Origin of late phase histamine release
Authors: Robert M. Naclerio, Walter Hubbard, Lawrence M. Lichtenstein, Anne Kagey-Sobotka, David Proud
Journal: Journal of Allergy and Clinical Immunology (1996)

The early response to antigen precedes the onset of a chronic inflammatory response that includes the late reaction, defined as the recurrence of symptoms and mediator release hours later. We hypothesized that during the late-phase nasal response to antigen provocation, released histamine originates from basophils, on the basis of the pattern of mediator release.1Naclerio RM Proud D Togias AG Adkinson Jr, NF Meyers DA Kagey-Sobotka A et al.Inflammatory mediators in late antigen-induced rhinitis.N Engl J Med. 1985; 313: 65-70Crossref PubMed Scopus (590) Google Scholar We subsequently showed the presence of basophils in the late reaction2Iliopoulos O Baroody F Naclerio RM Bochner BS Kagey-Sobotka A Lichtenstein LM 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 but could not exclude mast cells as a source of histamine release. With the development of assays to measure tryptase, a sensitive and specific marker of mast cell degranulation, and 9α,11β PGF 2, the major metabolite of prostaglandin (PG) D 2, it became possible to exclude the mast cell as the source of histamine release. Twelve volunteers who were free of symptoms but had a history of ragweed- or grass-induced allergic rhinitis, a positive intradermal skin test result, and a positive early response to nasal challenge were selected. The Internal Review Board of the Johns Hopkins Medical Institutions gave approval for the study, and each patient gave informed consent. During the laboratory visit, the subjects underwent a nasal challenge with a relevant antigen extract.1Naclerio RM Proud D Togias AG Adkinson Jr, NF Meyers DA Kagey-Sobotka A et al.Inflammatory mediators in late antigen-induced rhinitis.N Engl J Med. 1985; 313: 65-70Crossref PubMed Scopus (590) Google Scholar The recovered fluid from the lavage was processed immediately for prostanoids, and the remainder was stored on ice until the completion of the experiment. After centrifuging, the supernatants obtained were processed for the measurement of histamine, tryptase, and prostanoids.3Proud D Bailey GS Naclerio RM Reynolds CJ Cruz AA Eggleston PA et al.Tryptase and histamine as markers to evaluate mast cell activation during the responses to nasal challenge with allergen, cold, dry air and hyperosmolar solutions.J ALLERGY CLIN IMMUNOL. 1992; 89: 1098-1110Abstract Full Text PDF PubMed Scopus (85) Google Scholar, 4Liu MC Bleecker ER Proud D McLemore TL Hubbard WC Profiling of bisenoic prostaglandins and thromboxane B 2 in broncholaveolar fluids from the lower respiratory tract of human subjects by combined capillary gas chromatography-mass spectrometry.Prostaglandins. 1988; 35: 67-69PubMed Google Scholar Samples that contained levels of mediators less than the sensitivity of the assay were reported as 0.5 ng/ml for histamine, 5 pg/ml for prostanoids, and 1.7 ng/ml for tryptase. Immediately after every challenge and at hourly intervals after challenge, the subjects maintained a diary of rhinorrhea, nasal congestion, sneezing, and other symptoms, rated on a scale of 0 (none) to 3 (severe). The Wilcoxon matched-pairs signed-rank test was used to compare the peak response and early response of each mediator. Two-tailed p values are reported. Peak value refers to the maximum value in the early and late (2 to 11 hours) reactions for each individual. Peak values for the late reaction do not always occur at the same time; thus, the group mean (Fig. 1) will not equal the mean of the peaks. Six of the 12 subjects challenged showed both early and late increases in histamine. Tryptase and prostanoids were measured in the lavages from these six subjects, because we were only interested in the origin of late-phase histamine release. Antigen challenge induced an immediate increase in symptoms, which was associated with striking increases in histamine, tryptase, PGD 2 and 9α,11β-PGF 2 (p < 0.02) (Fig. 1). During the late reaction, the peak values of histamine (35 ± 15 ng/ml) and symptoms (8 ± 2) were not different from the peak values (histamine, 42 ± 14 ng/ml) (symptoms, 6.3 ± 1.2) found during the early reaction. In contrast, during the late reaction the peak levels of tryptase (256 ± 126 vs 15 ± 8 ng/ml), PGD 2 (4351 ± 1706 vs 5 ± 0.2 pg/ml), and 9α,11β-PGF 2 (800 ± 467 vs 5 ± 0 pg/ml) were all significantly (p < 0.02) less than their corresponding levels in the early reaction. On average, the levels of tryptase, PGD 2, and 9α,11β-PGF 2 detected during the early reaction were 16, 837, and 160 times greater than those detected during the late reaction, respectively. Most values for these parameters were less than the detection limits of the assays used. By using gas chromatography–mass spectrometry, picogram quantities of the other important prostanoids can be detected. No consistent changes in PGF 2 α, PGE 2, thromboxane B 2, and 6 keto-PGF 1 α levels were found in either the early or late reaction. The results of this study are clear: in subjects demonstrating release of histamine during both early and late reactions to nasal challenge with antigen, the early release of histamine occurs concordant with the release of tryptase, PGD 2, and 9α,11β-PGF 2; whereas the release of histamine during the late reaction does not. These data indicate that the late release of histamine does not originate from mast cells. Combined with our prior observations, these results strongly suggest that late histamine release originates from basophils. Our ability to accurately detect the mast cell products, tryptase, PGD 2, and 9α,11β-PGF 2 during the immediate response indicates that the negative results obtained in lavages from the same individuals during the late reactions were not due to technical aspects of the assays. Prior studies have also shown that these products are not detected when nonallergic subjects are challenged with antigen.2Iliopoulos O Baroody F Naclerio RM Bochner BS Kagey-Sobotka A Lichtenstein LM 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 Potentially variable dilutional effects as a result of recovery of different volumes of secretions also have no effect on the results presented, because we quantified all mediators in the same samples in which the dilutional effect of lavage on nasal secretions was identical. The hourly lavages permitted observation of the development of inflammation. Biopsy specimens obtained during the late reaction would show degranulated mast cells, and whether these mast cells degranulated during the early or late reaction could not be determined. Although this study excludes a role for mast cells in late-phase histamine release, it does not exclude a role for them in the development of the late reaction.5Plaut M Pierce JH Satson J Hanley-Hyde J Nordan RP Paul WE. Mast cell lines produce lymphokines in response to cross-linkage of F cϵ-R1 or to calcium ionophores.Nature. 1989; 339: 64-67Crossref PubMed Scopus (1032) Google Scholar The absence of consistently detectable levels of PGF 2 α, PGE 2, thromboxane B 2, and 6 keto-PGF 1 α speaks against an important role for these mediators in either the early or late reaction.