Background

Excess reactive oxygen species (ROS) can cause oxidative stress damaging cells and tissues, leading to adverse health effects in the respiratory tract. Yet, few human epidemiological studies have quantified the adverse effect of early life exposure to ROS on child health. Thus, this study aimed to examine the association of levels of ROS exposure at birth and the subsequent risk of developing common respiratory and allergic diseases in children.

Methods

1,284 Toronto Child Health Evaluation Questionnaire (T-CHEQ) participants were followed from birth (born between 1996 and 2000) until outcome, March 31, 2016 or loss-to-follow-up. Using ROS data from air monitoring campaigns and land use data in Toronto, ROS concentrations generated in the human respiratory tract in response to inhaled pollutants were estimated using a kinetic multi-layer model. These ROS values were assigned to participants' postal codes at birth. Cox proportional hazards regression models, adjusted for confounders, were then used to estimate hazard ratios (HR) with 95% confidence intervals (CI) per unit increase in interquartile range (IQR).

Results

After adjusting for confounders, iron (Fe) and copper (Cu) were not significantly associated with the risk of asthma, allergic rhinitis, nor eczema. However, ROS, a measure of the combined impacts of Fe and Cu in PM_2.5, was associated with an increased risk of asthma (HR = 1.11, 95% CI: 1.02-1.21, p < 0.02) per IQR. There were no statistically significant associations of ROS with allergic rhinitis (HR = 0.96, 95% CI: 0.88-1.04, p = 0.35) and eczema (HR = 1.03, 95% CI: 0.98-1.09, p = 0.24).

Conclusion

These findings showed that ROS exposure in early life significantly increased the childhood risk of asthma, but not allergic rhinitis and eczema.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.

The COPA syndrome is a monogenic, autoimmune lung and joint disorder first identified in 2015. This study sought to define the main pulmonary features of the COPA syndrome in an international cohort of patients, analyse patient responses to treatment and highlight when genetic testing should be considered. We established a cohort of subjects (N=14) with COPA syndrome seen at multiple centres including the University of California, San Francisco, CA, USA. All subjects had one of the previously established mutations in the COPA gene, and had clinically apparent lung disease and arthritis. We analysed cohort characteristics using descriptive statistics. All subjects manifested symptoms before the age of 12 years, had a family history of disease, and developed diffuse parenchymal lung disease and arthritis. 50% had diffuse alveolar haemorrhage. The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy. All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity. All subjects received immunosuppressive therapy. COPA syndrome is an autoimmune disorder defined by diffuse parenchymal lung disease and arthritis. We analysed an international cohort of subjects with genetically confirmed COPA syndrome and found that common pulmonary features included cysts, follicular bronchiolitis and diffuse alveolar haemorrhage. Common extrapulmonary features included early age of onset, family history of disease, autoantibody positivity and arthritis. Longitudinal data demonstrated improvement on chest radiology but an overall decline in pulmonary function despite chronic treatment.

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.