Local Allergic Rhinitis


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Local Allergic Rhinitis

Presented by Sadudee Boonmee, MD.

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  • Many of these patientswere given a diagnosis of IR or NARES previously. These data indicatethat LAR might be a common, although underestimated,entity
  • IR and PAR hadsinificant difference from normal ( p0.007 and 0.002)IR and AR sig diff P 0.025
  • All patients underwent surgery for nasal obstruction in and out ofthe main UK pollen season. Normal control nasal mucosa wasobtained from patients operated on for mechanical obstructionsecondary to a septal deviation
  • Staining wasabsent from all 12 of the normal control patients and in thenegative controls
  • We believe that this concept has a wider implication and may occur in allergic diseases of the skin, gastrointestinal tract, and eye.
  • sIgEเอาทุกตัวที่ทำ SPT
  • However, in only 22% of this subgroup could we detectspecific IgE antibodies in nasal fluids. The reasons forthis low percentage may be another immunologic mechanismor low sensitivity of the technique.
  • Before NAPT 15 min and after nasal challenge 15 min,1 hr,6hr,and 24 hr evaluate NSS by VAS and vol of nasal cavity
  • Compared to the control group, the IR-PosNAPT group showed significantdifferences in nasal ECP (P = 0.009), eosinophils(P = 0.008), basophils (P < 0.01), and total lymphocytesand CD3+ cells (P < 0.05 for both). No differenceswere found in the other values.
  • CD 68 = monocyte, macrophage
  • Exclusion criteriaincluded nasal polyposis, septal deformity, infection-relatedrhinitis in the previous 2 weeks, uncontrolled asthma, uncontrolledheart or lung disease, nasal surgery in the previous 6 weeks, chronic sinusitis, pregnancy or lactation, dermographism,and current immunotherapy.
  • Total Symptom Score\\Symptomswere scored on a scale from 0 to 12. A positive challengewas defined as a TSS of 5 or greater. Specifically, thissystem scores the number of sneezes (0–2 0 points, 3–4 1 point, and 5 3 points), rhinorrhea (anterior 1 point,posterior 1 point, both 2 points, and marked 3 points),nasal blockage (breathing with difficulty 1 point, 1 nostrilblocked 2 points, and both nostrils blocked 3 points),nasal itch (present 1 point), palate or ear itching (present 1 point), and conjunctivitis (present 1 point).
  • each section consisted of anepithelial and submucosal layer of approximately 2 mm in width, 3mm in length, and 2 mm in depth
  • After culture, tissue was fixed in 4%paraformaldehyde, washed in a solution of 15% sucrose-PBS, andblocked in optimal cutting temperature medium by snap-freezing inisopentane cooled in liquid nitrogen
  • B cells were observed just beneaththe basement membrane (A), infiltrating the epithelial layer (B), and clustering within the submucosa ingroups of 3 or 4 cells
  • Although we did not observe anincrease in B-cell number in allergen-stimulated tissue,this may be due to loss of the CD20 surface molecule onactivated B cells31 or to B-cell migration across theepithelium, which is consistent with our observation ofintraepithelial B cells and previous reports of their presencewithin nasal lavage fluid.10 The prospect of B-cellclonal expansion in the nasal mucosa is an interestingarea of investigation
  • The patients were selected from atotal of 16,000 adult rhinitis subjects seen over this period, of whom 3,000 hadNAR. In July and August 2007, 230 of these were randomly selected for reevaluationfrom a nameless database and asked to participate in the study, 180(88%) of whom accepted and completed the study
  • ImR = immediated reactionLR = late reactionDR = dual reaction
  • Local Allergic Rhinitis

    1. 1. Local allergic rhinitis Sadudee Boonmee, MD
    2. 2. Topic outline• Etiologic classification of rhinitis• Epidemiology of LAR• Pathophysiology of LAR• Clinical manifestration• Diagnostic approach• Treatment
    3. 3. Classification of rhinitis Allergic Rhinitis and its Impact on Asthma (ARIA) 2008
    4. 4. • Local allergic rhinitis is a newly described type of rhinitis involving nasal production of specific immunoglobulin (sIg) E antibodies in the absence of atopy (SPT –ve, serum sIgE -ve) J Investig Allergol Clin Immunol 2010; Vol. 20(5): 364-371
    5. 5. • NAR : idiopathic rhinitis and NARES most frequent diagnosed• Idiopathic rhinitis - Dx by exclusion - pathophysiology : unknown ( neurologic, inflammatory , change in mucosal permeability?) Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in press
    6. 6. • True prevalence data are not available• European centers suggest that among patients with negative SPT responses and undetectable sIgE antibodies in serum LAR  47% to 62.5% of patients with perennial and seasonal Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in press
    7. 7. • Few information published identified prevalent of allergens as LAR culprits• HDM, grass, and olive pollen Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in press
    8. 8. Local IgE production in tissue• 1947s : Samter M, Becker E. evaluation of locally produced IgE outside the regional lymph, was recognized that the nasal secretions of ragweed allergic individuals could be used to passively transfer a local reaction to previously nonallergic individuals Ragweed reagins in nasal secretion. Proc Soc Exp Biol Med. 1947:140 –141.• 1970s : Tse KS, Wicher K. reported ragweed specific IgE in the nasal washings of ragweed allergic patients IgE antibodies in nasal secretions of ragweed- allergic subjects. J Allergy. 1970;46:352–357
    9. 9. • Patients history suggestive of allergic rhinitis to HDM - 14 pt : SPT negative to Der p - 6 pt : SPT positive to Der p -5 : healthy controls• Nasal provocation test - The allergen extracts were diluted in 50% glycerolsaline to 40, 200, and 1000 protein nitrogen units per ml. administered as an aerosol, beginning with the lowest dose - positive reaction : sneezed or reported itching and nasal obstruction• RAST assays were performed on both nasal secretion and serum
    10. 10. Results• Two groups of pt 1. study group : history of HDM allergy but SPT -ve 2. positive control group : both a positive history and SPT Both group responded to HDM on nasal provocation
    11. 11. Serum RAST assays were performed onall patients- SPT +ve gr.  raised serum-RAST levels- No significant difference between theserum-RAST level of the study group(SPT-ve) and the non-atopic controlsNasal secretion for RAST that indicatedthe presence of sIgE- RAST titer raised in all patient whencompare with non atopic control- presence of sIgE Ab in all pt. who provenHDM allergy ( SPT +ve /-ve or raisedserum RAST or not)
    12. 12. Discussion• We identified a group of pt. with allergic to HDM confirm by nasal provocation test who do not response to SPT or negative serum RAST• We demonstrated that pts. have sIgE Ab in their nasal secretion  indicating local production of Ab in nasal mucosa
    13. 13. • 23 pt. with idiopathic rhinitis compared to 8 perennial AR and 8 normal control• Nasal saline challenges were performed to exclude nasal hypersensitivity• Bilateral nasal challenge using metered spray aerosal delivering 100 µL of reconstituted freeze dried allergen solution (Dp+Df, cat, dog and grass pollen) performed weekly for each allergen• Nasal patency assess by anterior rhinometry ( before and after nasal allergen challenge 15 min ) and positive if > 50% increase in unilateral nasal resistance
    14. 14. Inclusion criteria
    15. 15. • 62 % of IR had positive challenge at least unilaterally (nasal resistance increase > 50%)• Medial change of 278% in nasal resistance• 85% had +ve challenge to HDM
    16. 16. • Conclusion : Significant proportion of IR have positive nasal challenge• These finding add to the evidence of “ local allergy” may exist in absence of systemic atopic marker
    17. 17. • Two groups have performed much of the work regarding local IgE production in NAR: - Rondon et al. in Spain - Powe et al. in the Netherlands
    18. 18. • Division of Otorhinolaryngology at Queen’s Medical Centre (QMC), Nottingham, UK• Objective : hypothesized that it is possible to have an allergic Th2 disease pathway localized in the nasal mucosa of ‘non- allergic’ rhinitis subjects despite an absence of atopic responses• non-atopic persistent rhinitis (n=10) and atopic persistent rhinitis (n = 11) compared to normal control (n=12)• age 17-61 yr• Nasal mucosal biopsy D. G. Powe, et.al, Clin Exp Allergy 2003; 33:1374–1379
    19. 19. 3/10 pt detect sAb for HDM & GP 7/11 pt detect sAb for HDM & GPSPT : HDM, cladosporium, grass ,tree pollen mix, silver birch,cat,dog danders, and bird allergens. D. G. Powe, et.al, Clin Exp Allergy 2003; 33:1374–1379
    20. 20. • Conclusion : - This evidence supports the concept local mucosal inflammatory responses can occur independent of remote atopic responses - This is the first report of mucosal allergen capture in non-atopic rhinitis subjects -‘entopy’ (Greek ‘entopos’ – meaning local resident)  describe a localized mucosal response independent of systemic atopic responses D. G. Powe, et.al, Clin Exp Allergy 2003; 33:1374–1379
    21. 21. • Objective: To evaluate in the nose the inflammatory response, specific IgE to Dermatophagoides pteronyssinus (DP), and the response to a nasal allergen provocation test with DP (NAPTDP), in patients with persistent nonallergic rhinitis (PNAR) compared with patients with persistent allergic rhinitis (PAR) and healthy controls• 110 subjects : PNAR = 50 pt , PAR = 30 pt, and 30 healthy control (age 18-70 yr) J Allergy Clin Immunol -
    22. 22. J Allergy Clin Immunol -
    23. 23. • SPT : - HDM (DP, DF, lepidoglyphus destructor, and blomia tropicalis) - pollens (poa, phleum, lolium, cassuarina, eucalyptus, cupresus, platanus, olea, helianthus, chenopodium, plantago, artemisia, parietaria judaica, salsola kali, rumex and ricinus), - - molds (alternaria, aspergillus, cladosporium and penicillium), - latex - animal epithelia (dog, cat, and hamster)• Intradermal skin test : all PNAR pt. with Der p 1• Nasal larvage and sample : standard anterior rhinoscopy• Flow cytometry (nasal fluid) : CD16, CD8, CD4, CD33, CD3, and CD45• Albumin, ECP, total IgE, and specific IgE ( Serum,nasal fluid sIgE to DP )• NAPT : freshly reconstituted freeze-dried allergen solutions of Der p 1 J Allergy Clin Immunol -
    24. 24. • ResultPNAR 6 pt had nasal sIgE –DPPAR : 25/30 pt had sIgE-DP in serum a/o nasal lavage : 8 /30 pt only had sIgE –DP in nasal larvage J Allergy Clin Immunol -
    25. 25. Result PNAR and PAR groups presented similar levels of CD45+ cells, neutrophils, eosinophils, basophils, and CD3+ CD8+ T cell populationsPNAR patients with positive nasal sIgE-DP and/orNAPT-DP showed a similar leukocyte phenotype to the PAR group, withincreased levels of Eo (P <0.001), CD3 +T cells (P < .005), and CD3+CD4+T cells (P < .05) compared with control J Allergy Clin Immunol -
    26. 26. • Result : NAPT For pt. with PNAR the response after NAPT-DP 54% Immediate = 63% Dual = 37% No isolated late response • Of the 27/50 pt with a positive NAPT-DP in the PNAR group, 6 had selective nasal sIgE-DP (22%) • PNAR pt with +ve response to NAPT-DP, found a significant + ve correlation between nasal sIgE-DP and % of Eo in nasal larvage fluid , P=0.001 J Allergy Clin Immunol -
    27. 27. • Summary• Nasal lavage analysis of the cell by flow cytometry and the supernatant of PNAR showed similarities with PAR and clear differences with healthy controls• specific IgE Ab to other perennial allergens needs further study• do not know whether these patients will progress to the classic disease ( serum sIgE +ve )or whether they will remain unchanged J Allergy Clin Immunol -
    28. 28. • Aim : to study nasal inflammation, presence of nasal sIgE and NAPT response to grass and Olea europea pollen common seasonal allergens in Spain, in patients with IR with seasonal symptoms only during the spring• Subjected : 147 pt. (age 18-70 yr) divided to 4 group - 32 with seasonal IR - 35 with persistent AR to pollen (PAR-P) (symptom occur only during spring) - 30 with persistent AR to HDM (PAR-HDM) (symptom occur most of the year - 50 healthy control (HC) C. Rondon et al. Allergy 2008: 63: 1352–1358
    29. 29. • Natural exposure to pollen (April-June) - SPT house dust mite, pollens, molds, latex and animal epithelia - ID performed in the IR pt. with grass pollen mixture and O. europea• Nasal lavage and flow cytometry : CD33+, CD16+ ,CD3+CD4+ (T cell),CD3+CD8+ (cytotoxic T cell)• Inflammatory mediators, total and sIgE in serum and nasal lavage : ECP , total IgE , sIgE (same for SPT)• NAPT outside the pollen season (Oct - Nov) : freshly reconstituted grass : O. europea extract C. Rondon et al. Allergy 2008: 63: 1352–1358
    30. 30. • ResultsEpidemiological and clinical data P = 0.009 C. Rondon et al. Allergy 2008: 63: 1352–1358
    31. 31. • ResultsDeterminations made during naturalexposure to pollen (April–June)• SPT - PAR-P positive to grass pollen in 17/35 (49%) and to O. europea in 10/35 (28%), with 8/35 subjects positive to both (23%) - negative in all the IR patients C. Rondon et al. Allergy 2008: 63: 1352–1358
    32. 32. • Results Frequency and severity of symptom during the pollen season C. Rondon et al. Allergy 2008: 63: 1352–1358
    33. 33. • ResultsLaboratory data during the pollen season in seasonal IRsubjects regardless of response to NAPT Serum Nasal larvage Flow cytometry C. Rondon et al. Allergy 2008: 63: 1352–1358
    34. 34. • ResultsDeterminations made outside the pollenseason (October–November)• IR group 20 pt. had +ve NAPT to grass (62.5%) and five to O. europea (15.62%) 62.5% 15.62%• All cases with nasal sIgE had + ve NAPT C. Rondon et al. Allergy 2008: 63: 1352–1358
    35. 35. • Results • In all cases, the response was immediate or dual; no isolated late responses • Most of pt. had bilateral response to acoustic rhinometry Grass Olea europa C. Rondon et al. Allergy 2008: 63: 1352–1358
    36. 36. • ResultsLaboratory data outside the pollen season in seasonalIR subjects with positive or negative response to NAPT IR-PosNAPT showedIR-NegNAPT showed Serum - similar inflammatory - similar levels to the response to the PAR-PPAR-P groupNasal larvage Patients in CD45+ T cells, - significant +ve neutrophils, eosinophilsFlow cytometry between nasal sIgE to basophilsmast and grass pollen and nasal Cell ECP ( Rho = 0.836, P - significantly lower < 0.05) levels of serum and nasal - significant +ve ECP (P < 0.05), nasal total between ECP and % of lymphocytes (P = 0.01) Eo in nasal mucosa (Rho CD3+ T cells (P = and = 0.813, P < 0.05) 0.002) C. Rondon et al. Allergy 2008: 63: 1352–1358
    37. 37. • 35% of IR-PosNAPT pt.(7/20) had nasal sIgE Ab to grass and two toboth grass and olive• all cases with nasal local sIgE had a positive NAPT to grass or olive• support an IgE mechanism (has not been reported previously)• IR-PosNAPT : inflammatory pattern in the nasal fluid during theseasonal exposure - increased nasal Eo Similar to to similar PAR-P PAR-P group - increase total lymphocytes and ECP• IR-PosNAPT had significantly higher in basophil-mast cells andCD3+ T cellsIR-NegNAPT group also showed a nasal inflammatory patterncompared with HCs, but only with increased levels of eosinophilsand nasal ECP C. Rondon et al. Allergy 2008: 63: 1352–1358
    38. 38. Summary• patients with IR who develop well-defined symptoms during the pollen season show an inflammatory pattern equivalent to that existing in PAR-P patients produced by pollen, with an important percentage having a positive NAPT response and nasal sIgE antibodies C. Rondon et al. Allergy 2008: 63: 1352–1358
    39. 39. Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in press
    40. 40. • OPD ENT of the Leyenburge Hospital in medical centre Rotterdam university , Netherland• 65 symptomatic IR pt. and 20 healthy control (age 16-64 yr)• Nasal biopsy for cells density of CD1, CD3, CD4, CD8, CD14, CD25, CD68, chymase, tryptase, IgE and BMK13 (Eo) by incubated nasal biopsy tissue with monoclonal Ab• Daily record for defined nasal symptom in pt. with IR
    41. 41. Selection criteria •• Inclusion criteria Exclusion criteria - The use of systemic or inhaled corticosteroids - Age between 16 and 64 within the previous month. years. - Use of inhaled sodium cromoglycate or nedocromil - Negative skin prick test: sodium within the previous month. house dust mite, tree pollen - Use of astemizole within the previous month. mix, grass pollen - Inability of the patient to stop taking medication affecting nasal function. mix, mugwort, alternaria, aspe - A serious and/or unstable disease. rgillus, cladosporium, - Nasal surgery within the previous 6 weeks. penicillum, dog, cat, parakeet, - Nasal polyps or a history of nasal polyps. rabbit, hamster, horse, guinea - Significant anatomical abnormalities affecting nasal pig. (ALK-Diephuis, Holland) function. - Negative Phadiatop - Nasal or paranasal sinus infection (abnormal sinus (Pharmacia, Uppsala, Sweden) X-ray). - Pregnancy or lactation. - Symptoms for more than 1 - Abnormal findings at physical examination. year. - Abnormal laboratory results for: blood: Na, K, Ca, - Periods of nasal total protein, albumin, urea, creatinine, bilirubin, discharge, sneezing and alkaline phosphatase, aspartate aminotransferase, congestion for an average of at alanine aminotransferase, gammaglutamyl least 1 h per day on at least 5 transpeptidase, haemoglobin, red blood cell count, plasma cell volume, mean corpuscular volume, days during a period of 14 platelets, total white blood cell count, neutrophils, days. lymphocytes, monocytes, eosinophils, basophils. • urine: blood, protein, glucose.
    42. 42. • Result
    43. 43. • Conclusion : Inflammatory cells do not seem to play an important role in this meticulously characteristic of IR pt.
    44. 44. • To determine the prevalence of localized allergy in patients with negative skin prick test results via nasal challenges with an array of allergens• Single- blinded prospective study of 20 perennial NAR (age 24-62 y) and 3 AR (positive control)• Nasal provocation test : placing 100 μL of solution onto inferior turbinate via pipette , sequential challenge every 15 min Before each challenge, total symptom scores, nasal smears, and peak nasal inspiratory flow rates were obtained Ann Allergy Asthma Immunol. 2008;100:533–537.
    45. 45. • Provocation test +ve if TSS ≥ 5, the remaining challenges were postponed for another day (3 to 5 months later)• If the TSS was negative, subsequent challenges with cockroach mix, timothy grass, cat hair and D pteronyssinus• Peak nasal inspiratiry flow (PNIF): nasal inspiratory flow meter with a cushioned face mask, significant decline in PNIF  greater than 20% from the baseline• Nasal Eosinophil Counts : obtained by having the patient blow into wax paper Ann Allergy Asthma Immunol. 2008;100:533–537.
    46. 46. • Result- Total symptom score 4 IR pt. +ve glycerin nasal challenges  did not undergo further nasal allergen challenges 11 pt. had -ve symptom scores after sequential nasal challenges with Alternaria, cockroach, timothy grass, cat hair, and HDM 5 pt. (25%) with NAR + ve nasal challenges ≥ 1 allergen challenges, return to rechallenge in 3 mo 3 Positive control +ve nasal challenge with HDM (2 pt, TSS 9 and 10 ) and cat (1 pt , TSS 11 ) Ann Allergy Asthma Immunol. 2008;100:533–537.
    47. 47. • % change in PNIF for pt. with +ve challenge did not significantly differ from % change for the other patients challenged after each respective allergen• no significant correlation between symptom scores and change in PNIF values after allergen challenges• Nasal Eo  very low numbers - no correlation between TSS and Eo counts in patients with –ve and + ve challenge Ann Allergy Asthma Immunol. 2008;100:533–537.
    48. 48. • In conclusion : this study does not support the concept of localized allergy in the nose : The positive nasal challenges in patients with perennial nonallergic rhinitis were not reproducible on repeated allergen challenge : The positive challenges did not correlate with PNIF values or nasal eosinophil numbers : Thus, further investigation with larger numbers of patients is warranted. Ann Allergy Asthma Immunol. 2008;100:533–537.
    49. 49. • There are other limitations to this study - Circadian variation of nasal congestion (confounding variable) - Imaging to exclude sinusitis was not routinely performed, and this could have affected the results. - A priming effect could have conceivably affected the results of patient 18 because his initial positive challenge to timothy Grass occurred during the grass pollinating season, and his subsequent negative challenge was performed outside the season. - There was no known exposure change to dust mite or cat allergen in the other relevant patients
    50. 50. Local Allergic Response in Patients With Allergic Rhinitis J Investig Allergol Clin Immunol 2010; Vol. 20(5): 364-371
    51. 51. • Class switching to IgE originally considered a process restricted to the germinal centers of lymphoid tissue, such as regional LN and spleen• Ig E found in local respiratory tissue (nasal and bronchial mucosa) was believed to migrate from regional lymphoid tissue or serum Joseph P. Forester, Christopher W. Calabria, Ann Allergy Asthma Immunol. 2010;105:249 –256
    52. 52. • B cells require 2 signal to undergo class switching recombination(CSR) 1. IL-4, IL-13 produced from Th2 (mast cell and Eo)  activates IgE production by B-cells 2. Th2 cells express CD40L  activates CD40 on Bcells and allows CSR to continue • CSR to an ε heavy chain occur in 3 step – germline gene transcription – DNA recombination with heavy chain locus producing ε circle transcriptions(ε CTs) – Synthesis of heavy chain mRNALocal isotype switching to IgE in airwaymucosa ,Pierre Olivier Fiset, Lisa Cameron, J Allergy ClinImmunol 2005;116:233-6.
    53. 53. • 13 pt. with asymptomatic SAR (+ve SPT to ragweed) were undergo inferior turbinate biopsy• 9 nonallergic subject• These sections were placed on filtered inserts, in well with 2 mL of defined medium with or without 250 μL of ragweed allergen (5, 50, 500, or 1000 protein nitrogen units [PNU]/mL) and incubated in 5% CO2/95% air for a period of 24 hours J Allergy Clin Immunol 2000;106:46-52
    54. 54. • Simultaneous immunocytochemistry and in situ hybridization - Alkaline phosphatase antialkaline phosphatase immunocytochemistry was carried out with antibody against CD20 (B cell), CD3 (T cells) , or tryptase (mast cells) 35 - sections were then hybridized with S-labeled probes for Cε, Iε, IL-4, or IL-13 mRNA - Double-positive cells were visualized as those associated with both a red stain for CD20, CD3, or tryptase immunoreactivity and an accumulation of silver grains corresponding to hybridized antisense riboprobes J Allergy Clin Immunol 2000;106:46-52
    55. 55. • ResultsNasal mucosal tissue was cultured for 24 hours in the presence orabsence of specific allergen ( isolated from systemic circulation )B lymphocyte with in nasal mucosa• B lymphocyte identified on the basis of CD 20 immunoreactivity within allergic nasal mucosa cultured for 24 hr in ragweed allergen J Allergy Clin Immunol 2000;106:46-52
    56. 56. • CD20+ cells are a component of both allergic and nonallergic nasal tissue, allergic significantly higher number of cells (10.5 [5.8-6.3] vs 5 [2-5] cells; P < 0.05• B cells seem to migrate and infiltrate epithelial layer and to cluster into groups of 3 or 4 cells within the submucosa of allergic tissue cultured with allergen. J Allergy Clin Immunol 2000;106:46-52
    57. 57. Allergen-induced expression of Iε and Cε RNA P < 0.05 P < 0.05• Significantly higher numbers of Iε and Cε RNA+ cell in allergen-stimulatedcompared with unstimulated allergic tissue but not within tissue obtained fromnonallergic patients J Allergy Clin Immunol 2000;106:46-52
    58. 58. • Because ε germline gene transcripts (Iε+/Cε+) also encode the Cε gene sequence, the observed increase in Cε RNA+ cells may be due either to previously switched B cells or to those presently undergoing ε germline transcription• Gene encoding Iε is deleted from genome during isotype switching  ε germline transcripts are not produced by cells expressing mature ε mRNA and IgE protein
    59. 59. • ΔCε (Cε RNA+ cells minus Iε RNA+ cells) within allergic tissue cultured with allergen was significantly higher than the baseline number of Cε RNA+ cells in unstimulated tissue suggests the production of mature ε mRNA P < 0.05 • Cε RNA+ cells (mature ε mRNA) observed in unstimulated tissue was most likely attributed to B cells that had previously switched to IgE before biopsy• significant increase in number of cells expressing Iε RNAin allergen-stimulated compared with unstimulated tissuedemonstrates that ε germline transcription was inducedlocally, since the ex vivo exposure excludes the possibilitythat it occurred elsewhere J Allergy Clin Immunol 2000;106:46-52
    60. 60. Allergen-induced expression of IL-4 and IL-13 mRNA• IL-4 and IL-13 mRNA+ cell found in allergic and non-allergic tissue• Simultaneous immunocytochemistry and in situ hybridization demonstrated that the majority of these cells were T cells and mast cells J Allergy Clin Immunol 2000;106:46-52
    61. 61. • Here, we provide first-time evidence for the allergen-Induced production of IL-4 and IL- 13 from T cells (68% and 44%, respectively) residing within the nasal mucosa itself• Both these cytokines induce ε germline gene transcription in vitro• Although only a modest proportion of the total T cell (11% and 11%, respectively) and mast cell (12% and 11%, respectively) populations were responsible for the production of these cytokines, it appears to have been sufficient for inducing ε germline transcription in neighboring B cells• In addition to these cytokines, CD40 activation is required for DNA recombination and IgE synthesis• Because activated T cells and mast cells both express CD40L, it is possible that these B cells were class switching to IgE• No significant increase in the number of cells expressing IL-4 or IL-13 mRNA was observed in either stimulated or unstimulated nonallergic tissue J Allergy Clin Immunol 2000;106:46-52
    62. 62. • Summary - The results shown here provide clear evidence that ε germline gene transcription, as well as mast cell and T cell production of IL-4 and IL-13, occur within allergic nasal mucosa - Further work is required to determine whether the cells actually undergo recombination - These findings suggest the nasal mucosa as a site of IgE synthesis and local regulation of the allergic response to allergen J Allergy Clin Immunol 2000;106:46-52
    63. 63. METHODS: Nasal mucosal scrapings and washes were collected withIRB approval from controls and patients with allergic (positive SPT) andnon-allergic rhinitis (negative SPT). RNA was purified from sample tissueand converted to cDNA which was amplified via two cycles of nested PCRfor the epsilon germline transcripts.RESULTS: Local mucosal IgE isotype switching suggestive of an ongoingallergic inflammatory process was confirmed in 3/6 allergic rhiniticsubjects.Interestingly, active production of epsilon germline transcripts wasobserved in 10/10 subjects with non-allergic rhinitis.CONCLUSIONS: Epsilon germline transcription takes place in the nasalmucosa in a subset of patients with active allergic disease which reflectslocal IgE production. Similarly, patients with NAR demonstrated epsilongermline transcripts indicating that this disease may, in fact, reflect anallergic process JACI vol 127, Issue 2, Supplement, February 2011, Page AB52
    64. 64. Clinical manifestration of LAR• Nasal symptoms and comorbidities - present with symptoms typical of AR (ie, rhinorrhea, obstruction, sneezing, and itching) - frequently associated with conjunctivitis (25% to 57%) and asthma (33% to 47%) - can be grouped : seasonal, perennial, and occupational : intermittent and persistent (mostly  persistent rhinitis with moderate-to- severe symptoms)Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in
    65. 65. Diagnostic approach• LAR can be confirmed based on - detection of nasal sIgE or both - positive NAPT response - absence of systemic atopy • Nasal sIgE high specificity but low sensitivity (22%-40%) • NAPT very useful diagnostic test with higher sensitivity
    66. 66. Diagnostic approachLocal allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in
    67. 67. Treatment• correct differentiation between LAR and NAR is a key point for the management• Pt. with LAR have reported a good response to topical INS oral antihistamines (contrast with NAR)Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in
    68. 68. Local allergic rhinitis: allergen tolerance andimmunologic changes after preseasonalimmunotherapy with grass pollen.• Pilot observational study in patients with LAR sensitized to grass pollen• 50% of pt were treated with pre seasonal grass specific SCIT for 6 months in the spring (SCIT group), VS 50% of pt received rescue medication alone (control group)• SCIT with grass pollen increased tolerance to the aeroallergen and reduced symptoms and rescue medication in patients with LAR compared with control group• Need phase II DBPC to evaluated wheater LAR might be consider a new indication for IT Carmen Rondo´ n J Allergy Clin Immunol 2011;127: -
    69. 69. • Once allergy has been ruled out, most of these patients are not usually followed up in allergy clinics, despite the persistence of rhinitis symptoms• This study re-evaluate over time the severity, accompanying disorders, and possible allergen sensitizations in subjects with NAR• Randomly selected 180 pt. diagnoses of NAR in allergy clinic between 2000 and 2004 (age 19 to 69 years) Carmen Rondo´ n , et.al, J Allergy Clin Immunol 2009;123:1098-102
    70. 70. • Clinical questionnaire and medical interview First evaluation initial data from medical record second evaluation  Questionaire• SPTs and specific IgE measurement SPT : Dermatophagoides pteronyssinus, Dermatophagoides farinae, Lepidoglyphus destructor, Blomia tropicalis, Poa, Phleum, Lolium, Casuarina, Eucalyptus, Cupressus arizonica, Platanus, Olea europea, Helianthus, Chenopodium, Plantago, Artemisia, Parietaria judaica, Salsola kali, Rumex, Ricinus, Alternaria alternata, Aspergillus fumigatus, Cladosporium herbarum, Penicillium notatum, and animal epithelia of dog, cat, and hamster specific IgE to D pteronyssinus, O. europea, grass, Cupressus arizonica, P judaica, Alternaria alternata, Aspergillus fumigatus, cat, and dog were determined in patients with a negative SPT response• Lung function tests : FEV1, FEV1/FVC Carmen Rondo´ n , et.al, J Allergy Clin Immunol 2009;123:1098-102
    71. 71. • Results 12% 9% 23% 24% 15% 10% 11%
    72. 72. • Results Carmen Rondo´ n , et.al, J Allergy Clin Immunol 2009;123:1098-102
    73. 73. • Result Newly sensitization : evaluate by SPT & sIgE 18% 11.5% 3.85% Carmen Rondo´ n , et.al, J Allergy Clin Immunol 2009;123:1098-102
    74. 74. Summary• this study confirms that de novo sensitization to aeroallergens, new comorbidities, and worsening in the persistence, severity, and effect on quality of life are frequent in the natural evolution of adults with NAR• Patients with NAR need to be evaluated over time to identify new comorbidities, including the appearance of AR. Carmen Rondo´ n , et.al, J Allergy Clin Immunol 2009;123:1098-102
    75. 75. • Pt. with NAR might have local sIgE antibody in absence of systemic sIgE• Nasal provocation test is the gold standard to show evidence for local IgE mediated allergy in nonallergic pt., standardized are required• Futher research - Prevalence , incidence in adult and children - Natural Hx : LAR  AR - Treatment : IT ??
    76. 76. Rhinitis Non allergic Allergic rhinitis rhinitis Allergic rhinitis Local allergic Infectious with systemic rhinitis without Occupational atopy systemic atopy Drug-induced Hormonal Irritant Seasonal Intermittent Food Perennial Persistent Emotional Atrophic GERJ Investig Allergol Clin Immunol 2010; Vol. 20(5): 364-371 Idiopathic (NARES include)
    77. 77. Thank you
    78. 78. Pathophysiological Characteristics of Local Allergic Rhinitis• Specific IgE and Inflammatory mediators in nasal secretion• TH 2 Nasal Inflammatory pattern• Positive response to nasal allergen provocation test
    79. 79. • The possible reasons for not detecting sIgE in patients with LAR with a positive NAPT response might be - low sensitivity of the assays used (dilutional effect of nasal lavage) - another immunologic mechanism, such as the possibility of nonspecific protease activity stimulation of HDM on airway innate immune cell - others
    80. 80. Class switching to IgE• IgE have 2 heavy chain and 2 light chain• Fc portion binds to the high affinity receptor (FcεRI) on mast cell and Basophil• Fab portion binds to specific antigen• Cross-linked of adjacent, membrane bound, allergen specific IgE molecules on mast cells lead to immediated hypesensitivity reaction  cell degranulation and release of mediators (eg. Histamine, tryptase and leukotriene) and cytokine (eg. IL-4, IL-13)
    81. 81. Local allergic rhinitis: Concept, pathophysiology, and management. J Allergy Clin Immunol article in press
    82. 82. Subjects had to fulfill the following requirements:1. General inclusion criteria for the PNAR and PAR groups: subjects cellaged 18-70 years, with no evidence of other immunologicdisease, chronic rhinosinusitis and/or nasal polyposisby CT scanning, vasomotor rhinitis (clear rhinorrhea and responseto ipratropium bromide), or respiratory infection duringthe previous 4 weeks (purulent sputum or rhinorrhea,fever, or abnormal laboratory test for white blood cells); notreatment with systemic or nasal corticosteroids during the previousmonth or systemic antihistamines or nasal vasoconstrictorsduring the previous 2 weeks. No patient was pregnant orbreast feeding.2. Specific inclusion criteria for the PNAR group: a history of persistentrhinitis for at least 2 years, negative skin prick test andserum specific IgE to perennial aeroallergens, negative intradermalskin test to DP, and fulfilling the exclusion criteria foridiopathic rhinitis outlined in the ARIA1 and Rijswijk reviews.93. Specific inclusion criteria for the PAR group: history of persistentrhinitis for at least 2 years, positive skin prick test(>5-mm wheal) and/or positive serum specific IgE to DP.All PAR subjects had to have a positive response to NAPTDPand no evidence of treatment with immunotherapy duringthe previous 10 years.4. Inclusion criteria for the CG: age 18-70 years, healthy, noallergic or nasal diseases, no pregnancy or lactation, negativeskin prick test, negative serum specific IgE to aeroallergens,and negative NAPT-DP.