John T. Connell and nasal priming
Authors: A SAHINYILMAZ, R NACLERIO
Journal: Journal of Allergy and Clinical Immunology (2006)

Nasal primingIn 1968, Connell1Connell J.T. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.J Allergy. 1968; 41: 123-139Abstract Full Text PDF PubMed Scopus (131) Google Scholar described the results of quantitative intranasal challenges with ragweed pollen. When he administered the pollen daily to patients with ragweed-induced allergic rhinitis, he found that smaller doses were required on each succeeding day to cause the same or greater degree of symptomatic allergic response. He titled this phenomenon of increased nasal reactivity to pollen after repeated challenges “the priming effect.”1Connell J.T. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.J Allergy. 1968; 41: 123-139Abstract Full Text PDF PubMed Scopus (131) Google Scholar, 2Connell J.T. Quantitative intranasal pollen challenges. 3. The priming effect in allergic rhinitis.J Allergy. 1969; 43: 33-44Abstract Full Text PDF PubMed Scopus (255) Google Scholar Connell observed that priming of the nasal membrane could also increase symptoms to nonpriming allergens and to nonallergic stimuli. Daily unilateral pollen challenges primed only the nostril challenged. Complete recovery from priming occurred when challenges were withheld for 4 weeks. On the basis of this evidence, he described priming as a nonspecific, local, and reversible phenomenon. The clinical correlate of this laboratory finding is the increased symptoms reported by patients as the pollen counts decrease toward the end of seasonal exposure.Subsequent studies on the priming effect. In 1981, Bacon et al3Bacon J.R. McLean J.A. Mathews K.P. Banas J.M. Priming of the nasal mucosa by ragweed extract or by an irritant (ammonia).J Allergy Clin Immunol. 1981; 67: 111-116Abstract Full Text PDF PubMed Scopus (33) Google Scholar revisited Connell's observations on priming. They verified that priming was reproducible and transient, but they failed to demonstrate that priming caused hyperresponsiveness to an irritant (ammonia gas). In consecutive studies Naclerio and colleagues4Naclerio R.M. Proud D. Togias A.G. Adkinson Jr., N.F. Meyers D.A. Kagey-Sobotka A. et al.Inflammatory mediators in late antigen-induced rhinitis.N Engl J Med. 1985; 313: 65-70Crossref PubMed Scopus (584) Google Scholar, 5Pipkorn U. Proud D. Lichtenstein L.M. Schleimer R.P. Peters S.P. Adkinson Jr., N.F. et al.Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.J Clin Invest. 1987; 80: 957-961Crossref PubMed Scopus (129) Google Scholar performed a second allergen challenge at 11 hours after the first, which resulted in an augmented clinical response, a confirmation of priming to an antigen. In these studies mediator release was also measured. During the rechallenge reaction, the amount of histamine release increased, but the amount of prostaglandin D2 generation did not change. Because mast cells release both histamine and prostaglandin D2 and basophils release only histamine, they speculated that basophils recruited hours after the initial antigen challenge provided additional targets for antigen, thus providing a potential explanation for priming; that is, mast cells respond to the initial reaction, and basophils plus mast cells react to the rechallenge.In a subsequent study by Bascom et al,6Bascom R. Wachs M. Naclerio R.M. Pipkorn U. Galli S.J. Lichtenstein L.M. Basophil influx occurs after nasal antigen challenge: effects of topical corticosteroid pretreatment.J Allergy Clin Immunol. 1988; 81: 580-589Abstract Full Text PDF PubMed Scopus (184) Google Scholar the authors showed the presence of basophils in nasal lavage fluid. In an eloquent study Iliopoulos et al7Iliopoulos O. Baroody F.M. Naclerio R.M. Bochner B.S. Kagey-Sobotka A. Lichtenstein L.M. Histamine-containing cells obtained from the nose hours after antigen challenge have functional and phenotypic characteristics of basophils.J Immunol. 1992; 148: 2223-2228PubMed Google Scholar used flow cytometry to demonstrate cell markers on the surface of the cells in lavage fluid, which were consistent with basophils. Furthermore, they harvested the cells from lavage fluid and showed that they responded in vitro like basophils. Studies by other investigators have shown the presence of basophils in allergic inflammatory responses.In studies first performed by Pipkorn and Enerback,8Pipkorn U. Enerback L. Nasal mucosal mast cells and histamine in hay fever. Effect of topical glucocorticoid treatment.Int Arch Allergy Appl Immunol. 1987; 84: 123-128Crossref PubMed Google Scholar they showed that mast cells migrate toward the epithelium during the allergy season, thus potentially contributing to priming during long-term seasonal exposure to allergen.Other studies stressed the role of eosinophils and eosinophil-derived mediators in the late antigen-induced reaction and the possibility of priming. Eosinophil-derived cytotoxic proteins, such as major basic protein, eosinophil-derived neurotoxin, or eosinophilic cationic protein, were postulated to play a role in nasal obstruction and to contribute to nasal mucosal damage and development of nasal hyperreactivity. One idea considered was that loss of barrier function caused by these proteins would allow greater antigen penetration into the nasal mucosa and thus a greater allergic reaction on re-exposure to antigen (ie, priming).Wachs et al9Wachs M. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Norman P.S. Naclerio R.M. Observations on the pathogenesis of nasal priming.J Allergy Clin Immunol. 1989; 84: 492-501Abstract Full Text PDF PubMed Scopus (78) Google Scholar verified that priming occurred and found significant correlations between the augmented clinical response, hyperresponsiveness, and the inflammatory cell influx of eosinophils, neutrophils, and basophils. In healthy control subjects rechallenge with neither histamine nor methacholine resulted in increased nonspecific nasal reactivity.10Gronborg H. Borum P. Mygind N. Histamine and methacholine do not increase nasal reactivity.Clin Allergy. 1986; 16: 597-602Crossref PubMed Scopus (36) Google Scholar Later, Walden et al11Walden S.M. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Naclerio R.M. Antigen-provoked increase in histamine reactivity. Observations on mechanisms.Am Rev Respir Dis. 1991; 144: 642-648Crossref PubMed Google Scholar confirmed that the histamine provocation did not induce increased reactivity to itself or to antigen, but antigen challenge induced a reversible increase in responsiveness to histamine, which is associated with an inflammatory cell infiltration. Juliusson and Bende12Juliusson S. Bende M. Priming effect of a birch pollen season studied with laser Doppler flowmetry in patients with allergic rhinitis.Clin Allergy. 1988; 18: 615-618Crossref PubMed Scopus (26) Google Scholar verified the increased sensitivity of the resistance vessels caused by the priming effect by using laser Doppler flowmetry. These studies shed light on the question why allergic subjects complain more about nonallergic irritants during seasonal exposure than nonallergic subjects.The relationship of priming to other allergic responses was another area of investigation. Andersson et al13Andersson M. von Kogerer B. Andersson P. Pipkorn U. Allergen-induced nasal hyperreactivity appears unrelated to the size of the nasal and dermal immediate allergic reaction.Allergy. 1987; 42: 631-637Crossref PubMed Scopus (32) Google Scholar found no correlation between the increased responsiveness in the nose and the presence or size of the initial allergen response in the nose or skin. Bousquet et al14Bousquet J. Lebel B. Dhivert H. Bataille Y. Martinot B. Michel F.B. Nasal challenge with pollen grains, skin-prick tests and specific IgE in patients with grass pollen allergy.Clin Allergy. 1987; 17: 529-536Crossref PubMed Scopus (68) Google Scholar noted a significant correlation between nasal provocation test and skin prick test end points, but no correlation was present between nasal challenge and serum-specific IgE levels. In a study of randomly selected and previously unchallenged subjects (n = 55) who had ragweed-induced allergic rhinitis, 47% had a late-phase reaction, 41% showed an increase in mediators during a rechallenge reaction, and an additional 20% had an enhanced symptomatic response without a concomitant increase in mediators. These investigators noted that a preceding late-phase reaction was not obligatorily linked to an enhanced rechallenge reaction, and the association between the levels of histamine generated during the late phase and during the rechallenge response was stronger than the association between other mediators. The cellular influx was proposed to serve as a connection between the late and enhanced rechallenge responses, and the basophil influx was postulated to serve as a target for antigen during the rechallenge response.15Iliopoulos O. Proud D. Adkinson Jr., N.F. Norman P.S. Kagey-Sobotka A. Lichtenstein L.M. et al.Relationship between the early, late, and rechallenge reaction to nasal challenge with antigen: observations on the role of inflammatory mediators and cells.J Allergy Clin Immunol. 1990; 86: 851-861Abstract Full Text PDF PubMed Scopus (102) Google Scholar This study also provided the best estimate of the incidence of the priming phenomenon in allergic subjects, although it does not exclude the possibility that more prolonged exposure to allergen over several days would increase the incidence. In addition, these studies demonstrated the heterogeneity of the responses after an antigen challenge and showed that different mechanisms could be involved in the individual components of the mucosal changes that make up priming.In 1998, Ciprandi et al16Ciprandi G. Ricca V. Landi M. Passalacqua G. Bagnasco M. Canonica G.W. Allergen-specific nasal challenge: response kinetics of clinical and inflammatory events to rechallenge.Int Arch Allergy Immunol. 1998; 115: 157-161Crossref PubMed Scopus (25) Google Scholar evaluated the effects of nasal rechallenge on symptoms and inflammatory cell infiltration of 40 allergic patients who underwent 2 nasal challenges at baseline and another after 3 days and after 1, 2, and 4 weeks. They showed that the priming effect is detectable by using a rechallenge after a 3-day period, that the 1- and 4-week challenges show a reactivity equal to the baseline value, and that evidence of a hyporesponsive phase was seen in the target organ after 2 weeks. The hyporesponsive phase points to a continually changing immunologic response days after antigen exposure.Whether a preceding airway response to one allergen leads to priming of the airway response to another allergen was studied. The data indicated that a preceding airway response to one allergen might lead to priming, with enhancement of the early and late airway responses to the subsequent challenge with another allergen.17Koh Y.Y. Choi J.W. Lee M.H. Sun Y.H. Lee S.I. Lee S.Y. et al.A preceding airway reaction to one allergen may lead to priming of the airway responses to another allergen.Allergy. 1997; 52: 284-292Crossref PubMed Scopus (11) Google Scholar Similarly, Bousquet et al18Bousquet J. Hejjaoui A. Becker W.M. Cour P. Chanal I. Lebel B. Clinical and immunologic reactivity of patients allergic to grass pollens and to multiple pollen species. I. Clinical and immunologic characteristics.J Allergy Clin Immunol. 1991; 87: 737-746Abstract Full Text PDF PubMed Scopus (48) Google Scholar showed that polysensitized patients had nasal symptoms that occurred earlier than those in monosensitized patients, possibly because of the priming effect caused by other plants pollenating earlier.There is increasing evidence that once an antigen challenge transpires and local symptoms are induced, the ensuing inflammatory cascade has both a local and a systemic nature. For example, Saini et al19Saini S. Bloom D.C. Bieneman A. Vasagar K. Togias A. Schroeder J. Systemic effects of allergen exposure on blood basophil IL-13 secretion and FcepsilonRIbeta.J Allergy Clin Immunol. 2004; 114: 768-774Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar recently demonstrated that repeated nasal allergen challenge is capable of inducing systemic effects on circulating basophils, causing these cells to increase their expression of FcɛRIβ (β chain of the high-affinity receptor for IgE) and spontaneously to secrete IL-13. This suggests a potential explanation of how an allergic reaction in the nose might lead to an augmented late reaction in other organs after allergen exposure there.Studies on inhibition of the priming effect are few. Systemic steroids were shown effectively to inhibit the clinical and cellular manifestations of an antigen-induced late-phase allergic reaction and the increased rechallenge reaction without affecting the early response.5Pipkorn U. Proud D. Lichtenstein L.M. Schleimer R.P. Peters S.P. Adkinson Jr., N.F. et al.Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.J Clin Invest. 1987; 80: 957-961Crossref PubMed Scopus (129) Google Scholar Two weeks of treatment with topical steroids was shown to have similar effects on the late and rechallenge reaction, but they were also capable of suppressing the early reaction to antigen.20Pipkorn U. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Norman P.S. Naclerio R.M. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids.N Engl J Med. 1987; 316: 1506-1510Crossref PubMed Scopus (228) Google Scholar Pretreatment with flunisolide prevented the influx of mediator-releasing cells, including basophils, into the nose. Immunotherapy ameliorates seasonal symptoms of allergic rhinitis and reduces the early, late, and rechallenge reactions to antigen challenge.21Iliopoulos O. Proud D. Adkinson Jr., N.F. Creticos P.S. Norman P.S. Kagey-Sobotka A. et al.Effects of immunotherapy on the early, late, and rechallenge nasal reaction to provocation with allergen: changes in inflammatory mediators and cells.J Allergy Clin Immunol. 1991; 87: 855-866Abstract Full Text PDF PubMed Scopus (137) Google Scholar The effect of other treatments on nasal priming has not been studied directly.Current understanding of the priming effectBy the end of the last millennium, it was well known that the mechanisms underlying the pathophysiology of allergic rhinitis involved an acute early-phase and a late-phase reaction, with the latter being associated with cellular infiltration in which eosinophils and lymphocytes are important components. The late response results in a state of nasal hyperresponsiveness of the nasal mucosa to further allergen exposure (ie, priming). More specific explanations for the mechanism underlying priming include the recruitment of basophils to act as additional target cells, hyperresponsiveness of nerves and blood vessels to subsequent stimulation, greater penetrability of antigen, movement of mast cells toward the surface, synergism between release of inflammatory mediators during cellular recruitment and in response to re-exposure to antigen, local synthesis of IgE, and priming of recruited cells. It is unlikely that one mechanism explains the pathophysiology of priming at all time points; it is most likely that there are multiple explanations.Priming is a well-recognized phenomenon and is seen when we review a study in which seasonal pollen exposure is plotted against patient symptoms. For the original description of this event, we are indebted to John Connell. Nasal primingIn 1968, Connell1Connell J.T. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.J Allergy. 1968; 41: 123-139Abstract Full Text PDF PubMed Scopus (131) Google Scholar described the results of quantitative intranasal challenges with ragweed pollen. When he administered the pollen daily to patients with ragweed-induced allergic rhinitis, he found that smaller doses were required on each succeeding day to cause the same or greater degree of symptomatic allergic response. He titled this phenomenon of increased nasal reactivity to pollen after repeated challenges “the priming effect.”1Connell J.T. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.J Allergy. 1968; 41: 123-139Abstract Full Text PDF PubMed Scopus (131) Google Scholar, 2Connell J.T. Quantitative intranasal pollen challenges. 3. The priming effect in allergic rhinitis.J Allergy. 1969; 43: 33-44Abstract Full Text PDF PubMed Scopus (255) Google Scholar Connell observed that priming of the nasal membrane could also increase symptoms to nonpriming allergens and to nonallergic stimuli. Daily unilateral pollen challenges primed only the nostril challenged. Complete recovery from priming occurred when challenges were withheld for 4 weeks. On the basis of this evidence, he described priming as a nonspecific, local, and reversible phenomenon. The clinical correlate of this laboratory finding is the increased symptoms reported by patients as the pollen counts decrease toward the end of seasonal exposure.Subsequent studies on the priming effect. In 1981, Bacon et al3Bacon J.R. McLean J.A. Mathews K.P. Banas J.M. Priming of the nasal mucosa by ragweed extract or by an irritant (ammonia).J Allergy Clin Immunol. 1981; 67: 111-116Abstract Full Text PDF PubMed Scopus (33) Google Scholar revisited Connell's observations on priming. They verified that priming was reproducible and transient, but they failed to demonstrate that priming caused hyperresponsiveness to an irritant (ammonia gas). In consecutive studies Naclerio and colleagues4Naclerio R.M. Proud D. Togias A.G. Adkinson Jr., N.F. Meyers D.A. Kagey-Sobotka A. et al.Inflammatory mediators in late antigen-induced rhinitis.N Engl J Med. 1985; 313: 65-70Crossref PubMed Scopus (584) Google Scholar, 5Pipkorn U. Proud D. Lichtenstein L.M. Schleimer R.P. Peters S.P. Adkinson Jr., N.F. et al.Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.J Clin Invest. 1987; 80: 957-961Crossref PubMed Scopus (129) Google Scholar performed a second allergen challenge at 11 hours after the first, which resulted in an augmented clinical response, a confirmation of priming to an antigen. In these studies mediator release was also measured. During the rechallenge reaction, the amount of histamine release increased, but the amount of prostaglandin D2 generation did not change. Because mast cells release both histamine and prostaglandin D2 and basophils release only histamine, they speculated that basophils recruited hours after the initial antigen challenge provided additional targets for antigen, thus providing a potential explanation for priming; that is, mast cells respond to the initial reaction, and basophils plus mast cells react to the rechallenge.In a subsequent study by Bascom et al,6Bascom R. Wachs M. Naclerio R.M. Pipkorn U. Galli S.J. Lichtenstein L.M. Basophil influx occurs after nasal antigen challenge: effects of topical corticosteroid pretreatment.J Allergy Clin Immunol. 1988; 81: 580-589Abstract Full Text PDF PubMed Scopus (184) Google Scholar the authors showed the presence of basophils in nasal lavage fluid. In an eloquent study Iliopoulos et al7Iliopoulos O. Baroody F.M. Naclerio R.M. Bochner B.S. Kagey-Sobotka A. Lichtenstein L.M. Histamine-containing cells obtained from the nose hours after antigen challenge have functional and phenotypic characteristics of basophils.J Immunol. 1992; 148: 2223-2228PubMed Google Scholar used flow cytometry to demonstrate cell markers on the surface of the cells in lavage fluid, which were consistent with basophils. Furthermore, they harvested the cells from lavage fluid and showed that they responded in vitro like basophils. Studies by other investigators have shown the presence of basophils in allergic inflammatory responses.In studies first performed by Pipkorn and Enerback,8Pipkorn U. Enerback L. Nasal mucosal mast cells and histamine in hay fever. Effect of topical glucocorticoid treatment.Int Arch Allergy Appl Immunol. 1987; 84: 123-128Crossref PubMed Google Scholar they showed that mast cells migrate toward the epithelium during the allergy season, thus potentially contributing to priming during long-term seasonal exposure to allergen.Other studies stressed the role of eosinophils and eosinophil-derived mediators in the late antigen-induced reaction and the possibility of priming. Eosinophil-derived cytotoxic proteins, such as major basic protein, eosinophil-derived neurotoxin, or eosinophilic cationic protein, were postulated to play a role in nasal obstruction and to contribute to nasal mucosal damage and development of nasal hyperreactivity. One idea considered was that loss of barrier function caused by these proteins would allow greater antigen penetration into the nasal mucosa and thus a greater allergic reaction on re-exposure to antigen (ie, priming).Wachs et al9Wachs M. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Norman P.S. Naclerio R.M. Observations on the pathogenesis of nasal priming.J Allergy Clin Immunol. 1989; 84: 492-501Abstract Full Text PDF PubMed Scopus (78) Google Scholar verified that priming occurred and found significant correlations between the augmented clinical response, hyperresponsiveness, and the inflammatory cell influx of eosinophils, neutrophils, and basophils. In healthy control subjects rechallenge with neither histamine nor methacholine resulted in increased nonspecific nasal reactivity.10Gronborg H. Borum P. Mygind N. Histamine and methacholine do not increase nasal reactivity.Clin Allergy. 1986; 16: 597-602Crossref PubMed Scopus (36) Google Scholar Later, Walden et al11Walden S.M. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Naclerio R.M. Antigen-provoked increase in histamine reactivity. Observations on mechanisms.Am Rev Respir Dis. 1991; 144: 642-648Crossref PubMed Google Scholar confirmed that the histamine provocation did not induce increased reactivity to itself or to antigen, but antigen challenge induced a reversible increase in responsiveness to histamine, which is associated with an inflammatory cell infiltration. Juliusson and Bende12Juliusson S. Bende M. Priming effect of a birch pollen season studied with laser Doppler flowmetry in patients with allergic rhinitis.Clin Allergy. 1988; 18: 615-618Crossref PubMed Scopus (26) Google Scholar verified the increased sensitivity of the resistance vessels caused by the priming effect by using laser Doppler flowmetry. These studies shed light on the question why allergic subjects complain more about nonallergic irritants during seasonal exposure than nonallergic subjects.The relationship of priming to other allergic responses was another area of investigation. Andersson et al13Andersson M. von Kogerer B. Andersson P. Pipkorn U. Allergen-induced nasal hyperreactivity appears unrelated to the size of the nasal and dermal immediate allergic reaction.Allergy. 1987; 42: 631-637Crossref PubMed Scopus (32) Google Scholar found no correlation between the increased responsiveness in the nose and the presence or size of the initial allergen response in the nose or skin. Bousquet et al14Bousquet J. Lebel B. Dhivert H. Bataille Y. Martinot B. Michel F.B. Nasal challenge with pollen grains, skin-prick tests and specific IgE in patients with grass pollen allergy.Clin Allergy. 1987; 17: 529-536Crossref PubMed Scopus (68) Google Scholar noted a significant correlation between nasal provocation test and skin prick test end points, but no correlation was present between nasal challenge and serum-specific IgE levels. In a study of randomly selected and previously unchallenged subjects (n = 55) who had ragweed-induced allergic rhinitis, 47% had a late-phase reaction, 41% showed an increase in mediators during a rechallenge reaction, and an additional 20% had an enhanced symptomatic response without a concomitant increase in mediators. These investigators noted that a preceding late-phase reaction was not obligatorily linked to an enhanced rechallenge reaction, and the association between the levels of histamine generated during the late phase and during the rechallenge response was stronger than the association between other mediators. The cellular influx was proposed to serve as a connection between the late and enhanced rechallenge responses, and the basophil influx was postulated to serve as a target for antigen during the rechallenge response.15Iliopoulos O. Proud D. Adkinson Jr., N.F. Norman P.S. Kagey-Sobotka A. Lichtenstein L.M. et al.Relationship between the early, late, and rechallenge reaction to nasal challenge with antigen: observations on the role of inflammatory mediators and cells.J Allergy Clin Immunol. 1990; 86: 851-861Abstract Full Text PDF PubMed Scopus (102) Google Scholar This study also provided the best estimate of the incidence of the priming phenomenon in allergic subjects, although it does not exclude the possibility that more prolonged exposure to allergen over several days would increase the incidence. In addition, these studies demonstrated the heterogeneity of the responses after an antigen challenge and showed that different mechanisms could be involved in the individual components of the mucosal changes that make up priming.In 1998, Ciprandi et al16Ciprandi G. Ricca V. Landi M. Passalacqua G. Bagnasco M. Canonica G.W. Allergen-specific nasal challenge: response kinetics of clinical and inflammatory events to rechallenge.Int Arch Allergy Immunol. 1998; 115: 157-161Crossref PubMed Scopus (25) Google Scholar evaluated the effects of nasal rechallenge on symptoms and inflammatory cell infiltration of 40 allergic patients who underwent 2 nasal challenges at baseline and another after 3 days and after 1, 2, and 4 weeks. They showed that the priming effect is detectable by using a rechallenge after a 3-day period, that the 1- and 4-week challenges show a reactivity equal to the baseline value, and that evidence of a hyporesponsive phase was seen in the target organ after 2 weeks. The hyporesponsive phase points to a continually changing immunologic response days after antigen exposure.Whether a preceding airway response to one allergen leads to priming of the airway response to another allergen was studied. The data indicated that a preceding airway response to one allergen might lead to priming, with enhancement of the early and late airway responses to the subsequent challenge with another allergen.17Koh Y.Y. Choi J.W. Lee M.H. Sun Y.H. Lee S.I. Lee S.Y. et al.A preceding airway reaction to one allergen may lead to priming of the airway responses to another allergen.Allergy. 1997; 52: 284-292Crossref PubMed Scopus (11) Google Scholar Similarly, Bousquet et al18Bousquet J. Hejjaoui A. Becker W.M. Cour P. Chanal I. Lebel B. Clinical and immunologic reactivity of patients allergic to grass pollens and to multiple pollen species. I. Clinical and immunologic characteristics.J Allergy Clin Immunol. 1991; 87: 737-746Abstract Full Text PDF PubMed Scopus (48) Google Scholar showed that polysensitized patients had nasal symptoms that occurred earlier than those in monosensitized patients, possibly because of the priming effect caused by other plants pollenating earlier.There is increasing evidence that once an antigen challenge transpires and local symptoms are induced, the ensuing inflammatory cascade has both a local and a systemic nature. For example, Saini et al19Saini S. Bloom D.C. Bieneman A. Vasagar K. Togias A. Schroeder J. Systemic effects of allergen exposure on blood basophil IL-13 secretion and FcepsilonRIbeta.J Allergy Clin Immunol. 2004; 114: 768-774Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar recently demonstrated that repeated nasal allergen challenge is capable of inducing systemic effects on circulating basophils, causing these cells to increase their expression of FcɛRIβ (β chain of the high-affinity receptor for IgE) and spontaneously to secrete IL-13. This suggests a potential explanation of how an allergic reaction in the nose might lead to an augmented late reaction in other organs after allergen exposure there.Studies on inhibition of the priming effect are few. Systemic steroids were shown effectively to inhibit the clinical and cellular manifestations of an antigen-induced late-phase allergic reaction and the increased rechallenge reaction without affecting the early response.5Pipkorn U. Proud D. Lichtenstein L.M. Schleimer R.P. Peters S.P. Adkinson Jr., N.F. et al.Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.J Clin Invest. 1987; 80: 957-961Crossref PubMed Scopus (129) Google Scholar Two weeks of treatment with topical steroids was shown to have similar effects on the late and rechallenge reaction, but they were also capable of suppressing the early reaction to antigen.20Pipkorn U. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Norman P.S. Naclerio R.M. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids.N Engl J Med. 1987; 316: 1506-1510Crossref PubMed Scopus (228) Google Scholar Pretreatment with flunisolide prevented the influx of mediator-releasing cells, including basophils, into the nose. Immunotherapy ameliorates seasonal symptoms of allergic rhinitis and reduces the early, late, and rechallenge reactions to antigen challenge.21Iliopoulos O. Proud D. Adkinson Jr., N.F. Creticos P.S. Norman P.S. Kagey-Sobotka A. et al.Effects of immunotherapy on the early, late, and rechallenge nasal reaction to provocation with allergen: changes in inflammatory mediators and cells.J Allergy Clin Immunol. 1991; 87: 855-866Abstract Full Text PDF PubMed Scopus (137) Google Scholar The effect of other treatments on nasal priming has not been studied directly.Current understanding of the priming effectBy the end of the last millennium, it was well known that the mechanisms underlying the pathophysiology of allergic rhinitis involved an acute early-phase and a late-phase reaction, with the latter being associated with cellular infiltration in which eosinophils and lymphocytes are important components. The late response results in a state of nasal hyperresponsiveness of the nasal mucosa to further allergen exposure (ie, priming). More specific explanations for the mechanism underlying priming include the recruitment of basophils to act as additional target cells, hyperresponsiveness of nerves and blood vessels to subsequent stimulation, greater penetrability of antigen, movement of mast cells toward the surface, synergism between release of inflammatory mediators during cellular recruitment and in response to re-exposure to antigen, local synthesis of IgE, and priming of recruited cells. It is unlikely that one mechanism explains the pathophysiology of priming at all time points; it is most likely that there are multiple explanations.Priming is a well-recognized phenomenon and is seen when we review a study in which seasonal pollen exposure is plotted against patient symptoms. For the original description of this event, we are indebted to John Connell. In 1968, Connell1Connell J.T. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.J Allergy. 1968; 41: 123-139Abstract Full Text PDF PubMed Scopus (131) Google Scholar described the results of quantitative intranasal challenges with ragweed pollen. When he administered the pollen daily to patients with ragweed-induced allergic rhinitis, he found that smaller doses were required on each succeeding day to cause the same or greater degree of symptomatic allergic response. He titled this phenomenon of increased nasal reactivity to pollen after repeated challenges “the priming effect.”1Connell J.T. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure, and placebo challenge on the nasal membrane.J Allergy. 1968; 41: 123-139Abstract Full Text PDF PubMed Scopus (131) Google Scholar, 2Connell J.T. Quantitative intranasal pollen challenges. 3. The priming effect in allergic rhinitis.J Allergy. 1969; 43: 33-44Abstract Full Text PDF PubMed Scopus (255) Google Scholar Connell observed that priming of the nasal membrane could also increase symptoms to nonpriming allergens and to nonallergic stimuli. Daily unilateral pollen challenges primed only the nostril challenged. Complete recovery from priming occurred when challenges were withheld for 4 weeks. On the basis of this evidence, he described priming as a nonspecific, local, and reversible phenomenon. The clinical correlate of this laboratory finding is the increased symptoms reported by patients as the pollen counts decrease toward the end of seasonal exposure. Subsequent studies on the priming effect. In 1981, Bacon et al3Bacon J.R. McLean J.A. Mathews K.P. Banas J.M. Priming of the nasal mucosa by ragweed extract or by an irritant (ammonia).J Allergy Clin Immunol. 1981; 67: 111-116Abstract Full Text PDF PubMed Scopus (33) Google Scholar revisited Connell's observations on priming. They verified that priming was reproducible and transient, but they failed to demonstrate that priming caused hyperresponsiveness to an irritant (ammonia gas). In consecutive studies Naclerio and colleagues4Naclerio R.M. Proud D. Togias A.G. Adkinson Jr., N.F. Meyers D.A. Kagey-Sobotka A. et al.Inflammatory mediators in late antigen-induced rhinitis.N Engl J Med. 1985; 313: 65-70Crossref PubMed Scopus (584) Google Scholar, 5Pipkorn U. Proud D. Lichtenstein L.M. Schleimer R.P. Peters S.P. Adkinson Jr., N.F. et al.Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.J Clin Invest. 1987; 80: 957-961Crossref PubMed Scopus (129) Google Scholar performed a second allergen challenge at 11 hours after the first, which resulted in an augmented clinical response, a confirmation of priming to an antigen. In these studies mediator release was also measured. During the rechallenge reaction, the amount of histamine release increased, but the amount of prostaglandin D2 generation did not change. Because mast cells release both histamine and prostaglandin D2 and basophils release only histamine, they speculated that basophils recruited hours after the initial antigen challenge provided additional targets for antigen, thus providing a potential explanation for priming; that is, mast cells respond to the initial reaction, and basophils plus mast cells react to the rechallenge. In a subsequent study by Bascom et al,6Bascom R. Wachs M. Naclerio R.M. Pipkorn U. Galli S.J. Lichtenstein L.M. Basophil influx occurs after nasal antigen challenge: effects of topical corticosteroid pretreatment.J Allergy Clin Immunol. 1988; 81: 580-589Abstract Full Text PDF PubMed Scopus (184) Google Scholar the authors showed the presence of basophils in nasal lavage fluid. In an eloquent study Iliopoulos et al7Iliopoulos O. Baroody F.M. Naclerio R.M. Bochner B.S. Kagey-Sobotka A. Lichtenstein L.M. Histamine-containing cells obtained from the nose hours after antigen challenge have functional and phenotypic characteristics of basophils.J Immunol. 1992; 148: 2223-2228PubMed Google Scholar used flow cytometry to demonstrate cell markers on the surface of the cells in lavage fluid, which were consistent with basophils. Furthermore, they harvested the cells from lavage fluid and showed that they responded in vitro like basophils. Studies by other investigators have shown the presence of basophils in allergic inflammatory responses. In studies first performed by Pipkorn and Enerback,8Pipkorn U. Enerback L. Nasal mucosal mast cells and histamine in hay fever. Effect of topical glucocorticoid treatment.Int Arch Allergy Appl Immunol. 1987; 84: 123-128Crossref PubMed Google Scholar they showed that mast cells migrate toward the epithelium during the allergy season, thus potentially contributing to priming during long-term seasonal exposure to allergen. Other studies stressed the role of eosinophils and eosinophil-derived mediators in the late antigen-induced reaction and the possibility of priming. Eosinophil-derived cytotoxic proteins, such as major basic protein, eosinophil-derived neurotoxin, or eosinophilic cationic protein, were postulated to play a role in nasal obstruction and to contribute to nasal mucosal damage and development of nasal hyperreactivity. One idea considered was that loss of barrier function caused by these proteins would allow greater antigen penetration into the nasal mucosa and thus a greater allergic reaction on re-exposure to antigen (ie, priming). Wachs et al9Wachs M. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Norman P.S. Naclerio R.M. Observations on the pathogenesis of nasal priming.J Allergy Clin Immunol. 1989; 84: 492-501Abstract Full Text PDF PubMed Scopus (78) Google Scholar verified that priming occurred and found significant correlations between the augmented clinical response, hyperresponsiveness, and the inflammatory cell influx of eosinophils, neutrophils, and basophils. In healthy control subjects rechallenge with neither histamine nor methacholine resulted in increased nonspecific nasal reactivity.10Gronborg H. Borum P. Mygind N. Histamine and methacholine do not increase nasal reactivity.Clin Allergy. 1986; 16: 597-602Crossref PubMed Scopus (36) Google Scholar Later, Walden et al11Walden S.M. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Naclerio R.M. Antigen-provoked increase in histamine reactivity. Observations on mechanisms.Am Rev Respir Dis. 1991; 144: 642-648Crossref PubMed Google Scholar confirmed that the histamine provocation did not induce increased reactivity to itself or to antigen, but antigen challenge induced a reversible increase in responsiveness to histamine, which is associated with an inflammatory cell infiltration. Juliusson and Bende12Juliusson S. Bende M. Priming effect of a birch pollen season studied with laser Doppler flowmetry in patients with allergic rhinitis.Clin Allergy. 1988; 18: 615-618Crossref PubMed Scopus (26) Google Scholar verified the increased sensitivity of the resistance vessels caused by the priming effect by using laser Doppler flowmetry. These studies shed light on the question why allergic subjects complain more about nonallergic irritants during seasonal exposure than nonallergic subjects. The relationship of priming to other allergic responses was another area of investigation. Andersson et al13Andersson M. von Kogerer B. Andersson P. Pipkorn U. Allergen-induced nasal hyperreactivity appears unrelated to the size of the nasal and dermal immediate allergic reaction.Allergy. 1987; 42: 631-637Crossref PubMed Scopus (32) Google Scholar found no correlation between the increased responsiveness in the nose and the presence or size of the initial allergen response in the nose or skin. Bousquet et al14Bousquet J. Lebel B. Dhivert H. Bataille Y. Martinot B. Michel F.B. Nasal challenge with pollen grains, skin-prick tests and specific IgE in patients with grass pollen allergy.Clin Allergy. 1987; 17: 529-536Crossref PubMed Scopus (68) Google Scholar noted a significant correlation between nasal provocation test and skin prick test end points, but no correlation was present between nasal challenge and serum-specific IgE levels. In a study of randomly selected and previously unchallenged subjects (n = 55) who had ragweed-induced allergic rhinitis, 47% had a late-phase reaction, 41% showed an increase in mediators during a rechallenge reaction, and an additional 20% had an enhanced symptomatic response without a concomitant increase in mediators. These investigators noted that a preceding late-phase reaction was not obligatorily linked to an enhanced rechallenge reaction, and the association between the levels of histamine generated during the late phase and during the rechallenge response was stronger than the association between other mediators. The cellular influx was proposed to serve as a connection between the late and enhanced rechallenge responses, and the basophil influx was postulated to serve as a target for antigen during the rechallenge response.15Iliopoulos O. Proud D. Adkinson Jr., N.F. Norman P.S. Kagey-Sobotka A. Lichtenstein L.M. et al.Relationship between the early, late, and rechallenge reaction to nasal challenge with antigen: observations on the role of inflammatory mediators and cells.J Allergy Clin Immunol. 1990; 86: 851-861Abstract Full Text PDF PubMed Scopus (102) Google Scholar This study also provided the best estimate of the incidence of the priming phenomenon in allergic subjects, although it does not exclude the possibility that more prolonged exposure to allergen over several days would increase the incidence. In addition, these studies demonstrated the heterogeneity of the responses after an antigen challenge and showed that different mechanisms could be involved in the individual components of the mucosal changes that make up priming. In 1998, Ciprandi et al16Ciprandi G. Ricca V. Landi M. Passalacqua G. Bagnasco M. Canonica G.W. Allergen-specific nasal challenge: response kinetics of clinical and inflammatory events to rechallenge.Int Arch Allergy Immunol. 1998; 115: 157-161Crossref PubMed Scopus (25) Google Scholar evaluated the effects of nasal rechallenge on symptoms and inflammatory cell infiltration of 40 allergic patients who underwent 2 nasal challenges at baseline and another after 3 days and after 1, 2, and 4 weeks. They showed that the priming effect is detectable by using a rechallenge after a 3-day period, that the 1- and 4-week challenges show a reactivity equal to the baseline value, and that evidence of a hyporesponsive phase was seen in the target organ after 2 weeks. The hyporesponsive phase points to a continually changing immunologic response days after antigen exposure. Whether a preceding airway response to one allergen leads to priming of the airway response to another allergen was studied. The data indicated that a preceding airway response to one allergen might lead to priming, with enhancement of the early and late airway responses to the subsequent challenge with another allergen.17Koh Y.Y. Choi J.W. Lee M.H. Sun Y.H. Lee S.I. Lee S.Y. et al.A preceding airway reaction to one allergen may lead to priming of the airway responses to another allergen.Allergy. 1997; 52: 284-292Crossref PubMed Scopus (11) Google Scholar Similarly, Bousquet et al18Bousquet J. Hejjaoui A. Becker W.M. Cour P. Chanal I. Lebel B. Clinical and immunologic reactivity of patients allergic to grass pollens and to multiple pollen species. I. Clinical and immunologic characteristics.J Allergy Clin Immunol. 1991; 87: 737-746Abstract Full Text PDF PubMed Scopus (48) Google Scholar showed that polysensitized patients had nasal symptoms that occurred earlier than those in monosensitized patients, possibly because of the priming effect caused by other plants pollenating earlier. There is increasing evidence that once an antigen challenge transpires and local symptoms are induced, the ensuing inflammatory cascade has both a local and a systemic nature. For example, Saini et al19Saini S. Bloom D.C. Bieneman A. Vasagar K. Togias A. Schroeder J. Systemic effects of allergen exposure on blood basophil IL-13 secretion and FcepsilonRIbeta.J Allergy Clin Immunol. 2004; 114: 768-774Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar recently demonstrated that repeated nasal allergen challenge is capable of inducing systemic effects on circulating basophils, causing these cells to increase their expression of FcɛRIβ (β chain of the high-affinity receptor for IgE) and spontaneously to secrete IL-13. This suggests a potential explanation of how an allergic reaction in the nose might lead to an augmented late reaction in other organs after allergen exposure there. Studies on inhibition of the priming effect are few. Systemic steroids were shown effectively to inhibit the clinical and cellular manifestations of an antigen-induced late-phase allergic reaction and the increased rechallenge reaction without affecting the early response.5Pipkorn U. Proud D. Lichtenstein L.M. Schleimer R.P. Peters S.P. Adkinson Jr., N.F. et al.Effect of short-term systemic glucocorticoid treatment on human nasal mediator release after antigen challenge.J Clin Invest. 1987; 80: 957-961Crossref PubMed Scopus (129) Google Scholar Two weeks of treatment with topical steroids was shown to have similar effects on the late and rechallenge reaction, but they were also capable of suppressing the early reaction to antigen.20Pipkorn U. Proud D. Lichtenstein L.M. Kagey-Sobotka A. Norman P.S. Naclerio R.M. Inhibition of mediator release in allergic rhinitis by pretreatment with topical glucocorticosteroids.N Engl J Med. 1987; 316: 1506-1510Crossref PubMed Scopus (228) Google Scholar Pretreatment with flunisolide prevented the influx of mediator-releasing cells, including basophils, into the nose. Immunotherapy ameliorates seasonal symptoms of allergic rhinitis and reduces the early, late, and rechallenge reactions to antigen challenge.21Iliopoulos O. Proud D. Adkinson Jr., N.F. Creticos P.S. Norman P.S. Kagey-Sobotka A. et al.Effects of immunotherapy on the early, late, and rechallenge nasal reaction to provocation with allergen: changes in inflammatory mediators and cells.J Allergy Clin Immunol. 1991; 87: 855-866Abstract Full Text PDF PubMed Scopus (137) Google Scholar The effect of other treatments on nasal priming has not been studied directly. Current understanding of the priming effectBy the end of the last millennium, it was well known that the mechanisms underlying the pathophysiology of allergic rhinitis involved an acute early-phase and a late-phase reaction, with the latter being associated with cellular infiltration in which eosinophils and lymphocytes are important components. The late response results in a state of nasal hyperresponsiveness of the nasal mucosa to further allergen exposure (ie, priming). More specific explanations for the mechanism underlying priming include the recruitment of basophils to act as additional target cells, hyperresponsiveness of nerves and blood vessels to subsequent stimulation, greater penetrability of antigen, movement of mast cells toward the surface, synergism between release of inflammatory mediators during cellular recruitment and in response to re-exposure to antigen, local synthesis of IgE, and priming of recruited cells. It is unlikely that one mechanism explains the pathophysiology of priming at all time points; it is most likely that there are multiple explanations.Priming is a well-recognized phenomenon and is seen when we review a study in which seasonal pollen exposure is plotted against patient symptoms. For the original description of this event, we are indebted to John Connell. By the end of the last millennium, it was well known that the mechanisms underlying the pathophysiology of allergic rhinitis involved an acute early-phase and a late-phase reaction, with the latter being associated with cellular infiltration in which eosinophils and lymphocytes are important components. The late response results in a state of nasal hyperresponsiveness of the nasal mucosa to further allergen exposure (ie, priming). More specific explanations for the mechanism underlying priming include the recruitment of basophils to act as additional target cells, hyperresponsiveness of nerves and blood vessels to subsequent stimulation, greater penetrability of antigen, movement of mast cells toward the surface, synergism between release of inflammatory mediators during cellular recruitment and in response to re-exposure to antigen, local synthesis of IgE, and priming of recruited cells. It is unlikely that one mechanism explains the pathophysiology of priming at all time points; it is most likely that there are multiple explanations. Priming is a well-recognized phenomenon and is seen when we review a study in which seasonal pollen exposure is plotted against patient symptoms. For the original description of this event, we are indebted to John Connell.