Study on Congenital Immune Dysfunction in Cystic Fibrosis

Research Background

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, primarily affecting the lungs and digestive system. One of the major problems faced by CF patients is recurrent infections and inflammation, leading to progressive lung damage. Although current highly effective CFTR modulator therapies can restore mucus clearance, inflammation and infections persist. This suggests that the immune system in CF may have congenital defects, particularly in the innate immune system. However, research on the specific role of the innate immune system in the early stages of the disease remains insufficient. Therefore, this study aims to explore the role of the innate immune system in the etiology of CF through a CF pig model and comparisons with preschool-aged children with CF.

Source of the Paper

This study was led by Florian Jaudas and conducted by a research team from multiple internationally renowned institutions, including the Technical University of Munich, Freie Universität Berlin, and Harvard University. The findings were published on January 22, 2025, in Science Translational Medicine, under the title “Perinatal dysfunction of innate immunity in cystic fibrosis.”

Research Process and Results

1. Establishment of the CF Pig Model and Selection of Subjects

The research team used a CFTR knockout (CFTR−/−) pig model and compared it with wild-type (WT) pigs. The study subjects included newborn CF pigs, WT pigs, preschool-aged children with CF, and healthy controls. The research process consisted of the following steps:

• Analysis of Lung Immune Cell Composition: Flow cytometry and transcriptomic analysis were used to study the immune cell composition in the lungs of newborn CF pigs, particularly the number and status of monocytes and neutrophils.
• Analysis of Blood and Spleen Immune Cells: Immune cells were isolated from blood and spleen to analyze their transcriptomic and proteomic profiles.
• Single-Cell RNA Sequencing (scRNA-seq): Single-cell RNA sequencing was performed on monocytes from the lungs, blood, and bone marrow to analyze differences in cell composition and gene expression between genotypes.
• Phagocytic Function and Reactive Oxygen Species (ROS) Production Testing: In vitro experiments were conducted to test the phagocytic function and ROS production capacity of monocytes and granulocytes from CF and WT pigs.

2. Key Research Findings

a) Changes in Lung Immune Cells in Newborn CF Pigs

The study found that in newborn CF pigs, the composition of lung immune cells had already changed before the onset of infection, with increased monocyte infiltration while neutrophil numbers remained unchanged. Flow cytometry and transcriptomic analysis revealed that the infiltrating myeloid cells exhibited a more immature state. This immature transcriptional profile was also validated in the blood of newborn CF pigs and preschool-aged children with CF.

b) Reduced Phagocytic Function and ROS Production in Monocytes

The study found that CD16 expression was reduced in myeloid cells of both CF pigs and humans, leading to significantly decreased phagocytic function and ROS production. This indicates that the innate immune system in both CF patients and CF pigs is functionally impaired from birth.

c) Single-Cell RNA Sequencing Analysis

Through single-cell RNA sequencing, the research team discovered significant expansion of myeloid cells in the lungs of CF pigs, particularly immature monocytes. These cells exhibited activated but non-proliferative characteristics, suggesting their migration from the circulatory system to the lungs. Additionally, abnormal expansion of myeloid cells was observed in the bone marrow of CF pigs, further supporting the presence of congenital immune system defects.

d) Origin of Granulocyte-Related Proteins in Bone Marrow

Single-cell RNA sequencing revealed abnormal expression of granulocyte-related proteins in the bone marrow of CF pigs, indicating that myeloid cells in the bone marrow may play an important role in the pathogenesis of CF.

3. Conclusions and Significance

This study found that congenital defects in the innate immune system are present at birth in both CF patients and CF pigs, particularly in the phagocytic function and ROS production capacity of monocytes and granulocytes. These findings suggest that the immune system in CF is “pre-programmed” to be dysfunctional early in life, which may be a key factor contributing to recurrent infections and persistent inflammation in CF patients. The study provides new insights for immune therapy in CF and indicates that additional treatments targeting innate immune system defects are needed alongside existing CFTR modulator therapies.

4. Research Highlights

• Discovery of Congenital Immune Defects: For the first time, congenital defects in the innate immune system were identified in both CF patients and CF pigs at birth.
• Application of Single-Cell RNA Sequencing: Single-cell RNA sequencing was used to comprehensively analyze the transcriptional profiles of immune cells in CF pigs and humans.
• Innovation in Cross-Species Research: Comparative studies between CF pigs and preschool-aged children with CF validated the conservation and functionality of immune system defects in CF.

Scientific Value and Application Prospects

The scientific value of this study lies in revealing the congenital defects of the innate immune system in CF and providing new targets for immune therapy. Future research can build on these findings to develop novel therapies targeting the innate immune system, further improving the quality of life and prognosis for CF patients. Additionally, the use of the CF pig model provides an important reference for studying other lung diseases.

Through this study, we have deepened our understanding of the pathogenesis of CF and laid a theoretical foundation for the development of new treatment strategies.