Rhinitis with negative skin tests and absent serum allergen-specific IgE: More evidence for local IgE?

Abstract

The phenomenon of local production of IgE in the nasal mucosa is well documented in subjects with allergic rhinitis who have raised serum specific IgE and positive skin prick tests to clinically relevant allergens.1Durham S.R. Gould H.J. Thienes C.P. Jacobson M.R. Masuyama K. Rak S. et al.Expression of epsilon germ-line transcripts and mRNA for the epsilon heavy chain of IgE in nasal B cells and the effects of topical corticosteroid.Eur J Immunol. 1997; 27: 2899-2906Crossref PubMed Scopus (158) Google Scholar, 2Smurthwaite L. Walker S.N. Wilson D.R. Birch D.S. Merrett T.G. Durham S.R. et al.Persistent IgE synthesis in the nasal mucosa of hayfever patients.Eur J Immunol. 2001; 31: 3422-3431Crossref PubMed Scopus (118) Google Scholar, 3Takhar P. Smurthwaite L. Coker H.A. Fear D.J. Banfield G.K. Carr V.A. et al.Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis.J Immunol. 2005; 174: 5024-5032PubMed Google Scholar, 4KleinJan A. Godthelp T. van Toornenenbergen A.W. Fokkens W.J. Allergen binding to specific IgE in the nasal mucosa of allergic patients.J Allergy Clin Immunol. 1997; 99: 515-521Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Local IgE has also been detected in high levels in nasal polyps in which Staphylococcus-derived enterotoxins are associated with elevated enterotoxin-specific IgE antibodies and likely act as superantigens, thereby promoting increases in polyclonal IgE.5Patou J. Gevaert P. Van Zele T. Holtappels G. van Cauwenberge P. Bachert C. Staphylococcus aureus enterotoxin B, protein A, and lipoteichoic acid stimulations in nasal polyps.J Allergy Clin Immunol. 2008; 121: 110-115Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar Nonallergic rhinitis in the absence of systemic allergen-specific IgE with/without associated eosinophilia affects approximately 25% of patients who experience symptoms of rhinitis.6Bousquet J. Fokkens W. Burney P. Durham S.R. Bachert C. Akdis C.A. et al.Important research questions in allergy and related diseases: nonallergic rhinitis: a GA2LEN paper.Allergy. 2008; 63: 842-853Crossref PubMed Scopus (147) Google Scholar In a subset of this group of heterogeneous disorders, IgE is detectable within the nasal mucosa and/or nasal secretions, implying that an IgE-mediated allergic response may be localized exclusively to the target organ. Huggins and Brostoff7Huggins K.G. Brostoff J. Local IgE antibodies in allergic rhinitis.Lancet. 1975; 2: 618Abstract PubMed Scopus (6) Google Scholar originally demonstrated the presence of specific IgE in nasal secretions of patients with rhinitis with negative skin prick tests. A number of studies since have provided further evidence of local allergic rhinitis in such patients.8Powe D.G. Jagger C. Kleinjan A. Carney A.S. Jenkins D. Jones N.S. “Entopy”: localized mucosal allergic disease in the absence of systemic responses for atopy.Clin Exp Allergy. 2003; 33: 374-379Crossref Scopus (175) Google Scholar, 9Powe D.G. Huskisson R.S. Carney A.S. Jenkins D. McEuen A.R. Walls A.F. et al.Mucosal T-cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells.Allergy. 2004; 59: 204-212Crossref PubMed Scopus (62) Google Scholar, 10Rondón C. Dona I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (134) Google Scholar, 11Carney A.S. Atypical nasal challenges in patients with idiopathic rhinitis: more evidence for the existence of allergy in the absence of atopy?.Clin Exp Allergy. 2002; 32: 1436-1440Crossref PubMed Scopus (118) Google Scholar Rondón et al12Rondón C. Romero J.J. Lopez S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar previously reported elevations in allergen-specific IgE in nasal lavage in a proportion of subjects who responded positively to a nasal allergen challenge in the absence of positive skin tests or elevated allergen-specific IgE. In this issue of the Journal,13Rondón C. Fernández J. López S. Campo P. Doña I. Torres M.J. et al.Nasal inflammatory mediators and specific IgE production after nasal challenge with grass in local allergic rhinitis.J Allergy Clin Immunol. 2009; 124: 1005-1011Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Rondón et al describe the associated local inflammatory response in 30 such patients. The mean age of onset of local allergic rhinitis in the cohort was 31 years, with a female to male bias of 19:11. Nearly half (14/30) of the patients with local allergic rhinitis had asthma, and 57% (17/30) had conjunctivitis. Symptoms were assessed by using a visual analogue scale and nasal patency by acoustic rhinometry at intervals after nasal provocation with grass pollen extract. Tryptase, eosinophilic cationic protein, and grass pollen–specific IgE were measured in nasal lavage. Intranasal challenge resulted in immediate (15 minutes to 1 hour) responses in all subjects and additional late responses (6-24 hours) in 70% of those tested. The proportion of patients with an isolated immediate response was similar to previous studies by the authors.10Rondón C. Dona I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (134) Google Scholar, 12Rondón C. Romero J.J. Lopez S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Although the significance of an absent late response is questionable, 90% of patients with isolated immediate responses had conjunctivitis compared with 57% in those with dual responses. Tryptase in nasal lavage, a marker of mast cell activation, was increased in 40% of subjects. Levels peaked at 15 minutes and remained elevated for 24 hours. Increased mast cell numbers have previously been identified in the nasal mucosa of patients with nonallergic rhinitis compared with healthy controls.14Powe D.G. Huskisson R.S. Carney A.S. Jenkins D. Jones N.S. Evidence for an inflammatory pathophysiology in idiopathic rhinitis.Clin Exp Allergy. 2001; 31: 864-872Crossref PubMed Scopus (123) Google Scholar, 15Berger G. Goldberg A. Ophir D. The inferior turbinate mast cell population of patients with perennial allergic and nonallergic rhinitis.Am J Rhinol. 1997; 11: 63-66Crossref PubMed Scopus (41) Google Scholar There was a correlation between tryptase and immediate nasal symptoms of itching and sneezing. Eosinophilic cationic protein, a marker of eosinophil activation, was detected at 15 minutes and continued to rise over a period of 24 hours in 43% of subjects. Eosinophilic cationic protein correlated only with nasal obstruction, which was more frequently reported during late responses. Time-dependent increases in grass pollen–specific IgE up to 24 hours were detected in nasal lavage in 9 of 30 subjects, in 4 of whom specific IgE was detectable before challenge despite the study being conducted outside the pollen season. These and previous data3Takhar P. Smurthwaite L. Coker H.A. Fear D.J. Banfield G.K. Carr V.A. et al.Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis.J Immunol. 2005; 174: 5024-5032PubMed Google Scholar, 10Rondón C. Dona I. López S. Campo P. Romero J.J. Torres M.J. et al.Seasonal idiopathic rhinitis with local inflammatory response and specific IgE in absence of systemic response.Allergy. 2008; 63: 1352-1358Crossref PubMed Scopus (134) Google Scholar, 12Rondón C. Romero J.J. Lopez S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar imply that the absence of systemic IgE does not necessarily exclude local IgE-mediated allergic disease. There are some limitations to the findings. Local specific IgE was not detected in the majority of positive responders to grass pollen. The specificity of the local IgE response could have been further examined by including, in addition to healthy controls, a control group of patients with rhinitis with negative responses to nasal grass pollen challenge. The authors argue that the detection of local IgE in only a proportion may be secondary to a dilution effect of the nasal lavage procedure, whereas their findings are consistent with previous studies. Powe et al8Powe D.G. Jagger C. Kleinjan A. Carney A.S. Jenkins D. Jones N.S. “Entopy”: localized mucosal allergic disease in the absence of systemic responses for atopy.Clin Exp Allergy. 2003; 33: 374-379Crossref Scopus (175) Google Scholar identified positive immunostaining for grass pollen–specific IgE within the nasal mucosa in 30% (3/10) of patients with idiopathic rhinitis. Rondón et al12Rondón C. Romero J.J. Lopez S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar previously identified specific IgE in nasal lavage in only 22% (7/32) of those subjects with idiopathic rhinitis who responded to grass pollen challenge. It remains to be determined what causes inflammation in the remaining 70%. One possibility is that grass pollen–associated proteins or lipid mediators activate eosinophils and/or other inflammatory cells directly and independently of IgE as previously shown for tree pollen.16Traidl-Hoffmann C.P. Mariani V. Hochrein H. Karg K. Wagner H. Ring J. et al.Pollen-associated phytoprostanes inhibit dendritic cell interleukin-12 production and augment T helper type 2 cell polarization.J Exp Med. 2005; 201: 627-636Crossref PubMed Scopus (243) Google Scholar What are the clinical implications? First, it is well known that some atopic individuals develop rhinitis whereas others develop asthma and/or atopic dermatitis, and some subjects have no clinical manifestations despite positive skin tests and/or specific IgE. The local provenance of IgE at mucosal sites might explain this discrepancy. Second, as shown by Rondón et al12Rondón C. Romero J.J. Lopez S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar and in previous studies of intrinsic rhinitis17Ghaffar O. Durham S.R. Gould H.J. Hamid Q.A. Expression of IgE heavy chain transcripts in the sinus mucosa of atopic and non-atopic patients with chronic sinusitis.Am J Respir Cell Biol. 1998; 18: 706-711Crossref PubMed Scopus (31) Google Scholar and asthma,18Ying S. Humbert M. Meng Q. Pfister R. Menz G. Gould H.J. et al.Local expression of epsilon germline gene transcripts and RNA for the epsilon heavy chain of IgE in the bronchial mucosa in atopic and nonatopic asthma.J Allergy Clin Immunol. 2001; 107: 686-692Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 19Takhar P. Corrigan C.J. Smurthwaite L. O'Connor B.J. Durham S.R. Lee T.H. et al.Class switch recombination to IgE in the bronchial mucosa of atopic and nonatopic patients with asthma.J Allergy Clin Immunol. 2007; 119: 213-218Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar local IgE could explain the occurrence of disease in the absence of systemic allergen-specific IgE. The implication is that nasal and/or bronchial allergen provocation might have a more prominent role in diagnosis when the clinical history is highly suggestive of involvement of an environmental allergen despite negative skin tests and serum allergen-specific IgE. Third, despite confirmation of local IgE protein production,12Rondón C. Romero J.J. Lopez S. Antúnez C. Martín-Casañez E. Torres M.J. et al.Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis.J Allergy Clin Immunol. 2007; 119: 899-905Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar, 20Wilson D.R. Merrett T.G. Varga E.M. Smurthwaite L. Gould H.J. Kemp M. et al.Increases in allergen-specific IgE in BAL after segmental allergen challenge in atopic asthmatics.Am J Respir Crit Care Med. 2002; 165: 22-26Crossref PubMed Scopus (68) Google Scholar it is not clear to what extent local versus systemically produced IgE contributes to disease burden. Local strategies directed against IgE might resolve this issue and potentially provide a novel treatment approach. A pilot study of local inhaled anti-IgE in atopic asthma21Fahy J.V. Cockcroft D.W. Boulet L.P. Wong H.H. Deschesnes F. Davis E.E. et al.Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects.Am J Respir Crit Care Med. 1999; 160: 1023-1027Crossref PubMed Scopus (136) Google Scholar was associated with the occurrence of sensitization against the mAb when used via the mucosal route. The development of small molecule inhibitors for topical use directed against either IgE interaction with its receptors22Hunt J. Bracher M.G. Shi J. Fleury S. Dombrowicz D. Gould H.J. et al.Attenuation of IgE affinity for Fc epsilon R1 radically reduces the allergic response in vitro and in vivo.J Biol Chem. 2008; 283: 29882-29887Crossref PubMed Scopus (10) Google Scholar or the mechanism of switching of B cells in favor of IgE might be effective and might circumvent this problem.