Article Text
PDF
Statistics from Altmetric.com
There are many studies dedicated to the allergic nose, but most of them deal with seasonal allergic rhinitis and particularly with acute experimental situations. Perennial allergic rhinitis is less well documented.
When studying the allergic nose, several aspects must be taken into consideration: the genetic background of the patient, various environmental factors (antigens, air pollution, climate), and the peculiar characteristics of the nose itself including its anatomy—total surface area: 150 cm2, volume: 15 ml—and histology—epithelium (ciliated, non ciliated, pseudostratified, columnar, goblet cells), mucus, immunocompetent cells, lamina propria, basement membrane, blood supply, and nerves and neurotransmitters.1
It is well recognised that the symptoms of perennial allergic rhinitis are caused by overproduction of different families of chemical mediators. These mediators are produced by migrating or resident inflammatory cells, by resident cells, or by inflammatory cells produced locally from progenitors—for example, T cells, mast cells, eosinophils, neutrophils, epithelial cells, endothelial cells, and antigen presenting cells (APCs). This review focuses on some recent aspects of perennial allergic rhinitis which cast new light on the pathophysiology of this common disease.
Cytokine profile in perennial allergic rhinitis
Since the description by Mosmann2 of the dichotomy of the murine T cell, a Th2/Th1 imbalance has been described in allergic conditions in humans. The nasal mucosa in perennial allergic rhinitis is characterised by the presence of a high percentage of activated Th2 cells accompanied by high levels of Th2 cytokines, increased expression of leucocyte endothelial adhesion molecules, and accumulation of activated eosinophils.3 As a result there is a significant increase in eosinophil cationic protein (ECP) levels in the nasal lavage fluid of patients with perennial allergic rhinitis compared with controls (±85 ng/ml versus 32 ng/ml).4
Nasal biopsy specimens taken from patients with perennial allergic rhinitis and measurements of cytokine mRNA expression show a significant increase in interleukin (IL)-5 expressing cells and a significant decrease in IL-2 expressing cells.5 In recent experiments attention has focused on the epithelial cells as regulators of airway inflammation. Several mediators are released by these cells including lipid mediators, cyclo-oxygenase derivatives, peptides (endothelin, vasopressin, substance P, CGRP), oxygen products, peptidases, and cytokines.6 Although keratinocytes, fibroblasts, Langerhans' cells, and mast cells seem to be prominent sources of stem cell factor (SCF), epithelial cells of patients with perennial allergic rhinitis also show increased expression of SCF mRNA.7 This increased expression is correlated with the number of mast cells and the histamine content.
It is known that several elements may play a role in the differentiation of Th0 cells into Th2 cells including the nature of the antigen itself, its concentration, the route of its administration, the CD40-CD40 ligand interaction, the costimulatory molecules CD80 and CD86 and their contrareceptor CD28, and the cytokine milieu but, in patients with perennial allergic rhinitis, it has been shown that CD86 (B7-2) expression on B cells and monocytes shows selective upregulation on in vitro challenge with house dust mite antigen which suggests a major role for CD86 in this differentiation.8
Interestingly, in 1997 Meissner et al 9 reported the presence of a subset of CD8+ T cells producing IL-4 and stimulating IgE production in vitro in the peripheral blood of cat sensitive patients with rhinitis or asthma. In this study the frequency of IL-4+ CD8+ T cells correlated with serum IgE levels. Also of interest is the presence of activated Th2-like γδ T cells in the nasal mucosa of patients with perennial allergic rhinitis as shown by Pawankar et al in 1996.10 It therefore seems likely that at least three types of Th2-like cells may coexist in the nose of subjects with perennial allergic rhinitis: αβ Th2, γδ Th2, and CD8+ Th2 cells. The situation could be even more complex since it is now possible to identify Th1, Th2, Th0, TC2 CD8+ (producing IL-4 and IL-5), Th3 CD4+ (producing TGF-β), Th3 CD8+ (producing TGF-β), Tr1 CD4+ (producing IL-10, IL-5, TGF-β) and so on.11 Allergy could also represent a pathological aberration of mucosal tolerance leading to the production of “helper” Th2 cells instead of “regulatory/suppressor” Th2 cells.12 Clearly the concept of murine T cell dichotomy must be questioned.
This review of the probable complexity of cytokine and T cell profiles in patients with perennial allergic rhinitis is substantiated by Metzet al 13 who showed that the cytokine profiles of patients with chronic allergic keratoconjunctivitis are characterised by increased expression of IL-5 together with interferon (IFN)-γ in T cells recovered from the conjunctiva—that is, a Th0 type rather than the expected Th2 type.
Another interesting observation is that the eosinophils of patients with allergic keratoconjunctivitis appear to be highly activated and to have a significantly higher expression of cytokines such as IL-4, GM-CSF, and IL-8.14 This pattern differs from that observed in patients with giant papillary conjunctivitis and vernal keratoconjunctivitis, suggesting the existence of different “populations” of eosinophils. Hingorani et alconcluded that the profiles may depend on the duration and stage of the disease: acute, subacute, chronic; existence of remodelling. There are probably similarities between allergic tissues (eyes, nose, bronchi, and skin), but there are also differences and the pattern of cells and cytokines in patients with perennial allergic rhinitis may be quite different from those in the eyes of patients with allergic keratoconjunctivitis.
Histamine in perennial allergic rhinitis
Histamine has long been considered to be the mediator of the acute type 1 allergic reaction. Accordingly, the H1antihistamines were also considered to be the ideal symptomatic treatment for pruritus, sneezing, and runny nose. Banu and Watanabe15 recently reported that T cells deficient in H1 receptors (histamine H1R knockout mice) have a low proliferation response to anti-CD3ε cross linking or antigen stimulation in vitro. A similarly deficient response was observed in B cells. This suggests that histamine may play a part in regulating some fundamental steps of the antigen-antibody conflict. It also means that the H1 antihistamines are probably more than symptomatic approaches to the allergic conditions.
It has also been recently reported that H1 receptor expression is increased in the nasal mucosa of patients with perennial allergic rhinitis.16. Moreover, it has been shown that histamine decarboxylase mRNA is significantly increased while histamine N-methyltransferase mRNA is decreased.17
Timmerman and coworkers recently presented some interesting preliminary data to the annual meeting of the European Academy of Allergology and Clinical Immunology held in Brussels on 3–7 July 1999. They showed that some H1 antagonists behave as inverse agonists, in the same way as H2 antagonists.18 These recent data cast a new light on histamine, on histamine H1receptors, on H1 antagonists, and on therapeutic approaches with compounds of this family which appear rather heterogeneous. Much remains to be done, of course, to elucidate the pathophysiology of perennial allergic disease and the mechanisms of action of the drugs commonly used to treat it.