Tejwani Vickram, Putcha Nirupama, Woo Han, Liu Chen, Lafon David, Alexis Neil E, Azar Antoine, Barr R Graham, Barjaktarevic Igor, Bowler Russell P, Comellas Alejandro, Couper David J, Fawzy Ashraf, Han MeiLan K, Hansel Nadia N, Kaner Robert J, Krishnan Jerry A, Marchetti Nathaniel, Martinez Fernando J, Ohar Jill, O'Neal Wanda, Ortega Victor E, Paine Iii Robert, Pottinger Tess D, Stämpfli Martin, Ruvuna Lisa, Woodruff Prescott G, Freeman Christine M, Huang Yvonne J, Curtis Jeffrey L
Department of Pulmonary and Critical Care Medicine, Integrated Hospital Care Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of Genomic Science and Systems Biology, Cleveland Clinic, Cleveland, OH, USA.
Respir Res. 2025 Jul 18;26(1):250. doi: 10.1186/s12931-025-03310-w.
Immunoglobulins (Ig) protect against pathogens frequently implicated in COPD exacerbations. We previously demonstrated an association of low-normal serum IgA and IgG concentrations with prospective exacerbation risk, but responsible mechanisms are undefined. Here, we examined associations of lower respiratory tract bacterial diversity to Ig levels in serum and bronchoalveolar lavage (BAL) and to the memory phenotypes of blood and BAL B cells.
We analyzed data from phase I of SPIROMICS, an observational cohort study of smoking-related COPD. A subset of participants completed comprehensive research bronchoscopies, including analysis of BAL bacterial microbiota by 16 S rRNA gene (V4 region) sequencing and of blood and BAL B-cells by 12-color flow cytometry. In some participants, we also analyzed serum and BAL Ig levels by ELISA. We constructed linear regression models including either serum or BAL (albumin-corrected) Ig measurements as the independent variable and separate dependent variables, including B-cell subsets, BAL bacterial diversity metrics (Faith phylogenetic diversity, inverse Simpson, and richness indices), and clinical measures (FEV% predicted, risk of prospective exacerbations), adjusted by age, sex, race, educational attainment, smoking status, and use of inhaled corticosteroids.
Serum IgG and IgA (n = 66 participants) were 1,486.1 ± 510.6 mg/dL [mean ± standard deviation (SD)] and 237.7 ± 131.6 mg/dL, respectively. Albumin-corrected BAL IgG and IgA (n = 117) were 0.03 ± 0.02 mg/dL and 0.01 ± 0.01 mg/dL, respectively. B-cells (n = 82) comprised 3.5 ± 3.0% of blood leukocytes. Serum IgA was associated with higher blood switched memory (IgD- CD27+) B-cell percentages (β 6.06, p = 0.01) and inversely associated with blood double-negative (IgD-CD27-) B-cell percentages (β - 9.96, p = 0.02). Available BAL microbiome data (n = 107) showed that reduced lung bacterial diversity associated with lower serum IgG, but not with serum IgA, BAL IgA, or BAL IgG concentrations. Neither BAL IgG nor IgA were associated with lung function or exacerbations.
These results demonstrate an association of low serum IgG with reduced lung bacterial diversity, a feature of dysbiosis that may predispose to exacerbation. Defining the role of Ig in specific anatomic compartments is relevant to designing vaccine strategies.
免疫球蛋白（Ig）可抵御慢性阻塞性肺疾病（COPD）急性加重期常见的病原体。我们之前证明血清IgA和IgG浓度处于正常低水平与未来急性加重风险相关，但具体机制尚不明确。在此，我们研究了下呼吸道细菌多样性与血清和支气管肺泡灌洗（BAL）液中Ig水平以及血液和BAL液中B细胞记忆表型之间的关联。
我们分析了SPIROMICS第一阶段的数据，这是一项关于吸烟相关COPD的观察性队列研究。一部分参与者完成了全面的研究性支气管镜检查，包括通过16S rRNA基因（V4区）测序分析BAL液中的细菌微生物群，以及通过12色流式细胞术分析血液和BAL液中的B细胞。在一些参与者中，我们还通过酶联免疫吸附测定（ELISA）分析了血清和BAL液中的Ig水平。我们构建了线性回归模型，将血清或BAL（白蛋白校正后）Ig测量值作为自变量，将不同的因变量纳入模型，包括B细胞亚群、BAL液细菌多样性指标（Faith系统发育多样性、逆辛普森指数和丰富度指数）以及临床指标（预测的第1秒用力呼气容积百分比、未来急性加重风险），并根据年龄、性别、种族、教育程度、吸烟状况和吸入性糖皮质激素的使用情况进行校正。
血清IgG和IgA（n = 66名参与者）分别为1486.1±510.6mg/dL[平均值±标准差（SD）]和237.7±131.6mg/dL。白蛋白校正后的BAL液IgG和IgA（n = 117）分别为0.03±0.02mg/dL和0.01±0.01mg/dL。B细胞（n = 82）占血液白细胞的3.5±3.0%。血清IgA与血液中转换记忆（IgD-CD27+）B细胞百分比升高相关（β 6.06，p = 0.01），与血液中双阴性（IgD-CD27-）B细胞百分比呈负相关（β -9.96，p = 0.02）。现有的BAL液微生物组数据（n = 107）显示，肺部细菌多样性降低与血清IgG降低相关，但与血清IgA、BAL液IgA或BAL液IgG浓度无关。BAL液IgG和IgA均与肺功能或急性加重无关。
这些结果表明血清IgG水平低与肺部细菌多样性降低有关，这是一种可能易导致急性加重的生态失调特征。明确Ig在特定解剖部位的作用与设计疫苗策略相关。
