Table2_Elevated serum polyclonal immunoglobulin free light chains in patients with severe asthma.docx

Background: Inflammation plays a pivotal role in the pathophysiology of asthma. Free light chains (FLC) can cause inflammation by mast cell antigen-activation. Serum immunoglobulin (Ig) FLC κ, but not λ, were shown elevated in adult males with asthma. We sought to investigate if serum Ig FLC concentrations are affected by asthma severity and their relationships with inflammatory outcomes.
Methods: By using immunoassays, we measured serum κ and λ Ig FLCs in 24 severe persistent asthma patients, 15 patients with moderate persistent asthma, 15 steroid-naïve mild persistent asthma patients and 20 healthy control subjects in a cross-sectional observational study. Total and specific serum IgE concentrations, fractional exhaled nitric oxide (FENO), lung function, peripheral blood eosinophils and neutrophils, and C reactive protein (CRP) were also measured.
Results: Serum κ FLC concentrations were elevated in severe asthma patients compared mild asthma patients (p < 0.05) and healthy subjects (p < 0.05). Serum λ FLCs were higher in severe asthma patients than in healthy subjects (p < 0.05) and correlated with blood eosinophil counts (percentage, κ: r = 0.51, p = 2.9678−6; λ: r = 0.42, p = 1.7377−4; absolute values, κ: r = 0.45, p = 6.1284−5; λ: r = 0.38, p = 7.8261−4), but not with total or specific serum IgE. In severe asthma patients, serum Ig FLC correlated with serum CRP (κ: r = 0.33; p = 0.003; λ: r = 0.38, p = 8.8305−4) and blood neutrophil cell counts (percentage, κ: r = 0.31; p = 0.008; λ: r = 0.29, p = 0.01; absolute values, κ: r = 0.40; p = 3.9176−4; λ: r = 0.40, p = 4.5479−4), were elevated in subjects with blood eosinophilia (≥300 cells/µL) (n = 13) compared with non-eosinophilic subjects (n = 10) (κ: 19.2 ± 1.2 mg/L versus 12.1 ± 1.3 mg/L, p < 0.001; λ: 27.2 ± 2.6 mg/L versus 16.8 ± 2.5 mg/L, p < 0.01), but were similar in atopic (n = 15) versus nonatopic subjects (n = 9) (κ: p = 0.20; λ: p = 0.80). Serum FLC were negatively correlated with lung function tests, including forced expiratory volume in one second (FEV1) (κ: r = −0.33; p = 0.0034; λ: r = −0.33; p = 0.0035), and FEV1/forced vital capacity ratio (κ: r = −0.33; p = 0.0034; λ: r = −0.33; p = 0.0036).
Conclusion: Serum Ig FLCs are elevated in severe asthma adults and might represent new surrogate markers of inflammation. The pathophysiological implications of these findings require further research. This study was approved by the ethics committee of the University Hospital Agostino Gemelli Foundation and Catholic University of the Sacred Heart (approval number P/1034/CE2012).

背景：炎症在哮喘的病理生理学过程中发挥关键作用。游离轻链（FLC）可通过肥大细胞抗原激活引发炎症反应。既往研究显示，成年男性哮喘患者的血清免疫球蛋白（Ig）游离轻链κ型（而非λ型）水平升高。本研究旨在探讨血清免疫球蛋白游离轻链浓度是否受哮喘严重程度影响，及其与炎症结局的关联。
方法：本研究为横断面观察性研究，采用免疫测定法检测了24例重度持续性哮喘患者、15例中度持续性哮喘患者、15例未使用过糖皮质激素的轻度持续性哮喘患者以及20例健康对照受试者的血清κ型和λ型免疫球蛋白游离轻链水平。同时检测了血清总IgE与特异性IgE浓度、呼出气一氧化氮分数（FENO）、肺功能、外周血嗜酸性粒细胞与中性粒细胞计数，以及C反应蛋白（CRP）水平。
结果：与轻度哮喘患者及健康对照受试者相比，重度哮喘患者的血清κ型游离轻链浓度升高（P<0.05）。重度哮喘患者的血清λ型游离轻链水平亦高于健康对照受试者（P<0.05），且与外周血嗜酸性粒细胞计数（百分比：κ型r=0.51，P=2.9678×10^-6；λ型r=0.42，P=1.7377×10^-4；绝对值：κ型r=0.45，P=6.1284×10^-5；λ型r=0.38，P=7.8261×10^-4）显著相关，但与血清总IgE或特异性IgE水平无关联。在重度哮喘患者中，血清免疫球蛋白游离轻链与血清C反应蛋白（κ型r=0.33，P=0.003；λ型r=0.38，P=8.8305×10^-4）及外周血中性粒细胞计数（百分比：κ型r=0.31，P=0.008；λ型r=0.29，P=0.01；绝对值：κ型r=0.40，P=3.9176×10^-4；λ型r=0.40，P=4.5479×10^-4）相关。外周血嗜酸性粒细胞增多症患者（≥300个细胞/微升，n=13）的血清免疫球蛋白游离轻链水平高于非嗜酸性粒细胞增多症患者（n=10）：κ型分别为19.2±1.2 mg/L与12.1±1.3 mg/L（P<0.001），λ型分别为27.2±2.6 mg/L与16.8±2.5 mg/L（P<0.01）；但特应性患者（n=15）与非特应性患者（n=9）的血清游离轻链水平无显著差异（κ型P=0.20，λ型P=0.80）。血清游离轻链水平与肺功能检查指标呈负相关，包括一秒用力呼气容积（FEV1，κ型r=-0.33，P=0.0034；λ型r=-0.33，P=0.0035）及FEV1/用力肺活量比值（κ型r=-0.33，P=0.0034；λ型r=-0.33，P=0.0036）。
结论：成年重度哮喘患者的血清免疫球蛋白游离轻链水平升高，或可作为新型炎症替代标志物。本研究结果的病理生理学意义有待进一步探究。本研究经阿戈斯蒂诺·杰梅利基金会大学医院及圣心天主教大学伦理委员会批准（批准号：P/1034/CE2012）。