than oral tolerance to dietary antigens operating in the gut.