Annals of the American Thoracic Society · 2026
Multi-Omics Analysis Defines Endotypes and Systemic Inflammation in Primary Ciliary Dyskinesia: A Comparison with Healthy Controls.
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Mosquera Ricardo A, Magana-Ceballos Ivan Gustavo, De Jesus Rojas Wilfredo, Huang Xiangsheng, Koochak Haniyeh, Tellez Maria E, Castillo-Moguel Jose Ariel, Bishehsari Faraz, Mahdavinia Mahboobeh, Ramos-Benitez Marcos J, Harris Tomika, Yadav Aravind, Owens Kereisha, Lemus-Rangel Ricardo, Romero Mar, Zuleta Suhei, Luz Ara, Baltazar-Fernandez Anel, McBeth Katrina E, Hashmi Syed, Rosario Ortiz Gabriel, Santoyo-Rios Joel, Loyo-Rodriguez Jose Francisco, Colasurdo Giuseppe N
Аннотация
INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterized by chronic airway inflammation and progressive lung injury. The inflammatory profile and systemic involvement remain poorly defined. We applied integrated multi omics (transcriptomics, proteomics, and metagenomics) to characterize inflammatory signatures and explore saliva as a noninvasive marker of systemic inflammation. These findings may support improved disease characterization and inform therapy and monitoring.
METHODS: This cross sectional, multicenter study included participants with PCD and healthy controls from Houston, Texas; Puerto Rico; and Mexico. Demographic and clinical data were collected in the absence of acute infection. Oral swabs underwent a bulk inflammatory transcriptomic profiling of 590-genes using NanoString nCounter® and microbiome evaluation via metagenomic sequencing. High sensitivity NULISA™ proteomic profiling of 250-proteins was performed on both saliva and plasma, with results correlated across omic layers. Pathway and gene set analyses were conducted using nSolver Advanced Analysis.
RESULTS: Seventy-six participants were enrolled: 51 with PCD and 25 healthy controls. PCD patients, especially those older than 10 years and those with microtubular defects, showed markedly elevated inflammatory gene and protein expression in saliva and plasma. Five inflammatory endotypes were identified: Neutrophilic protease dominant, Dipeptidyl Peptidase 1(DPP‑1) profile (78%); neutrophilic recruiting, high‑Th17 (71%); eosinophilic dominant, high‑Th2 (51%); Th2/Th17‑high (47%), and Th2/Th17‑low (25%). PCD demonstrated increased neutrophil, and CD45‑related gene expression and activation of ten inflammatory pathways, including NF‑κB, oxidative stress, T‑cell-receptor, TREG, Th17, TNF, Th1, Th2, TGF-B signaling, and TLR (P < .01). Saliva and plasma showed strong molecular concordance. Microbiome analysis revealed significant shifts in diversity and abundance linked to inflammatory pathways.
DISCUSSION: These findings show that PCD is characterized by baseline inflammatory activity with marked endotypic heterogeneity, most frequently involving neutrophilic-immune pathways driven by DPP1-associated protease activity and Th17-mediated neutrophil recruitment, while a distinct subset of patients demonstrates a Th2-predominant inflammatory endotype. Salivary inflammatory profiling, which closely mirrors plasma, may offer a practical, non-invasive approach to capturing this patient-level heterogeneity and monitoring systemic immune activity and treatment response, especially with the new anti-inflammatory medications for bronchiectasis.
METHODS: This cross sectional, multicenter study included participants with PCD and healthy controls from Houston, Texas; Puerto Rico; and Mexico. Demographic and clinical data were collected in the absence of acute infection. Oral swabs underwent a bulk inflammatory transcriptomic profiling of 590-genes using NanoString nCounter® and microbiome evaluation via metagenomic sequencing. High sensitivity NULISA™ proteomic profiling of 250-proteins was performed on both saliva and plasma, with results correlated across omic layers. Pathway and gene set analyses were conducted using nSolver Advanced Analysis.
RESULTS: Seventy-six participants were enrolled: 51 with PCD and 25 healthy controls. PCD patients, especially those older than 10 years and those with microtubular defects, showed markedly elevated inflammatory gene and protein expression in saliva and plasma. Five inflammatory endotypes were identified: Neutrophilic protease dominant, Dipeptidyl Peptidase 1(DPP‑1) profile (78%); neutrophilic recruiting, high‑Th17 (71%); eosinophilic dominant, high‑Th2 (51%); Th2/Th17‑high (47%), and Th2/Th17‑low (25%). PCD demonstrated increased neutrophil, and CD45‑related gene expression and activation of ten inflammatory pathways, including NF‑κB, oxidative stress, T‑cell-receptor, TREG, Th17, TNF, Th1, Th2, TGF-B signaling, and TLR (P < .01). Saliva and plasma showed strong molecular concordance. Microbiome analysis revealed significant shifts in diversity and abundance linked to inflammatory pathways.
DISCUSSION: These findings show that PCD is characterized by baseline inflammatory activity with marked endotypic heterogeneity, most frequently involving neutrophilic-immune pathways driven by DPP1-associated protease activity and Th17-mediated neutrophil recruitment, while a distinct subset of patients demonstrates a Th2-predominant inflammatory endotype. Salivary inflammatory profiling, which closely mirrors plasma, may offer a practical, non-invasive approach to capturing this patient-level heterogeneity and monitoring systemic immune activity and treatment response, especially with the new anti-inflammatory medications for bronchiectasis.