免疫球蛋白游离轻链在变应性鼻炎及非变应性鼻炎中表达及其意义
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摘要
鼻炎发病率的逐年增高、导致生活质量的降低、各种并发症的出现及对上下呼吸道的影响是耳鼻咽喉科临床医生面对的巨大挑战。在变应性鼻炎(allergic rhinitis，AR)诊治过程中，我们不得不面对一个挑战性的临床难题，即临床上存在大量过敏原皮肤点刺(Skin prick tests, SPT)及血清免疫球蛋白特异性IgE(serum-specific immunoglobulin E, sIgE)检测均为阴性的患者，其各种临床症状、生活质量以及其对下呼吸道的影响与IgE介导的变应性鼻炎极为相似，但发病机制、治疗原则及预后均有所差别，这类鼻炎一般定义为非变态反应性鼻炎或非变应性鼻炎（nonallergic rhinitis，NAR）。我们通过回顾性调查分析发现，虽然在临床诊疗中NAR与AR有很多相似之处，但仍有一定的差别。因此本文的第2章对一年中398例以高反应性鼻部症状首诊的诊断为AR及NAR的连续患者对其性别、年龄、发病季节、分型、诱发因素及临床症状等因素进行统计分析。结果发现AR与NAR的性别分布差异有统计学意义（P=0.01），NAR女性患者居多，AR男性患者居多（P＜0.05）；在发病年龄上，NAR以中青年为主，高发年龄在30～39岁（P=0.00），AR以青少年为主，高发年龄在10～19岁（P=0.00）；NAR发病无明显季节性，AR发病多在秋季。AR以中重度持续性为主（P=0.00），NAR以中重度间歇性为主（P=0.00）；除喷嚏及喘息外，AR与NAR临床症状出现的频率差异有统计学意义（P＜0.05），比较鼻、眼部临床症状，除鼻痒外AR均较NAR重（P＜0.05）；非特异性诱发因素在AR与NAR在发病过程中的作用大致相似（P＞0.05）。结论AR与NAR在性别构成、主要发病年龄、鼻炎分型及发病季节上有明显差异，除喷嚏及喘息外AR与NAR出现频率多，比较鼻、眼部临床症状，除鼻痒外AR均较NAR重。
根据欧洲变态反应与临床免疫学会（EAACI2001）及世界变态反应协会（WAO2004）,由免疫学机制诱导的过敏性鼻炎(hypersensitive rhinitis)称为变态反应性鼻炎(allergic rhinitis,AR),AR又分为IgE介导和non-IgE介导。IgE介导的变态反应性鼻炎或变应性鼻炎（Allergic Rhinitis,AR）是最常见的临床形式，non-IgE介导的过敏性鼻炎（non-IgE-mediated hypersensitiverhinitis，NIHR)作为一个临床实体，虽然缺乏足够的证据，但近年来也愈发引起关注。Redegeld等首先证明了免疫球蛋白游离轻链FLC可以直接作用于肥大细胞引起速发型过敏反应，随后相继证明由FLC可以诱发哮喘，并提出了免疫球蛋白游离轻链（Immunoglobulin free light chain, FLC）可以做为慢性炎症性疾病新的治疗靶点。
为了进一步探讨AR及NAR在发病机制上的问题，探讨FLC在AR与NAR细胞学及病理学上的差异。文中第3章我们采用免疫组织化学及实时荧光定量PCR等方法探讨了FLC在AR及NAR组织中的表达及细胞分布。采用ELISA方法对AR、NAR患者及健康人血清及鼻分泌物中FLC，ECP, MCT及总IgE进行检测。对比分析各种细胞因子及FLC的表达水平在三组中的差异，并对其意义进行讨论。通过免疫组化及荧光双染发现FLC表达与肥大细胞细胞密切相关，同时Real-time PCR结果显示FLC与MCT呈正相关。ELISA结果发现AR及NAR组鼻分泌物及血清中κFLC、λFLC、 ECP及Tryptase的水平均较正常组明显升高(P<0.01)；鼻分泌物中ECP水平AR组(17.270±11.80)较NAR组(11.34±7.38)明显升高(P<0.05)，鼻分泌物中总IgE水平在三组中比较均具有统计学意(p<0.05)；在血清中总IgE水平AR组明显高于NAR组及正常组(p<0.05)，而NAR与正常组无统计学意义(p>0.05)。相关性分析在鼻分泌物中FLC与Tryptase呈正相关，具有统计学意义（P<0.01）。
因此，我们认为FLC在变应性鼻炎及非变应性鼻炎发病机制中具有一定作用，FLC可能通过作用于肥大细胞并通过局部免疫反应参与非变应性鼻炎的发病。这种观点为我们研究变应性鼻炎及非变应性鼻炎的发病机理及临床干预提供了一种新的理论基础及治疗靶点。
Background：The high prevalence of the rhinitis and it impact on qualityof life is still challenge for physician in management as complication ofpathogenesis of the rhinitis. Rhinitis is generally categorized as allergic ornonallergic. The IgE-mediated allergic rhinitis is the most common clinicalform. Considerable cases of nonallergic rhinitis in clinical, however,manifestate nasal hypersensitivity. The symptoms of the hypersensitive rhinitisare very similar to allergic rhinitis but the causes appear to be entirely different.According to EAACI (2001) and WAO (2004), the pathogenic mechanism ofhypersensitivity may be immunologic or non-immunologic and the hypers-ensitive rhinitis induced by immunologic mechanism is classified IgE-mediatedand non-IgE-mediated. The non-IgE-mediated hypersensitive rhinitis (NIHR)induced by immunomechanism as clinical entity, Redegeld et al. demonstratedfirstly that the specific immunoglobulins free light chain (FLC) may induce theimmediate hypersensitive response depending upon the mast cells. After this,Redegeld and his research group proved sequentially that the FLC may elicitallergic asthma and proposal that FLC may be a novel target in the therapy ofchronic inflammatory diseases. According above, Powe et al.(2010) studiedpatients with nasal hypersensitivity and found that significantly increasedFLC-expressing cells in the mucosa of patients with persistent allergic andNon-allergic rhinitis with eosinophilia syndrome (NARES), localized in mastcells and plasma cells, and increased FLC serum levels in subjects withNARES. FLC may provide an additional non-IgE immune pathway to augmentor replace IgE-mediated hypersensitivity in chronic mucosal inflammatorydisease.
The pathogenesis of non-allergic rhinitis with nasal hypersensitivity is notclear so far resulting in confusion and weak on the basis of treatment. Thepresent study aim to proving hypothesis that The FLC may play important rolein nonallergic rhinitis (NAR) with nasal hyperreactivity but NARES throughobserving the expression level of FLC, tryptase (biomarker of mast cells), ECP(biomarker of eosinophils) in nasal mucosa, nasal secretion and serum frompatients without positive results of allergen skin test and serum level of allergenspecific IgE.
Method：On the first part,398consecutive patients were recruited in2009.Questionnaire survey based on ARIA2008was conducted to both groups of ARand NAR. Multiple aspects were analyzed to find the difference. On the secondpart, Selected60consecutive patients from Sep to Dec in2009involved30allergic rhinitis patients,30non-allergic rhinitis patients who were diagnosedby Symptom, Sign, SPT and sIgE, and10volunteers and20patients withdeviation of nasal septum who were choosen to be control. ELISA was used todetect the total IgE, eosinophil cationic protein(ECP), mast cell tryptase,κFLC，λFLC of nasal secretions and serum. Histopathological observations andimmunohistochemical staining for κFLC, λFLC, ECP and MCT wereperformed on30specimens (10AR,10NAR and10specimen’s inferiorturbinate of deviation of nasal septum). The serum and nasal secretionsexpression levels of totel IgE, ECP, MCT, κFLC，λFLC were determined byELISA (30AR,30NAR,10normal human and20specimens inferior turbinateof deviation of nasal septum). Whilst the mRNA expression of κFLC，λFLCAND MCT was determined by real-time quantitative PCR were performed on30specimens (10AR,10NAR and10specimens inferior turbinate of deviationof nasal septum).
Result: In AR, male was more than female, whereas in NAR (P﹤0.01).The highest morbidity age in AR was teenagers (P﹤0.01), while in NAR was middle-aged (P﹤.01). The main onset season in AR was autumn, while noseasonal diversity in NAR. The main classification of AR was moderate-severepersisten（tP﹤.01）, while in NAR was moderate-severe intermitten（tP﹤0.01）.The frequency of clinical symptoms was different except sneezing and gasping.（P﹤0.05）.The severity of clinical symptoms was different exceptrhinocnesmus（P﹤0.05）. There was consistency about induced factors in ARand NAR（P＞0.05）. The second parts shown that FLC main expressed on mastcell, ELISA examine shown that κFLC、λFLC、ECP&Tryptase were increase inAR and NAR compared to HC (P<0.01); There are significantly differencesbetween AR and NAR of ECP form nasal secretions (P<0.05), The total IgEfrom serum were increased in AR compared to NAR and HC (P<0.05), andthere are differences of the total IgE form nasal secretions among three groups(p<0.05).
Conclusion: There were significant differences between AR and NAR insex, age, classification and seasons. The frequency of clinical symptoms weresignificantly different between AR and NAR except sneezing andgasping.Comparised the clinical symptoms of nose and eye, The severity ofclinical symptoms in AR was higher than that in NAR except rhinocnesmus.There was consistency about induced factors in AR and NAR. This study hassome clinical significance in correct recognition and diagnosis of AR and NAR.Immunoglobulin free light chain took part in the pathophysiological process ofallergic rhinitis and non-allergic rhinitis with the immunological mechanism.
根据欧洲变态反应与临床免疫学会（EAACI2001）及世界变态反应协会（WAO2004）,由免疫学机制诱导的过敏性鼻炎(hypersensitive rhinitis)称为变态反应性鼻炎(allergic rhinitis,AR),AR又分为IgE介导和non-IgE介导。IgE介导的变态反应性鼻炎或变应性鼻炎（Allergic Rhinitis,AR）是最常见的临床形式，non-IgE介导的过敏性鼻炎（non-IgE-mediated hypersensitiverhinitis，NIHR)作为一个临床实体，虽然缺乏足够的证据，但近年来也愈发引起关注。Redegeld等首先证明了免疫球蛋白游离轻链FLC可以直接作用于肥大细胞引起速发型过敏反应，随后相继证明由FLC可以诱发哮喘，并提出了免疫球蛋白游离轻链（Immunoglobulin free light chain, FLC）可以做为慢性炎症性疾病新的治疗靶点。
为了进一步探讨AR及NAR在发病机制上的问题，探讨FLC在AR与NAR细胞学及病理学上的差异。文中第3章我们采用免疫组织化学及实时荧光定量PCR等方法探讨了FLC在AR及NAR组织中的表达及细胞分布。采用ELISA方法对AR、NAR患者及健康人血清及鼻分泌物中FLC，ECP, MCT及总IgE进行检测。对比分析各种细胞因子及FLC的表达水平在三组中的差异，并对其意义进行讨论。通过免疫组化及荧光双染发现FLC表达与肥大细胞细胞密切相关，同时Real-time PCR结果显示FLC与MCT呈正相关。ELISA结果发现AR及NAR组鼻分泌物及血清中κFLC、λFLC、 ECP及Tryptase的水平均较正常组明显升高(P<0.01)；鼻分泌物中ECP水平AR组(17.270±11.80)较NAR组(11.34±7.38)明显升高(P<0.05)，鼻分泌物中总IgE水平在三组中比较均具有统计学意(p<0.05)；在血清中总IgE水平AR组明显高于NAR组及正常组(p<0.05)，而NAR与正常组无统计学意义(p>0.05)。相关性分析在鼻分泌物中FLC与Tryptase呈正相关，具有统计学意义（P<0.01）。
因此，我们认为FLC在变应性鼻炎及非变应性鼻炎发病机制中具有一定作用，FLC可能通过作用于肥大细胞并通过局部免疫反应参与非变应性鼻炎的发病。这种观点为我们研究变应性鼻炎及非变应性鼻炎的发病机理及临床干预提供了一种新的理论基础及治疗靶点。
Background：The high prevalence of the rhinitis and it impact on qualityof life is still challenge for physician in management as complication ofpathogenesis of the rhinitis. Rhinitis is generally categorized as allergic ornonallergic. The IgE-mediated allergic rhinitis is the most common clinicalform. Considerable cases of nonallergic rhinitis in clinical, however,manifestate nasal hypersensitivity. The symptoms of the hypersensitive rhinitisare very similar to allergic rhinitis but the causes appear to be entirely different.According to EAACI (2001) and WAO (2004), the pathogenic mechanism ofhypersensitivity may be immunologic or non-immunologic and the hypers-ensitive rhinitis induced by immunologic mechanism is classified IgE-mediatedand non-IgE-mediated. The non-IgE-mediated hypersensitive rhinitis (NIHR)induced by immunomechanism as clinical entity, Redegeld et al. demonstratedfirstly that the specific immunoglobulins free light chain (FLC) may induce theimmediate hypersensitive response depending upon the mast cells. After this,Redegeld and his research group proved sequentially that the FLC may elicitallergic asthma and proposal that FLC may be a novel target in the therapy ofchronic inflammatory diseases. According above, Powe et al.(2010) studiedpatients with nasal hypersensitivity and found that significantly increasedFLC-expressing cells in the mucosa of patients with persistent allergic andNon-allergic rhinitis with eosinophilia syndrome (NARES), localized in mastcells and plasma cells, and increased FLC serum levels in subjects withNARES. FLC may provide an additional non-IgE immune pathway to augmentor replace IgE-mediated hypersensitivity in chronic mucosal inflammatorydisease.
The pathogenesis of non-allergic rhinitis with nasal hypersensitivity is notclear so far resulting in confusion and weak on the basis of treatment. Thepresent study aim to proving hypothesis that The FLC may play important rolein nonallergic rhinitis (NAR) with nasal hyperreactivity but NARES throughobserving the expression level of FLC, tryptase (biomarker of mast cells), ECP(biomarker of eosinophils) in nasal mucosa, nasal secretion and serum frompatients without positive results of allergen skin test and serum level of allergenspecific IgE.
Method：On the first part,398consecutive patients were recruited in2009.Questionnaire survey based on ARIA2008was conducted to both groups of ARand NAR. Multiple aspects were analyzed to find the difference. On the secondpart, Selected60consecutive patients from Sep to Dec in2009involved30allergic rhinitis patients,30non-allergic rhinitis patients who were diagnosedby Symptom, Sign, SPT and sIgE, and10volunteers and20patients withdeviation of nasal septum who were choosen to be control. ELISA was used todetect the total IgE, eosinophil cationic protein(ECP), mast cell tryptase,κFLC，λFLC of nasal secretions and serum. Histopathological observations andimmunohistochemical staining for κFLC, λFLC, ECP and MCT wereperformed on30specimens (10AR,10NAR and10specimen’s inferiorturbinate of deviation of nasal septum). The serum and nasal secretionsexpression levels of totel IgE, ECP, MCT, κFLC，λFLC were determined byELISA (30AR,30NAR,10normal human and20specimens inferior turbinateof deviation of nasal septum). Whilst the mRNA expression of κFLC，λFLCAND MCT was determined by real-time quantitative PCR were performed on30specimens (10AR,10NAR and10specimens inferior turbinate of deviationof nasal septum).
Result: In AR, male was more than female, whereas in NAR (P﹤0.01).The highest morbidity age in AR was teenagers (P﹤0.01), while in NAR was middle-aged (P﹤.01). The main onset season in AR was autumn, while noseasonal diversity in NAR. The main classification of AR was moderate-severepersisten（tP﹤.01）, while in NAR was moderate-severe intermitten（tP﹤0.01）.The frequency of clinical symptoms was different except sneezing and gasping.（P﹤0.05）.The severity of clinical symptoms was different exceptrhinocnesmus（P﹤0.05）. There was consistency about induced factors in ARand NAR（P＞0.05）. The second parts shown that FLC main expressed on mastcell, ELISA examine shown that κFLC、λFLC、ECP&Tryptase were increase inAR and NAR compared to HC (P<0.01); There are significantly differencesbetween AR and NAR of ECP form nasal secretions (P<0.05), The total IgEfrom serum were increased in AR compared to NAR and HC (P<0.05), andthere are differences of the total IgE form nasal secretions among three groups(p<0.05).
Conclusion: There were significant differences between AR and NAR insex, age, classification and seasons. The frequency of clinical symptoms weresignificantly different between AR and NAR except sneezing andgasping.Comparised the clinical symptoms of nose and eye, The severity ofclinical symptoms in AR was higher than that in NAR except rhinocnesmus.There was consistency about induced factors in AR and NAR. This study hassome clinical significance in correct recognition and diagnosis of AR and NAR.Immunoglobulin free light chain took part in the pathophysiological process ofallergic rhinitis and non-allergic rhinitis with the immunological mechanism.
引文
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