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Mucosal immunity in infectious disease and allergy
International Congress Series 1257 (2003) 11 – 20
www.ics-elsevier.com
Mucosal immunity in infectious disease and allergy Per Brandtzaeg * Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, Rikshospitalet, N-0027 Oslo, Norway Received 30 June 2003; received in revised form 29 July 2003; accepted 25 August 2003
Abstract. This brief review describes mechanisms for acquired anti-microbial defence in the upper airways originating from active export of secretory immunoglobulin A and IgM, as well as epithelial leakage of serum-derived or locally produced IgG. Evidence is presented for regionalization of mucosal immunity in the upper airways, directed by a preferential profile of adhesion molecules and chemokine receptors expressed on B cells induced in mucosa-associated lymphoid tissue of Waldeyer’s ring, especially the palatine tonsils and adenoids, which differs from that imprinted on B cells in gut-associated lymphoid tissue. The possibility is also discussed that allergy is more common in the airways than in the gut because of differences in mucosally induced tolerance mechanisms. The nature of the mucosal epithelium, as well as functional properties of intra- or subepithelial dendritic cells and macrophages, may contribute to less robust local immune tolerance in the respiratory tract. D 2003 Elsevier B.V. All rights reserved. Keywords: Secretory immunity; B cell homing; Atopic disease; Dendritic cells; Immunotherapy
1. Secretory immunity in infectious defence The upper airway mucosa is mainly covered by a thin, specialized epithelium, thus constituting a vulnerable barrier that is continuously bombarded by exogenous soluble antigens and infectious agents. Adequate surface protection of the upper respiratory tract therefore depends on intimate cooperation between natural nonspecific defence mechanisms (innate immunity) such as antimicrobial peptides and the ciliary function, as well as on acquired adaptive immunity. The latter is primarily mediated by specific antibodies belonging to the secretory immunoglobulin A (SIgA) and—to a much lesser extent— secretory IgM (SIgM) class, with some additional serum-derived or locally produced IgG [1]. Locally produced antibodies consist mainly of J chain-containing dimers and some larger polymers of IgA (collectively called pIgA) which are selectively transported through glandular cells by an epithelial receptor called membrane secretory component (SC) or the * Tel.: +47-23-07-27-43; fax: +47-23-07-15-11. E-mail address: [email protected] (P. Brandtzaeg). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)01397-9
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polymeric Ig receptor (pIgR) [2,3]. Pentameric IgM can be transported externally by the same mechanism (Fig. 1). The expression of pIgR/(SC) is constitutive but can also be enhanced by immunoregulatory and proinflammatory cytokines at a transcriptional level [3]. Important cytokines with this effect are interferon-g (IFN-g), tumour necrosis factor-a and interleukin-4 (IL-4) [4 –6]. Secretory antibodies perform surface protection by immune exclusion of infectious agents and soluble antigens, thereby blocking microbial colonization and penetration of dangerous substances (Fig. 1). Viruses can also be neutralized inside of epithelial cells when they meet specific pIgA or pentameric IgM antibodies in vesicles during transcytosis of secretory antibodies [3,7]. IgG may participate in immune exclusion because such serum-derived or locally produced antibodies can reach external secretions by passive epithelial paracellular diffusion [8], and the same may apply to IgE antibodies [1]. However, the pro-inflammatory properties of antibodies belonging to these two classes [9] explain their involvement in mucosal immunopathology when immune exclusion and elimination of penetrating antigens are unsuccessful [10].
Fig. 1. Model for external transport of J chain-containing dimeric IgA and pentameric IgM by pIgR, expressed basolaterally as membrane SC on glandular epithelial cells. The polymeric Ig molecules are produced with incorporated J chain (IgA + J and IgM + J) by local plasma cells. The resulting secretory Ig molecules (SIgA and SIgM) act in a first line of defence by performing immune exclusion of antigens in the mucus layer on the epithelial surface. Although the J chain is often (70 – 90%) produced by mucosal IgG plasma cells, it does not combine with this Ig class but is degraded intracellularly as denoted by ( F J) in the figure. Locally produced (and serum-derived) IgG is not subjected to active external transport, but can be transmitted paracellularly to the lumen as indicated by the broken arrows. Free SC (depicted in mucus) is generated when pIgR in its unoccupied state (top symbol) is cleaved at the apical face of the epithelium like bound SC in SIgA and SIgM. While bound SC is covalently linked to one subunit in SIgA, providing protection against degradation, SIgM contains only noncovalently bound SC in dynamic equilibrium with free SC in the secretion.
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Such an untoward development in the airways is overrepresented in subjects with selective IgA deficiency [11,12] because compensation with SIgM for the lacking SIgA is much poorer in the upper aerodigestive tract than in the gut [3]. Particularly, those IgAdeficient subjects that have completely absent or extremely poor mucosal IgM responses in their airways frequently show recurrent respiratory tract infections—including tonsillitis, acute otitis media, rhinosinusitis, and even pneumonia—thus indirectly demonstrating the protective role of secretory antibodies [1,13]. 2. Mucosal B cell induction and dispersion As discussed above, secretory immunity is central in the first-line defence of airway mucosae. B cells involved in this specialized adaptive surface protection are initially stimulated in mucosa-associated lymphoid tissue (MALT), including the palatine tonsils and adenoids [14 – 16]. The primed B cells then migrate through cervical lymph nodes and peripheral blood to distant secretory effector sites where they mainly become pIgAproducing plasma cells [3]. While MALT structures sample antigens from the surface via specialized epithelial membrane (M) cells [17], cervical lymph nodes receive antigens via draining lymph or dendritic cells (DCs) that migrate from the airway mucosa, which is extremely rich in sub- and intraepithelial DCs and macrophages [18,19]. Therefore, there is currently great interest in exploiting the nasal route of immunization for vaccination against infectious agents such as the influenza virus, targeting both regional MALT and mucosal DCs [7]. The dissemination or ‘‘homing’’ of primed mucosal B cells from MALT to distant secretory effector sites is guided by adhesion molecules and chemokine receptors [20]. Circumstantial evidence obtained by immunization in both humans and animals has suggested that mucosal B cell homing is regionalized, as implied from the levels of specific SIgA antibodies found in various exocrine secretions after topical delivery of antigens targeting nasopharynx-associated versus gut-associated lymphoid tissue (GALT) [21 –23]. However, it is not possible to test this notion directly in humans by tracing of labelled B cells in vivo. As an alternative approach, we have used a DNA marker to demonstrate how a primed tonsillar effector B cell subset is disseminated throughout the body [24]. The dispersion of this IgD+IgM subset revealed its preferential occurrence in Waldeyer’s ring, upper airway mucosa, regional exocrine structures such as salivary and lacrimal glands, cervical lymph nodes, bone marrow and—less frequently—in inguinal and mesenteric lymph nodes, ileal Peyer’s patches, colon and the uterine cervix [24]. Conversely, the small intestinal mucosa and the appendix were mostly negative. Interestingly, the homing receptor profile (a4h7intCCR9lo/negL-selectinhi) of this subset found circulating in peripheral blood did not favour access to the small intestinal mucosa (Fig. 2) but rather explained why the respiratory and systemic immune systems appear to be rather integrated [25,26]. Tonsillar IgD+ plasmablasts are often found to express high levels of the chemokine receptor CCR10, and so are many IgD-producing plasma cells in secretory effector tissues of the upper aerodigestive tract. Similarly to IgA and IgM immunocytes at these sites, the CCR10+ IgD immunocytes showed a mucosal phenotype by expressing the J chain [3,16,24]. A recent study has suggested that CCR10 is a unifying chemokine receptor for mucosal B cells [27]. Its ligand is the so-called mucosae-associated chemokine (MEC,
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CCL28) which is produced by secretory epithelial cells all over the body but, interestingly, at relatively low levels in the small intestine, ileocecum and appendix, in contrast to high levels in the upper aerodigestive tract [28,29]. Conversely, the so-called thymus-expressed
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Fig. 3. Main properties and functions of Th1- or Th2-polarized immune responses. The cytokine profiles of activated CD4+ Th cells depend on the nature of antigen exposure, various microenvironmental factors, and the type and maturational stage of the antigen-presenting cell (APC). The polarized responses promote different types of antimicrobial cell-mediated or humoral defences and/or inflammatory reactions including allergy as indicated. B, B cell; MHC II, major histocompatibility (in humans, HLA) class II molecule: TCR, T-cell receptor; DTH, delayed type hypersensitivity; Mf, macrophage; Tc, cytotoxic T cell; LTB4, leukotriene B4; GM-CSF, granulocyte-macrophage colony-stimulating factor; Eos., eosinophilic granulocyte.
chemokine (TECK, CCL25), which is the ligand for CCR9, appears to be selectively produced by mucosal epithelium in the small intestine [20]. Therefore, graded tissuedependent CCR10-MEC interactions, together with insufficient levels of classical guthoming receptors on effector B cells from Waldeyer’s ring, most likely explain the observed Fig. 2. Proposed model for homing of primed B cells from mucosal inductive sites with activated lymphoid follicles, to secretory effector sites in the integrated human mucosal immune system. Putative compartmentalization in trafficking from inductive to effector sites is indicated, the heavier arrows representing preferential B cell migration pathways. Homing from gut-associated lymphoid tissue (GALT) is believed to be determined mainly by integrin a4h7 on primed cells, interacting with mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on the microvascular endothelium in the intestinal lamina propria. In the small intestinal lamina propria, attraction and/or retention of CCR9-expressing cells is mediated by the chemokine TECK, while CCR10MEC interactions appear to be important in the large bowel. Other adhesion molecules such as L-selectin (L-sel) and a4h1 that bind to endothelial peripheral lymph node addressin (PNAd) and vascular cell adhesion molecule 1 (VCAM-1), respectively, may be employed mainly by B cells primed in bronchus-associated (BALT) and nasopharynx-associated (NALT) lymphoid tissue. Human NALT is comprised of the various lymphoepithelial structures of Waldeyer’s ring, including the palatine tonsils and the nasopharyngeal tonsil (adenoids). In this region, abundantly produced epithelial MEC attracts primed B cells via CCR10. The urogenital tract may employ similar molecular homing mechanisms as the upper aerodigestive tract and the large bowel, therefore probably receiving primed cells from inductive sites in both these regions. In addition, lactating mammary glands appear to receive primed cells from NALT as well as GALT, and much more efficiently so than the urogenital tract.
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dichotomy of their dispersion to the aerodigestive tract versus the small intestine and the appendix (Fig. 2). Altogether, in view of the immunization data referred to above, there is good reason to believe that the IgD+IgM tonsillar subset used as a surrogate marker for B cell migration from nasopharynx-associated MALT throughout the body, displays homing properties shared by most J chain-expressing B cells primed in Waldeyer’s ring. The compartmentalized differences thus revealed directly in the human mucosal immune system must be taken into account in the delivery design of future local vaccines. 3. Allergic reactions and atopic mucosal disease Activated in MALT or locally in the mucosa, CD4+ T helper (Th) cells may—by a Th2 profile of cytokines such as IL-4, IL-5 and IL-13—promote the development of atopic diseases due to IgE-mediated allergy (type I hypersensitivity) [11]. Antibodies of the IgE class are the basis for mast-cell degranulation causing immediate types of allergy, including allergic rhinitis or rhinoconjunctivitis (hay fever) and extrinsic asthma. IL-4 and IL-13 act as B cell switch factors crucial for production of IgE [30]. Other cytokines such as IL-3 and IL-5 promote persistent allergic inflammation with extravasation and
Fig. 4. Schematic representation of three biological variables that may contribute to the disparity in the immunosuppressive tone of the airways versus the gut. Upper panel: numbers and phenotypic distribution of intraepithelial lymphocytes (IELs). Middle panel: capacity for antigen presentation, including expression of costimulatory signals to T cells by HLA class I- and class II-positive (HLA I/II+) epithelial cells (e.g., ICAM-1), leading to preferential help or suppression. Bottom panel: distribution of subepithelial and intraepithelial professional APCs.
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priming of eosinophils, the so-called late-phase allergic reaction (Fig. 3). Eosinophils are potentially tissue-destructive cells, particularly after priming with IL-5 [11]. Cytokines also upregulate adhesion molecules on vascular endothelium and respiratory epithelial cells, thereby enhancing migration of eosinophils and other leukocytes into the lamina propria and surface epithelium [11,31,32]. Intercellular adhesion molecule-1 (ICAM-1, CD54) which readily becomes upregulated by IFN-g in airway epithelium, is of particular importance for further migration of leukocytes onto the mucosal surface [1]. However, epithelial ICAM-1 may also provide a co-signal for hyperactivation of CD4+ Th cells by antigen-presenting HLA class I- and II (HLA-DR)-expressing epithelium [33]. This latter feature may contribute to the fact that the airway mucosa appears less able than the gut mucosa to engage CD8+ intraepithelial lymphocytes (Fig. 4)—which moreover are relatively few in the airway epithelium [34]—for downregulation of hypersensitivity responses against harmless environmental antigens [11]. 4. Role of mucosal dendritic cells in allergy Dendritic cells (DCs) may be even more crucial than CD8+ intraepithelial lymphocytes in tolerance induction against soluble antigens such as allergens [35] and a variety of DCs and macrophages are present both within and below the human airway epithelium [19]. Some of these cells such as the CD123+ (IL-3R+) plasmacytoid variant (P-DC) can skew a Th cell response towards a Th2 cytokine profile, at least in a secondary immune response
Fig. 5. Hypothetical scheme for the pathogenesis of nasal allergy. An unknown ‘‘initiating hit’’ (e.g., virus infection) activates the surface epithelium or mast cells, which results in secretion of TSLP. This cytokine activates myeloid CD11c+ DCs, which makes them drive naı¨ve T cells towards a Th2 profile during initial allergen presentation. Virus-infected epithelial cells may release Type 1 interferons (IFN-a and IFN-h) that stimulate natural killer (NK) cells to release IL-3, an important growth factor for CD123+ plasmacytoid dendritic cells (P-DCs). In a secondary response to the same allergen, P-DCs may efficiently enhance Th2 skewing, thereby creating a vicious circle that leads to perpetuation of the allergic reaction and involvement of tissue-destructive eosinophilic (Eos.) granulocytes. Further details are discussed in the text.
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[36]. Notably, P-DCs are abundant in allergen-challenged nasal mucosa of patients with allergic rhinitis [37]. The initial event in this disease process may be activation of mucosal CD11c+ myeloid DCs by the IL-7-like cytokine ‘thymic stromal lymphopoietin’ (TSLP) derived from the airway epithelium or from activated mucosal mast cells (Fig. 5). TSLPactivated human myeloid DCs can prime naı¨ve CD4+ T cells to produce IL-4, IL-5 and IL13, while suppressing production of the crossregulatory cytokines IL-10 and IFN-g [38]. Such events may prepare the airway mucosa for secondary Th2 responses induced by PDCs, thus initiating a vicious circle (Fig. 5). Rational mucosal induction of immune tolerance may become possible in the future to prevent the development of respiratory allergy. Therapeutic control of mucosal expression of certain adhesion molecules and immunological modulation to achieve deviation from a skewed Th2 response towards a balanced Th1/Th2 cytokine profile may furthermore become an adjunct in the treatment of allergic disease [39]. A particularly interesting possibility is phenotypic modulation of DCs involved in allergy induction, for instance, via their Toll-like receptors (TLRs). Thus, CD11c+ myeloid DCs and CD123+ P-DCs express separate TLRs and may therefore be activated by different types of microbial components. Most importantly, in this context, human P-DCs express TLR9 which can engage unmethylated CpG motifs of microbial DNA selectively, thereby providing co-stimulatory signals for Th1 polarization [40]. Therefore, intranasal immunotherapy with CpG motifs as an adjuvant may be a future option to break the vicious circle (Fig. 5) in the pathogenesis of atopic disease. Acknowledgements Studies in the author’s laboratory are supported by the University of Oslo, the Research Council of Norway, the Norwegian Cancer Society, Anders Jahre’s Fund and Rakel and Otto Kr. Bruun’s Legacy. Hege Eliassen and Erik K. Hagen are gratefully acknowledged for excellent assistance with the manuscript. References [1] P. Brandtzaeg, Immunocompetent cells of the upper airway: functions in normal and diseased mucosa, Eur. Arch. Otorhinolaryngol. 252 (Suppl. 1) (1995) S8 – S21. [2] P. Brandtzaeg, H. Prydz, Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulin, Nature 311 (1984) 71 – 73. [3] P. Brandtzaeg, I.N. Farstad, F.-E. Johansen, H.C. Morton, I.N. Norderhaug, T. Yamanaka, The B-cell system of human mucosae and exocrine glands, Immunol. Rev. 171 (1999) 45 – 87. [4] H. Schjerven, P. Brandtzaeg, F.-E. Johansen, Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor: role of STAT6 in cell type-specific delayed transcriptional response, J. Immunol. 165 (2000) 3898 – 3906. [5] H. Schjerven, P. Brandtzaeg, F.-E. Johansen, A novel NF-nB/Rel site in intron 1 cooperates with proximal promoter elements to mediate TNF-a-induced transcription of the human polymeric Ig receptor, J. Immunol. 167 (2001) 6412 – 6420. [6] H. Schjerven, P. Brandtzaeg, F.-E. Johansen, Hepatocyte NF-1 and STAT6 cooperate with additional DNAbinding factors to activate transcription of the human polymeric Ig receptor gene in response to IL-4, J. Immunol. 170 (2003) 6048 – 6056. [7] P. Brandtzaeg, Role of secretory antibodies in the defence against infection, Int. J. Med. Microbiol. 293 (2003) 3 – 15. [8] C.G. Persson, J.S. Erjefalt, L. Greiff, I. Erjefalt, M. Korsgren, M. Linden, F. Sundler, M. Andersson,
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C. Svensson, Contribution of plasma-derived molecules to mucosal immune defence, disease and repair in the airways, Scand. J. Immunol. 47 (1998) 302 – 313. P. Brandtzaeg, K. Tolo, Mucosal penetrability enhanced by serum-derived antibodies, Nature 266 (1977) 262 – 263. P. Brandtzaeg, The role of humoral mucosal immunity in the induction and maintenance of chronic airway infections, Am. J. Respir. Crit. Care Med. 151 (1995) 2081 – 2087. P. Brandtzaeg, F.L. Jahnsen, I.N. Farstad, Immune functions and immunopathology of the mucosa of the upper respiratory pathways, Acta Otolaryngol. 116 (1996) 149 – 159. P. Brandtzaeg, D.E. Nilssen, Mucosal aspects of primary B-cell deficiency and gastrointestinal infections, Curr. Opin. Gastroenterol. 11 (1995) 532 – 540. ˚ . Hanson, The clinical condition of P. Brandtzaeg, G. Karlsson, G. Hansson, B. Petruson, J. Bjørkander, L.A IgA-deficient patients is related to the proportion of IgD-and IgM-producing cells in their nasal mucosa, Clin. Exp. Immunol. 67 (1987) 626 – 636. P. Brandtzaeg, The B-cell development in tonsillar lymphoid follicles, Acta Otolaryngol. Suppl. 523 (1996) 55 – 59. P. Brandtzaeg, Immunological functions of adenoids, in: P. van Cauwenberge, D.-Y. Wang, K. Ingels, C. Bachert (Eds.), The Nose, Kugler Publications, The Hague, 1998, pp. 233 – 246. P. Brandtzaeg, E.S. Baekkevold, I.N. Farstad, F.L. Jahnsen, F.-E. Johansen, E.M. Nilsen, T. Yamanaka, Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol. Today 20 (1999) 141 – 151. M.R. Neutra, N.J. Mantis, J.P. Kraehenbuhl, Collaboration of epithelial cells with organized mucosal lymphoid tissues, Nature Immunol. 2 (2001) 1004 – 1009. F.L. Jahnsen, E.D. Moloney, T. Hogan, J.W. Upham, C.M. Burke, P.G. Holt, Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge, Thorax 56 (2001) 823 – 826. F.L. Jahnsen, E. Gran, R. Haye, P. Brandtzaeg, Human nasal mucosa contains antigen-presenting cells of strikingly different functional phenotypes, Am. J. Respir. Cell Mol. Biol. (in press). E.J. Kunkel, E.C. Butcher, Chemokines and the tissue-specific migration of lymphocytes, Immunity 16 (2002) 1 – 4. P. Brandtzaeg, I.N. Farstad, G. Haraldsen, Regional specialization in the mucosal immune system: primed cells do not always home along the same track, Immunol. Today 20 (1999) 267 – 277. H. Inoue, T. Fukuizumi, T. Tsujisawa, C. Uchiyama, Simultaneous induction of specific immunoglobulin Aproducing cells in major and minor salivary glands after tonsillar application of antigen in rabbits, Oral Microbiol. Immunol. 14 (1999) 21 – 26. M. Yanagita, T. Hiroi, N. Kitagaki, S. Hamada, H.O. Ito, H. Shimauchi, S. Murakami, H. Okada, H. Kiyono, Nasopharyngeal-associated lymphoreticular tissue (NALT) immunity: fimbriae-specific Th1 and Th2 cell-regulated IgA responses for the inhibition of bacterial attachment to epithelial cells and subsequent inflammatory cytokine production, J. Immunol. 162 (1999) 3559 – 3565. P. Brandtzaeg, F.-E. Johansen, E.S. Baekkevold, I.N. Farstad, Direct tracking of mucosal B-cell migration in humans reveals distinct effector-site differences, 11th International Congress of Mucosal Immunology (ICMI), Orlando, Florida, Mucosal Immunol. Update (2002) 10, abstract 2476. A. Rudin, E.L. Johansson, C. Bergquist, J. Holmgren, Differential kinetics and distribution of antibodies in serum and nasal and vaginal secretions after nasal and oral vaccination of humans, Infect. Immun. 66 (1998) 3390 – 3396. E.L. Johansson, L. Wassen, J. Holmgren, M. Jertborn, A. Rudin, Nasal and vaginal vaccinations have differential effects on antibody responses in vaginal and cervical secretions in humans, Infect. Immun. 69 (2001) 7481 – 7486. E.J. Kunkel, C.H. Kim, N.H. Lazarus, M.A. Vierra, D. Soler, E.P. Bowman, E.C. Butcher, CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells, J. Clin. Invest. 111 (2003) 1001 – 1010. J. Pan, E.J. Kunkel, U. Gosslar, N. Lazarus, P. Langdon, K. Broadwell, M.A. Vierra, M.C. Genovese, E.C. Butcher, D. Soler, A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues, J. Immunol. 165 (2000) 2943 – 2949.
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[29] W. Wang, H. Soto, E.R. Oldham, M.E. Buchanan, B. Homey, D. Catron, N. Jenkins, N.G. Copeland, D.J. Gilbert, N. Nguyen, J. Abrams, D. Kershenovich, K. Smith, T. McClanahan, A.P. Vicari, A. Zlotnik, Identification of a novel chemokine (CCL28), which binds CCR10 (GPR2), J. Biol. Chem. 275 (2000) 22313 – 22323. [30] D.B. Corry, F. Kheradmand, Induction and regulation of the IgE response, Nature 402 (1999) B18 – B23 (suppl.). [31] F.L. Jahnsen, G. Haraldsen, R. Haye, P. Brandtzaeg, Nasal polyps: adhesion molecules and recruitment of eosinophils, in: N. Mygind, T. Lindholdt (Eds.), Nasal Polyposis. An Inflammatory Disease and its Treatment, Copenhagen, Munksgaard, 1997, pp. 88 – 97. [32] F.L. Jahnsen, R. Haye, E. Gran, P. Brandtzaeg, F.-E. Johansen, Glucocorticosteroids inhibit mRNA expression for eotaxin, eotaxin-2, and monocyte-chemotactic protein-4 in airway inflammation with eosinophilia, J. Immunol. 163 (1999) 1545 – 1551. [33] T.H. Kalb, M.T. Chuang, Z. Marom, L. Mayer, Evidence for accessory cell function by class II MHC antigen-expressing airway epithelial cells, Am. J. Respir. Cell Mol. Biol. 4 (1991) 320 – 329. [34] F.L. Jahnsen, I.N. Farstad, J.P. Aanesen, P. Brandtzaeg, Phenotypic distribution of T cells in human nasal mucosa differs from that in the gut, Am. J. Respir. Cell Mol. Biol. 18 (1998) 392 – 401. [35] K. Shortman, Y.J. Liu, Mouse and human dendritic cell subtypes, Nature Rev. Immunol. 2 (2002) 151 – 161. [36] M.C. Rissoan, V. Soumelis, N. Kadowaki, G. Grouard, F. Briere, R. de Waal Malefyt, Y.J. Liu, Reciprocal control of T helper cell and dendritic cell differentiation, Science 283 (1999) 1183 – 1186. [37] F.L. Jahnsen, F. Lund-Johansen, J.F. Dunne, L. Farkas, R. Haye, P. Brandtzaeg, Experimentally induced recruitment of plasmacytoid (CD123high) dendritic cells in human nasal allergy, J. Immunol. 165 (2000) 4062 – 4068. [38] V. Soumelis, P.A. Reche, H. Kanzler, W. Yuan, G. Edward, B. Homey, M. Gilliet, S. Ho, S. Antonenko, A. Lauerma, K. Smith, D. Gorman, S. Zurawski, J. Abrams, S. Menon, T. McClanahan, Rd.R. de Waal Malefyt, F. Bazan, R.A. Kastelein, Y.J. Liu, Human epithelial cells trigger dendritic cell-mediated allergic inflammation by producing TSLP, Nature Immunol. 3 (2002) 673 – 680. [39] P.J. Barnes, Therapeutic strategies for allergic diseases, Nature 402 (1999) B31 – B38 (suppl.). [40] A. Boonstra, C. Asselin-Paturel, M. Gilliet, C. Crain, G. Trinchieri, Y.J. Liu, A. O’Garra, Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation, J. Exp. Med. 197 (2003) 101 – 109.
www.ics-elsevier.com
Mucosal immunity in infectious disease and allergy Per Brandtzaeg * Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, Rikshospitalet, N-0027 Oslo, Norway Received 30 June 2003; received in revised form 29 July 2003; accepted 25 August 2003
Abstract. This brief review describes mechanisms for acquired anti-microbial defence in the upper airways originating from active export of secretory immunoglobulin A and IgM, as well as epithelial leakage of serum-derived or locally produced IgG. Evidence is presented for regionalization of mucosal immunity in the upper airways, directed by a preferential profile of adhesion molecules and chemokine receptors expressed on B cells induced in mucosa-associated lymphoid tissue of Waldeyer’s ring, especially the palatine tonsils and adenoids, which differs from that imprinted on B cells in gut-associated lymphoid tissue. The possibility is also discussed that allergy is more common in the airways than in the gut because of differences in mucosally induced tolerance mechanisms. The nature of the mucosal epithelium, as well as functional properties of intra- or subepithelial dendritic cells and macrophages, may contribute to less robust local immune tolerance in the respiratory tract. D 2003 Elsevier B.V. All rights reserved. Keywords: Secretory immunity; B cell homing; Atopic disease; Dendritic cells; Immunotherapy
1. Secretory immunity in infectious defence The upper airway mucosa is mainly covered by a thin, specialized epithelium, thus constituting a vulnerable barrier that is continuously bombarded by exogenous soluble antigens and infectious agents. Adequate surface protection of the upper respiratory tract therefore depends on intimate cooperation between natural nonspecific defence mechanisms (innate immunity) such as antimicrobial peptides and the ciliary function, as well as on acquired adaptive immunity. The latter is primarily mediated by specific antibodies belonging to the secretory immunoglobulin A (SIgA) and—to a much lesser extent— secretory IgM (SIgM) class, with some additional serum-derived or locally produced IgG [1]. Locally produced antibodies consist mainly of J chain-containing dimers and some larger polymers of IgA (collectively called pIgA) which are selectively transported through glandular cells by an epithelial receptor called membrane secretory component (SC) or the * Tel.: +47-23-07-27-43; fax: +47-23-07-15-11. E-mail address: [email protected] (P. Brandtzaeg). 0531-5131/ D 2003 Elsevier B.V. All rights reserved. doi:10.1016/S0531-5131(03)01397-9
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polymeric Ig receptor (pIgR) [2,3]. Pentameric IgM can be transported externally by the same mechanism (Fig. 1). The expression of pIgR/(SC) is constitutive but can also be enhanced by immunoregulatory and proinflammatory cytokines at a transcriptional level [3]. Important cytokines with this effect are interferon-g (IFN-g), tumour necrosis factor-a and interleukin-4 (IL-4) [4 –6]. Secretory antibodies perform surface protection by immune exclusion of infectious agents and soluble antigens, thereby blocking microbial colonization and penetration of dangerous substances (Fig. 1). Viruses can also be neutralized inside of epithelial cells when they meet specific pIgA or pentameric IgM antibodies in vesicles during transcytosis of secretory antibodies [3,7]. IgG may participate in immune exclusion because such serum-derived or locally produced antibodies can reach external secretions by passive epithelial paracellular diffusion [8], and the same may apply to IgE antibodies [1]. However, the pro-inflammatory properties of antibodies belonging to these two classes [9] explain their involvement in mucosal immunopathology when immune exclusion and elimination of penetrating antigens are unsuccessful [10].
Fig. 1. Model for external transport of J chain-containing dimeric IgA and pentameric IgM by pIgR, expressed basolaterally as membrane SC on glandular epithelial cells. The polymeric Ig molecules are produced with incorporated J chain (IgA + J and IgM + J) by local plasma cells. The resulting secretory Ig molecules (SIgA and SIgM) act in a first line of defence by performing immune exclusion of antigens in the mucus layer on the epithelial surface. Although the J chain is often (70 – 90%) produced by mucosal IgG plasma cells, it does not combine with this Ig class but is degraded intracellularly as denoted by ( F J) in the figure. Locally produced (and serum-derived) IgG is not subjected to active external transport, but can be transmitted paracellularly to the lumen as indicated by the broken arrows. Free SC (depicted in mucus) is generated when pIgR in its unoccupied state (top symbol) is cleaved at the apical face of the epithelium like bound SC in SIgA and SIgM. While bound SC is covalently linked to one subunit in SIgA, providing protection against degradation, SIgM contains only noncovalently bound SC in dynamic equilibrium with free SC in the secretion.
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Such an untoward development in the airways is overrepresented in subjects with selective IgA deficiency [11,12] because compensation with SIgM for the lacking SIgA is much poorer in the upper aerodigestive tract than in the gut [3]. Particularly, those IgAdeficient subjects that have completely absent or extremely poor mucosal IgM responses in their airways frequently show recurrent respiratory tract infections—including tonsillitis, acute otitis media, rhinosinusitis, and even pneumonia—thus indirectly demonstrating the protective role of secretory antibodies [1,13]. 2. Mucosal B cell induction and dispersion As discussed above, secretory immunity is central in the first-line defence of airway mucosae. B cells involved in this specialized adaptive surface protection are initially stimulated in mucosa-associated lymphoid tissue (MALT), including the palatine tonsils and adenoids [14 – 16]. The primed B cells then migrate through cervical lymph nodes and peripheral blood to distant secretory effector sites where they mainly become pIgAproducing plasma cells [3]. While MALT structures sample antigens from the surface via specialized epithelial membrane (M) cells [17], cervical lymph nodes receive antigens via draining lymph or dendritic cells (DCs) that migrate from the airway mucosa, which is extremely rich in sub- and intraepithelial DCs and macrophages [18,19]. Therefore, there is currently great interest in exploiting the nasal route of immunization for vaccination against infectious agents such as the influenza virus, targeting both regional MALT and mucosal DCs [7]. The dissemination or ‘‘homing’’ of primed mucosal B cells from MALT to distant secretory effector sites is guided by adhesion molecules and chemokine receptors [20]. Circumstantial evidence obtained by immunization in both humans and animals has suggested that mucosal B cell homing is regionalized, as implied from the levels of specific SIgA antibodies found in various exocrine secretions after topical delivery of antigens targeting nasopharynx-associated versus gut-associated lymphoid tissue (GALT) [21 –23]. However, it is not possible to test this notion directly in humans by tracing of labelled B cells in vivo. As an alternative approach, we have used a DNA marker to demonstrate how a primed tonsillar effector B cell subset is disseminated throughout the body [24]. The dispersion of this IgD+IgM subset revealed its preferential occurrence in Waldeyer’s ring, upper airway mucosa, regional exocrine structures such as salivary and lacrimal glands, cervical lymph nodes, bone marrow and—less frequently—in inguinal and mesenteric lymph nodes, ileal Peyer’s patches, colon and the uterine cervix [24]. Conversely, the small intestinal mucosa and the appendix were mostly negative. Interestingly, the homing receptor profile (a4h7intCCR9lo/negL-selectinhi) of this subset found circulating in peripheral blood did not favour access to the small intestinal mucosa (Fig. 2) but rather explained why the respiratory and systemic immune systems appear to be rather integrated [25,26]. Tonsillar IgD+ plasmablasts are often found to express high levels of the chemokine receptor CCR10, and so are many IgD-producing plasma cells in secretory effector tissues of the upper aerodigestive tract. Similarly to IgA and IgM immunocytes at these sites, the CCR10+ IgD immunocytes showed a mucosal phenotype by expressing the J chain [3,16,24]. A recent study has suggested that CCR10 is a unifying chemokine receptor for mucosal B cells [27]. Its ligand is the so-called mucosae-associated chemokine (MEC,
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CCL28) which is produced by secretory epithelial cells all over the body but, interestingly, at relatively low levels in the small intestine, ileocecum and appendix, in contrast to high levels in the upper aerodigestive tract [28,29]. Conversely, the so-called thymus-expressed
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Fig. 3. Main properties and functions of Th1- or Th2-polarized immune responses. The cytokine profiles of activated CD4+ Th cells depend on the nature of antigen exposure, various microenvironmental factors, and the type and maturational stage of the antigen-presenting cell (APC). The polarized responses promote different types of antimicrobial cell-mediated or humoral defences and/or inflammatory reactions including allergy as indicated. B, B cell; MHC II, major histocompatibility (in humans, HLA) class II molecule: TCR, T-cell receptor; DTH, delayed type hypersensitivity; Mf, macrophage; Tc, cytotoxic T cell; LTB4, leukotriene B4; GM-CSF, granulocyte-macrophage colony-stimulating factor; Eos., eosinophilic granulocyte.
chemokine (TECK, CCL25), which is the ligand for CCR9, appears to be selectively produced by mucosal epithelium in the small intestine [20]. Therefore, graded tissuedependent CCR10-MEC interactions, together with insufficient levels of classical guthoming receptors on effector B cells from Waldeyer’s ring, most likely explain the observed Fig. 2. Proposed model for homing of primed B cells from mucosal inductive sites with activated lymphoid follicles, to secretory effector sites in the integrated human mucosal immune system. Putative compartmentalization in trafficking from inductive to effector sites is indicated, the heavier arrows representing preferential B cell migration pathways. Homing from gut-associated lymphoid tissue (GALT) is believed to be determined mainly by integrin a4h7 on primed cells, interacting with mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on the microvascular endothelium in the intestinal lamina propria. In the small intestinal lamina propria, attraction and/or retention of CCR9-expressing cells is mediated by the chemokine TECK, while CCR10MEC interactions appear to be important in the large bowel. Other adhesion molecules such as L-selectin (L-sel) and a4h1 that bind to endothelial peripheral lymph node addressin (PNAd) and vascular cell adhesion molecule 1 (VCAM-1), respectively, may be employed mainly by B cells primed in bronchus-associated (BALT) and nasopharynx-associated (NALT) lymphoid tissue. Human NALT is comprised of the various lymphoepithelial structures of Waldeyer’s ring, including the palatine tonsils and the nasopharyngeal tonsil (adenoids). In this region, abundantly produced epithelial MEC attracts primed B cells via CCR10. The urogenital tract may employ similar molecular homing mechanisms as the upper aerodigestive tract and the large bowel, therefore probably receiving primed cells from inductive sites in both these regions. In addition, lactating mammary glands appear to receive primed cells from NALT as well as GALT, and much more efficiently so than the urogenital tract.
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dichotomy of their dispersion to the aerodigestive tract versus the small intestine and the appendix (Fig. 2). Altogether, in view of the immunization data referred to above, there is good reason to believe that the IgD+IgM tonsillar subset used as a surrogate marker for B cell migration from nasopharynx-associated MALT throughout the body, displays homing properties shared by most J chain-expressing B cells primed in Waldeyer’s ring. The compartmentalized differences thus revealed directly in the human mucosal immune system must be taken into account in the delivery design of future local vaccines. 3. Allergic reactions and atopic mucosal disease Activated in MALT or locally in the mucosa, CD4+ T helper (Th) cells may—by a Th2 profile of cytokines such as IL-4, IL-5 and IL-13—promote the development of atopic diseases due to IgE-mediated allergy (type I hypersensitivity) [11]. Antibodies of the IgE class are the basis for mast-cell degranulation causing immediate types of allergy, including allergic rhinitis or rhinoconjunctivitis (hay fever) and extrinsic asthma. IL-4 and IL-13 act as B cell switch factors crucial for production of IgE [30]. Other cytokines such as IL-3 and IL-5 promote persistent allergic inflammation with extravasation and
Fig. 4. Schematic representation of three biological variables that may contribute to the disparity in the immunosuppressive tone of the airways versus the gut. Upper panel: numbers and phenotypic distribution of intraepithelial lymphocytes (IELs). Middle panel: capacity for antigen presentation, including expression of costimulatory signals to T cells by HLA class I- and class II-positive (HLA I/II+) epithelial cells (e.g., ICAM-1), leading to preferential help or suppression. Bottom panel: distribution of subepithelial and intraepithelial professional APCs.
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priming of eosinophils, the so-called late-phase allergic reaction (Fig. 3). Eosinophils are potentially tissue-destructive cells, particularly after priming with IL-5 [11]. Cytokines also upregulate adhesion molecules on vascular endothelium and respiratory epithelial cells, thereby enhancing migration of eosinophils and other leukocytes into the lamina propria and surface epithelium [11,31,32]. Intercellular adhesion molecule-1 (ICAM-1, CD54) which readily becomes upregulated by IFN-g in airway epithelium, is of particular importance for further migration of leukocytes onto the mucosal surface [1]. However, epithelial ICAM-1 may also provide a co-signal for hyperactivation of CD4+ Th cells by antigen-presenting HLA class I- and II (HLA-DR)-expressing epithelium [33]. This latter feature may contribute to the fact that the airway mucosa appears less able than the gut mucosa to engage CD8+ intraepithelial lymphocytes (Fig. 4)—which moreover are relatively few in the airway epithelium [34]—for downregulation of hypersensitivity responses against harmless environmental antigens [11]. 4. Role of mucosal dendritic cells in allergy Dendritic cells (DCs) may be even more crucial than CD8+ intraepithelial lymphocytes in tolerance induction against soluble antigens such as allergens [35] and a variety of DCs and macrophages are present both within and below the human airway epithelium [19]. Some of these cells such as the CD123+ (IL-3R+) plasmacytoid variant (P-DC) can skew a Th cell response towards a Th2 cytokine profile, at least in a secondary immune response
Fig. 5. Hypothetical scheme for the pathogenesis of nasal allergy. An unknown ‘‘initiating hit’’ (e.g., virus infection) activates the surface epithelium or mast cells, which results in secretion of TSLP. This cytokine activates myeloid CD11c+ DCs, which makes them drive naı¨ve T cells towards a Th2 profile during initial allergen presentation. Virus-infected epithelial cells may release Type 1 interferons (IFN-a and IFN-h) that stimulate natural killer (NK) cells to release IL-3, an important growth factor for CD123+ plasmacytoid dendritic cells (P-DCs). In a secondary response to the same allergen, P-DCs may efficiently enhance Th2 skewing, thereby creating a vicious circle that leads to perpetuation of the allergic reaction and involvement of tissue-destructive eosinophilic (Eos.) granulocytes. Further details are discussed in the text.
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[36]. Notably, P-DCs are abundant in allergen-challenged nasal mucosa of patients with allergic rhinitis [37]. The initial event in this disease process may be activation of mucosal CD11c+ myeloid DCs by the IL-7-like cytokine ‘thymic stromal lymphopoietin’ (TSLP) derived from the airway epithelium or from activated mucosal mast cells (Fig. 5). TSLPactivated human myeloid DCs can prime naı¨ve CD4+ T cells to produce IL-4, IL-5 and IL13, while suppressing production of the crossregulatory cytokines IL-10 and IFN-g [38]. Such events may prepare the airway mucosa for secondary Th2 responses induced by PDCs, thus initiating a vicious circle (Fig. 5). Rational mucosal induction of immune tolerance may become possible in the future to prevent the development of respiratory allergy. Therapeutic control of mucosal expression of certain adhesion molecules and immunological modulation to achieve deviation from a skewed Th2 response towards a balanced Th1/Th2 cytokine profile may furthermore become an adjunct in the treatment of allergic disease [39]. A particularly interesting possibility is phenotypic modulation of DCs involved in allergy induction, for instance, via their Toll-like receptors (TLRs). Thus, CD11c+ myeloid DCs and CD123+ P-DCs express separate TLRs and may therefore be activated by different types of microbial components. Most importantly, in this context, human P-DCs express TLR9 which can engage unmethylated CpG motifs of microbial DNA selectively, thereby providing co-stimulatory signals for Th1 polarization [40]. Therefore, intranasal immunotherapy with CpG motifs as an adjuvant may be a future option to break the vicious circle (Fig. 5) in the pathogenesis of atopic disease. Acknowledgements Studies in the author’s laboratory are supported by the University of Oslo, the Research Council of Norway, the Norwegian Cancer Society, Anders Jahre’s Fund and Rakel and Otto Kr. Bruun’s Legacy. Hege Eliassen and Erik K. Hagen are gratefully acknowledged for excellent assistance with the manuscript. References [1] P. Brandtzaeg, Immunocompetent cells of the upper airway: functions in normal and diseased mucosa, Eur. Arch. Otorhinolaryngol. 252 (Suppl. 1) (1995) S8 – S21. [2] P. Brandtzaeg, H. Prydz, Direct evidence for an integrated function of J chain and secretory component in epithelial transport of immunoglobulin, Nature 311 (1984) 71 – 73. [3] P. Brandtzaeg, I.N. Farstad, F.-E. Johansen, H.C. Morton, I.N. Norderhaug, T. Yamanaka, The B-cell system of human mucosae and exocrine glands, Immunol. Rev. 171 (1999) 45 – 87. [4] H. Schjerven, P. Brandtzaeg, F.-E. Johansen, Mechanism of IL-4-mediated up-regulation of the polymeric Ig receptor: role of STAT6 in cell type-specific delayed transcriptional response, J. Immunol. 165 (2000) 3898 – 3906. [5] H. Schjerven, P. Brandtzaeg, F.-E. Johansen, A novel NF-nB/Rel site in intron 1 cooperates with proximal promoter elements to mediate TNF-a-induced transcription of the human polymeric Ig receptor, J. Immunol. 167 (2001) 6412 – 6420. [6] H. Schjerven, P. Brandtzaeg, F.-E. Johansen, Hepatocyte NF-1 and STAT6 cooperate with additional DNAbinding factors to activate transcription of the human polymeric Ig receptor gene in response to IL-4, J. Immunol. 170 (2003) 6048 – 6056. [7] P. Brandtzaeg, Role of secretory antibodies in the defence against infection, Int. J. Med. Microbiol. 293 (2003) 3 – 15. [8] C.G. Persson, J.S. Erjefalt, L. Greiff, I. Erjefalt, M. Korsgren, M. Linden, F. Sundler, M. Andersson,
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