집먼지진드기 항원을 이용한 고식적인 면역요법이 말초혈액 호염기구 히스타민 유리능에 미치는 영향

심정연(Jung Yeon Shim),김봉성(Bong Seong Kim),조상헌(Sang Heon Cho),민경업(Kyung Up Min),홍수종(Soo Jong Hong) 대한천식알레르기학회 2000 천식 및 알레르기 Vol.20 No.5

Background: Allergen-specific immunotherapy has been shown to be clinically effective in the treatment of patients with atopic asthma, but the mechanisms are still unclear. Some of the immunologic changes include increase of an allergen-specific IgG antibody, decrease of allergen-specific IgE after transient increase, allergen-specific T-cell shift in cytokine expression from Th2 to Th1 cytokines, and decrease of basophil histamine releasability. Objectives : To investigate the influence of immunotherapy on basophil releasability, we examined the changes of IgE-mediated and non-IgE-mediated basophil histamine releasability during immunotherapy. Methods : Fourteen Dermatophagoides farinae(D.f) sensitive asthmatic children with conventional immunotherapy were investigated. Basophil histamine releasability was measured prior to immunotherapy and 4 and 9 months after immunotherapy. Basophils were stimulated with D.f and goat antihuman IgE antibody as IgE-mediated stimuli which act on IgE-receptor, and formyl-Met-Leu-Phe(fMLP) as non-IgE-mediated stimuli which acts on non-IgE receptor, and calcium ionophore A23187 as non-IgE-mediated stimuli which does not act on cell surface receptors, Histamine was measured by automated fluorometric technique. Results : Before immunotherapy. there were significant correlations between histamine release by D.f and histamine release by fMLP, and between histamine release by D.f and histamine release by anti-IgE antibody, but no correlation between histamine release by D.f and histamine release by calcium ionophore. Histamine release by D.f and by anti-IgE antibody decreased at 4 and 9 months after immunotherapy compared to those before immunotherapy. Histamine release by fMLP and by calcium ionophore showed no significant changes after immunotherapy. There was no significant change of total histamine release after immunotherapy. Conclusion : Conventional immunotherapy has influenced only the IgE-mediated basophil releasability. IgE-mediated and non-IgE-receptor-mediated basophil releasability was correlated before immunotherapy, but only IgE-receptor-mediated basophil releasability decreased after immunotherapy. These findings suggest that a kind of physicochemical change may happen on the IgE receptors of basophil, which may induce decrease of IgE-mediated basophil histamine releasability after immunotherpy. (J Asthma Allergy Clin Immunol 20: 731-740, 2000)

특발성 전신 간질(IGEs)에서 GABRG2 유전자의 단일염기 다형성

연영흠(Yeong Heum Yeon),승소진(So Jin Seung),황희승(Hui Sung Hwang),김유진(Eugene Kim),최병준, 김영훈(Young Hoon Kim),이인구(In Goo Lee),정승연(Seung Yun Chung) 대한소아신경학회 2007 대한소아신경학회지 Vol.15 No.2

목 적 : 최근에 Generalized epilepsy with febrile seizures plus(GEFS+) 환자가 포함된 가족과 Childhood absence epilepsy(CAE) 및 열성경련을 가진 소아가 포함된 가족에서 γ-aminobutyric acid(GABA) A receptor γ2 subunit gene(GABRG2)에 두 개의 다른 돌연변이가 있는 것이 발견되었다. 본 연구는 한국의 특발성 전신 간질(idiopathic generalized epilepsies, IGEs) 환아에서 GABRG2 유전자의 다형성이 질환의 감수성에 미치는 영향을 알아보기 위하여 시도되었다. 방 법 : 가톨릭대학교 의정부성모병원 및 성모자애병원 소아과에서 진단받은 IGEs환자 23명과 건강한 대조군 94명, 총 117명을 대상으로 하였다. GABRG2의 SNP211037은 Denaturing high performance liquid chromatography(DHPLC)를 이용하여 분석하였다. 이후 DHPLC에서 변이를 보인 deoxyribonucleic acid조각에 대해서는 염기 서열법을 시행하였다. 두 군에서 GABRG2 유전자 다형성의 유전형 분포와 대립유전자 빈도를 비교하였다. 결 과: GABRG2(SNP211037)에 대한 유전형 분포와 대립유전자 빈도는 통계학적으로 유의한 차이는 없었다. 환자군과 건강한 대조군 모두에서 GABRG2(SNP211037) 유전자에 대한 가장 흔한 유전형은 C/T 이형 접합자였다. GABRG2(SNP211037)에 대한 C와 T의 대립유전자 빈도는 환자군에서 45.7%와 54.3%이었고, 정상대조군에서 42.6%와 57.4%이었다. GABRG2(SNP211037)-CC 유전자형은 건강대조군에 비하여 환자군에서 더 많이 표현되었고(21.7% versus 12.8%) GABRG2(SNP 211037)-CC 유전자형을 가진 소아에서 IGEs로 발전할 수 있는 교차비는 GABRG2(SNP211037)-TT 유전자형을 가진 소아에 비하여 1.65배 높았으나 통계학적으로 유의하지는 않았다. 결 론: 이러한 결과는 GABRG2의 유전자 다형성이 한국의 소아에서 특발성 전신 간질을 일으키는데 크게 기여하지는 않음을 시사한다. Purpose : Mutations in γ-aminobutyric acid(GABA) A receptor γ2 subunit gene(GABRG2) were independently identified in families of generalized epilepsy with febrile seizures plus(GEFS+) and families of absence epilepsy and febrile seizures(FSs). The present study assessed the role of GABRG2 gene in idiopathic generalized epilepsies(IGEs) of Korean population. Methods : Twenty-three IGEs and 94 healthy control subjects were selected through a collaborative study of Catholic Child Neurology Research Group. The SNP211037 of GABRG2 were screened by DHPLC. DNA fragments showing variant chromatograms were subsequently sequenced. Genotypes and allelic frequencies for GABRG2 gene polymorphism in three groups were compared. Results : Genotypes and allelic frequencies of the γ2 subunit of the GABA receptor gene(SNP211037) in both groups were not significantly different. The most common genotypes for GABRG2(SNP211037) gene in both groups were T/C heterozygote. The allele C and T frequencies for GABRG2(SNP211037) in the IGEs group were 45.7% and 54.3%, respectively and in healthy control group, 42.6% and 57.4%, respectively. The number of individuals with the GABRG2 (SNP211037)-C/C genotype in the IGEs group was greater compared with that in the healthy control group(21.7% versus 12.8%). The odds ratio for developing IGEs in individuals with the GABRG2 (SNP211037)-CC genotype was 1.65 compared with individuals with the GABRG2 (SNP211037)-T/T genotype, which was not significantly different. Conclusion : These data suggest that genomic variations of GABRG2 might not be one of the susceptibility factors for IGEs in the Korean population.

$\beta_2$ 교감신경 수용체 다형성이 아토피 및 혈청 IgE에 미치는 영향

이신형,심재정,강용구,정혜철,김경규,권영환,김제형,이승룡,이소라,이상엽,조재연,인광호,유세화,강경호,Lee, Sin-Hyung,Shim, Jae-Jeong,Kang, Yong-Koo,Jeong, Hye-Cheol,Kim, Kyung-Kyu,Kwon, Young-Hwan,Kim, Je-Hyeong,Lee, Sung-Yong,Lee, So-Ra,Lee, San 대한결핵및호흡기학회 1999 Tuberculosis and Respiratory Diseases Vol.46 No.6

연구배경 : $\beta_2$ 교감신경 수용체의 다형성이 기관지 천식의 표현형에 영향을 미친다고 알려져 있다. 이에 저자들은 먼저 기관지 천식 환자와 정상인에서의 $\beta_2$ 교감신경 수용체의 다형성의 빈도에 차이가 있는가를 알아보고, 또한 기관지 천식 환자에서 아토피의 유무 및 혈청 총 IgE의 증가 여부와 $\beta_2$ 교감신경 수용체의 다형성이 관계가 있는지 알아보고자 본 연구를 시행하였다. 방 법 : 기관지 천식 환자 109명과 정상인 42명에 대하여 혈청 총 IgE를 측정하고, 항원 특이 IgE 검사 및 피부 단자 검사를 실시하였고, mutated allele specific amplification 법으로 $\beta_2$ 교감신경 수용체와 다형성을 검색하였다. 결 과 : $\beta_2$ 교감신경 수용체의 다형성을 조사한 결과 16번 아미노산 위치에서는 Arg 야생형 및 Arg/Gly 이형접합체 변이형, Gly 동형 접합체 변이형이, 그리고 27번은 Gln 야생형, Gln/Glu 이형 접합체 변이형, Glu 동형 접합체 변이형이 관찰되었다. 34번 아미노산의 경우는 Val 야생형과 Val/Met 이형 접합체 변이형이, 164번은 Thr 야생형만 있었다. 1) 정상인과 기관지 천식 환자에서 $\beta_2$ 교감신경 수용체의 16, 27, 34번 아미노산 위치에 있어서 다형성의 빈도는 통계학적으로 차이가 없었다(p>0.05)(Table 3). 2) 기관지 천식환자에서 $\beta_2$ 교감신경 수용체 다형성의 빈도와 아토피의 존재 유무는 16, 27, 34 번 아미노산에서 모두 통계학적으로 관계가 없었다(p>0.05) (Table 4). 3) 기관지 천식 환자 중 혈청 총 IgE가 증가된 군과 정상 군에서 $\beta_2$ 교감신경 신경 수용체 다형성과 혈청 총 IgE의 증가 여부의 비교는 16, 27, 34번 아미노산 모두 통계학적인 관련이 없었다(p>0.05) (Table 5). 결 론 : 결론적으로 기관지 천식 환자와 정상인 사이의 $\beta_2$ 교감신경 수용체의 다형성은 16, 27, 34번 아미노산 위치에서 차이가 없었고, 기관지 천식환자에서 아토피의 유무 및 혈청 총 IgE의 증가 여부와 $\beta_2$ 교감신경 수용체의 다형성의 빈도는 통계적으로 유의한 관계가 없었다. Background : The $\beta_2$ adrenergic receptor ($\beta_2$ AR) polymorphisms occurring at amino acid position 16 (Arg to Gly), 27 (Gln to Glu), 34 (Val to Met), and 164 (Thr to Ile) are known to be functionally relevant and also disease-modifying in subjects with asthma. However the contribution of these polymorphisms to the development of the asthmatic phenotype or other markers for allergic disease remains to be established. Methods : 109 patients with bronchial asthma and 42 healthy person were included. Serum total IgE, allergen specific IgE, and skin prick test were performed to all of the subjects. $\beta_2$ AR polymorphisms were checked by mutated allele specific amplification (MASA) method. Results : The results were as follows. The frequencies of $\beta_2$ AR polymorphisms in asthmatic patients and healthy person were not statistically different(p>0.05). There was no association between $\beta_2$ AR polymorphisms of amino acid position 16, 27, 34 and the existence of atopy among asthmatic patients(p>0.05). Between asthmatic patients with or without elevated IgE level and $\beta_2$ AR polymorphisms of amino acid position 16, 27, 34, there was no statistically significant association(p>0.05). Conclusion : There was no difference in frequency of the $\beta_2$ AR polymorphism between asthmatic patients and healthy person. In the bronchial asthma, association of $\beta_2$ AR polymorphism and atopy/serum total IgE was not found.

In Vitro and In Vivo Validation of EP2-Receptor Agonism to Selectively Achieve Inhibition of Mast Cell Activity

Fernando de Mora 대한천식알레르기학회 2020 Allergy, Asthma & Immunology Research Vol.12 No.4

Purpose: Agonism of the prostaglandin E2 receptor, E-prostanoid receptor 2 (EP2), may represent an alternative protective mechanism in mast cell (MC)-mediated diseases. Previous studies have suggested that activation of the MC EP2 receptor prevents pathological changes in the murine models of allergic asthma. This work aimed to analytically validate the EP2 receptor on MCs as a therapeutic target. Methods: Murine MC lines and primary cultures, and MCs bearing the human immunoglobulin E (IgE) receptor were subjected to IgE-mediated activation subsequent to incubation with selective EP2 agonists. Two molecularly unrelated agonists, butaprost and CP-533536, were tested either in vitro or in 2 in vivo models of allergy. Results: The diverse range of MC populations was consistently inhibited through selective EP2 agonism in spite of exhibiting a heterogeneous phenotype. Such inhibition occurred in both mouse and human IgE (hIgE)-mediated activation. The use of molecularly unrelated selective EP2 agonists allowed for the confirmation of the specificity of this protective mechanism. This effect was further demonstrated in 2 in vivo murine models of allergy where MCs are a key to pathological changes: cutaneous anaphylaxis in a transgenic mouse model expressing the hIgE receptor and aeroallergen-induced murine model of asthma. Conclusions: Selective EP2 agonism is a powerful pharmacological strategy to prevent MCs from being activated through IgE-mediated mechanisms and from causing deleterious effects. The MC EP2 receptor may be an effective pharmacological target in allergic and other MC-mediated conditions.

Antibody to FcεRIα Suppresses Immunoglobulin E Binding to High-Affinity Receptor I in Allergic Inflammation

손명현,홍정연,배종환,이경은,김미나,김민희,강현정,박은혜,유경숙,정세규,김경원,김규언 연세대학교의과대학 2016 Yonsei medical journal Vol.57 No.6

Purpose: High-affinity receptor I (FcεRI) on mast cells and basophils plays a key role in the immunoglobulin E (IgE)-mediated type I hypersensitivity mediated by allergen cross-linking of the specific IgE-FcεRI complex. Thus, prevention of IgE binding to FcεRI on these cells is an effective therapy for allergic disease. We have developed a strategy to disrupt IgE binding to FcεRI using an antibody targeting FcεRIα. Materials and Methods: Fab fragment antibodies, which lack the Fc domain, with high affinity and specificity for FcεRIα and effectiveinhibitory activity against IgE-FcεRI binding were screened. IgE-induced histamine, β-hexosaminidase and Ca2+ release in basophils were determined by ELISA. A B6.Cg-Fcer1atm1Knt Tg(FCER1A)1Bhk/J mouse model of passive cutaneous anaphylaxis (PCA) was used to examine the inhibitory effect of NPB311 on allergic skin inflammation. Results: NPB311 exhibited high affinity to human FcεRIα (KD=4 nM) and inhibited histamine, β-hexosaminidase and Ca2+ releasein a concentration-dependent manner in hFcεRI-expressing cells. In hFcεRIα-expressing mice, dye leakage was higher in the PCA group than in controls, but decreased after NPB311 treatment. NPB311 could form a complex with FcεRIα and inhibit the release of inflammation mediators. Conclusion: Our approach for producing anti-FcεRIα Fab fragment antibody NPB311 may enable clinical application to a therapeuticpathway in IgE/FcεRI-mediated diseases.

B 림프구 활성화 자극에 따른 Interleukin-4 수용체와 Type II IgE 수용체 발현조절양상의 상호관련성

이충은,윤석란,변광호,소의영 大韓免疫學會 1995 大韓免疫學會誌 Vol.17 No.3

Interleukin-4(IL-4) specifically induces the expression of its own receptor, IL-4R and type II IgE receptor, FceR1l in a dose-dependent manner in human B lymphocytes. We observed that the IL-4-induced expression of IL-4R and Fce Rll were both down-regulated by interferon-T(IFN-T) at mRNA as well as surface protein levels in normal B lymphocytes. Such co-ordinated regulation of the IL-4-induced IL-4R and FceRlI also occurred by anti-CD40 and steroid, each regulating the IL-4-induced response in an opposite direction. While anti-CD40, which is re-ported to agument the IL-4-induced B cell activation, further enhanced the IL-4-induced IL-4R and Fee RU expression, methylprednisolon(MPD) strongly inhibited the level of these receptors. The anti-CD40 or MPD-induced modulation of the IL-4-induced IL-4R and FceRII was further subject to the down-regulation by lFN-T. As compared to normal B lymphocytes, a differential regulation of IL-4R and FceRII was noted in a transformed B cell line, where IFN- Tup-regulated the IL-4-induced responses. Still, there was a co-ordinated regulation of the IL-4R and FceRII in these cells. Taken together, these results suggest that modulation of IL-4R expression and FccRII induction are closely correlated events during the IL-4-induced cellular activation

Interleukin 4 및 interferon-Gamma가 정상인 말초혈액 B 림프구의 FcεRII 표현에 미치는 영향

문종호 ( Mun Jong Ho ),박춘식 ( Park Chun Sig ),어수택 ( Eo Su Taeg ),한동철 ( Han Dong Cheol ),황승덕 ( Hwang Seung Deog ),이희발 ( Lee Hui Bal ) 대한내과학회 1993 대한내과학회지 Vol.44 No.3

Background : FcεRII is one of Ige binding receptor and is generally known as the low affinity receptor for IgE. FcεRII is identified on B cells, monocytes, macrophages, Langerhan`s cells, T cells and eosinophils. IgE upregulates FcεRII, and IL-4 upregulates FcεRII by increasing the rate of synthesis of both FcεRII and IgE. Interferon-r blocks IL-4-induced upregulation of FcεRII. The purpose of this study is to search the kinetics of FcεRII expression on normal human peripheral blood B cells. Methods : We measured time and dose-dependent expression of FcεRII on peripheral blood B cells with flow-cytometry after stimulation with IL-4 and INF-r in healthy volunteers. Results : 1) The percentage of FcεRII positive B lymphocytes significantly decreased 24hrs after incubation without stimulation when compared to that before incubation (p<0.05). 2) IL-4-induced upregulation of FcεRII expression by B lymphocytes reached maximum level at 48 to 72hrs after stimulation, then decreased gradually and was dose dependent up to 1000 u/ml. 3) IL-4 did not change the fraction of B lymphocytes in cultured PBMC. 4) The stimulating effect of IL-4 (100 u/ml) on FcεRII expression of B lymphocytes was partially suppressed by the addition of INF-r (100 u/ml). Conclusion : IL-4 increased FcεRII expression on normal peripheral blood B lymphocytes without proliferative effect and INF-r partially inhibits IL-4 induced upregulation of FcεRII.

Probable Role of Beta 2-Adrenergic Receptor Gene Haplotype in Toluene Diisocyanate-Induced Asthma

박해심,예영민,Young-Mi Kang,김승현,Hyun-Young Lee,김철우,박춘식,홍천수 대한천식알레르기학회 2010 Allergy, Asthma & Immunology Research Vol.2 No.4

Purpose: A genetic polymorphism of the beta 2-adrenergic receptor is a major factor associated with the asthmatic phenotype. The association of this polymorphism with toluene diisocyanate (TDI)-induced asthma has not been investigated. We examined 103 TDI-induced asthma patients (TDIOA),60 asymptomatic exposed controls (AEC), and 263 unexposed healthy controls (NC) in order to identify beta 2-adrenergic receptor gene (ADRB2)polymorphisms and the possible association with TDI-induced asthma. Methods: Single nucleotide polymorphisms (SNPs) of ADRB2 were genotyped by direct sequencing. Serum-specific IgE and IgG levels were measured using an enzyme-linked immunosorbent assay. Phenotypes and clinical patient parameters were compared. Results: SNPs were identified (−47 T>C, −20 T>C, Arg16Gly A>G, Gln27Glu C>G, Leu134Leu G>A, Arg175Arg C>A) during ADRB2 screening (from –231 to 793 bp). No significant differences in allelic and genotypic frequencies were noted for any of the six ADRB2SNPs. The Arg16Gly A>G, Leu134Leu G>A, and Arg175Arg C>A SNPs and haplotype 1 [TTACGC] were significantly associated with specific IgE antibodies to the TDI-human serum albumin (HSA) conjugate in TDI- exposed subjects (P<0.05). Exposed workers with the ADRB2 ht1/ht1 homozygote had a significantly higher TDI-HSA conjugate-specific IgE sensitization rate than did those with the null ht1 haplotype (odds ratio, 15.40; 95% confidence interval, 1.81–131.06). Conclusions: ADRB2 polymorphisms may affect IgE-specific sensitization to TDI-HSA conjugate in TDI-exposed workers.

Altered Expression of Substance P and NK1R in CCR3+ and CD123+HLA-DR− Basophils Under Airway Allergic Conditions

Geng Shiyang,Xie Hua,Chen Liping,Chen Dong,Lu Sijing,Zhao Nan,Yang Ruiming,Wang Zhao,He Shaoheng,Zhang Huiyun 대한천식알레르기학회 2022 Allergy, Asthma & Immunology Research Vol.14 No.6

Purpose: To explore expression of SP and NK1R in basophils of allergic asthma (AA), allergic rhinitis (AR) and AR combined with AA (ARA), and influence of allergens and immunoglobulin E (IgE) mediated mechanisms on SP and NK1R expression. Methods: Expression of SP and NK1R was detected by flow cytometry, NK1R mRNA expression was detected by real time quantitative polymerase chain reaction (qPCR), and mouse AR and AA models were employed for in vivo study. Results: SP+ and NK1R+ cells increased in CCR3+ and CD123+HLA-DR− granulocytes of AA. PPE elevated proportions of SP+ cells in CCR3+ and CD123+HLA-DR− granulocytes, whereas ASWE and HDME augmented SP+ cells in CD123+HLA-DR− granulocytes of AR and ARA patients. ASWE, HDME and PPE increased proportions of NK1R+ cells in CCR3+ PBMC and CD123+HLA-DR− granulocytes of AR patients. OVA, Der p1, IL-33, IL-37, IgE and SP enhanced NK1R expression on KU812 cells. NK1R expressing basophils were increased in blood of OVA sensitized and challenged AR and AA mice. FcεRI-KO AA mice seemed to have less NK1R+ basophils than WT AA mice in their blood. Conclusion: CCR3+ and CD123+HLA-DR− cells are likely involved in AA and AR via SP and NK1R. IgE-related mechanism may participate in upregulation of NK1R expression.

β2 교감신경 수용체 다형성이 아토피 및 혈청 IgE에 미치는 영향

이신형 ( Sin Hyung Lee ),심재정 ( Jae Jeong Shim ),강용구 ( Yong Koo Kang ),정혜철 ( Hye Cheol Jeong ),김경규 ( Kyung Kyu Kim ),권영환 ( Young Hwan Kwon ),김제형 ( Je Hyeong Kim ),이승룡 ( Sung Yong Lee ),이소라 ( So Ra Lee ),이 대한결핵 및 호흡기학회 1999 Tuberculosis and Respiratory Diseases Vol.46 No.6