Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms.

BACKGROUND: Autoimmunity has been reported in patients with severe coronavirus disease 2019 (COVID-19). We investigated whether anti-nuclear/extractable-nuclear antibodies (ANAs/ENAs) were present up to a year after infection, and if they were associated with the development of clinically relevant post-acute sequalae of COVID-19 (PASC) symptoms. METHODS: A rapid-assessment line immunoassay was used to measure circulating levels of ANAs/ENAs in 106 convalescent COVID-19 patients with varying acute phase severities at 3, 6 and 12 months post-recovery. Patient-reported fatigue, cough and dyspnoea were recorded at each time point. Multivariable logistic regression model and receiver operating curves were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines. RESULTS: Compared to age- and sex-matched healthy controls (n=22) and those who had other respiratory infections (n=34), patients with COVID-19 had higher detectable ANAs at 3 months post-recovery (p<0.001). The mean number of ANA autoreactivities per individual decreased between 3 and 12 months (from 3.99 to 1.55) with persistent positive titres associated with fatigue, dyspnoea and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, area under the curve (AUC) 0.86) and dyspnoea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and C-reactive protein predicted the elevated ANAs at 12 months. TNF-α, D-dimer and interleukin-1ß had the strongest association with symptoms at 12 months. Regression analysis showed that TNF-α predicted fatigue (ß=4.65, p=0.004) and general symptomaticity (ß=2.40, p=0.03) at 12 months. INTERPRETATION: Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNF-α) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC.

Peroxisome proliferator-activated receptor gamma gene variants modify human airway and systemic responses to indoor dibutyl phthalate exposure.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptor gamma (PPAR-γ; gene: PPARG) and oxidative stress genes are associated with asthma risk. However, whether such variants modulate responses to dibutyl phthalate (DBP), a common plasticizer associated with increased asthma development, remains unknown. The purpose of this study is to investigate how SNPs in PPARG and oxidative stress genes, as represented by two separate genetic risk scores, modify the impact of DBP exposure on lung function and the airway and systemic response after an inhaled allergen challenge. METHODS: We conducted a double-blinded human crossover study with sixteen allergen-sensitized participants exposed for three hours to DBP and control air on distinct occasions separated by a 4-week washout. Each exposure was followed by an allergen inhalation challenge; subsequently, lung function was measured, and blood and bronchoalveolar lavage (BAL) were collected and analyzed for cell counts and allergen-specific immunoglobulin E (IgE). Genetic risk scores for PPAR-γ (P-GRS; weighted sum of PPARG SNPs rs10865710, rs709158, and rs3856806) and oxidative stress (OS-GRS; unweighted sum of 16 SNPs across multiple genes) were developed, and their ability to modify DBP effects were assessed using linear mixed-effects models. RESULTS: P-GRS and OS-GRS modified DBP effects on allergen-specific IgE in blood at 20 h (interaction effect [95% CI]: 1.43 [1.13 to 1.80], p = 0.005) and 3 h (0.99 [0.98 to 1], p = 0.03), respectively. P-GRS also modified DBP effects on Th2 cells in blood at 3 h (- 25.2 [- 47.7 to - 2.70], p = 0.03) and 20 h (- 39.1 [- 57.9 to - 20.3], p = 0.0005), and Th2 cells in BAL at 24 h (- 4.99 [- 8.97 to - 1.01], p = 0.02). An increasing P-GRS associated with reduced DBP effect on Th2 cells. Neither GRS significantly modified DBP effects on lung function parameters. CONCLUSIONS: PPAR-γ variants modulated several airway and systemic immune responses to the ubiquitous chemical plasticizer DBP. Our results suggest that PPAR-γ variants may play a greater role than those in oxidative stress-related genes in airway allergic responses to DBP. TRIAL REGISTRATION: This study reports results from The Phthalate-Allergen Immune Response Study that was registered on ClinicalTrials.gov with identification NCT02688478.

Particle depletion of diesel exhaust restores allergen-induced lung-protective surfactant protein D in human lungs.

RATIONALE: Exposure to air pollution is linked with increased asthma morbidity and mortality. To understand pathological processes linking air pollution and allergen exposures to asthma pathophysiology, we investigated the effect of coexposure to diesel exhaust (DE) and aeroallergen on immune regulatory proteins in human airways. METHODS: Fourteen allergen-sensitised participants completed this randomised, double-blinded, cross-over, controlled exposure study. Each participant underwent four exposures (allergen-alone exposure, DE and allergen coexposure, particle-depleted DE (PDDE) and allergen coexposure, and sham exposure) on different order-randomised dates, each separated by a 4-week washout. Serum and bronchoalveolar lavage (BAL) were assayed for pattern recognition molecules, cytokines, chemokines and inflammatory mediators. RESULTS: In human airways, allergen-alone exposure led to accumulation of surfactant protein D (SPD; p=0.02). Coexposure to allergen and DE did not elicit the same increase of SPD as did allergen alone; diesel particulate reduction restored allergen-induced SPD accumulation. Soluble receptor for advanced glycation end products was higher with particle reduction than without it. In the systemic circulation, there was a transient increase in SPD and club cell protein 16 (CC16) 4 hours after allergen alone. CC16 was augmented by PDDE, but not DE. % eosinophils in BAL (p<0.005), eotaxin-3 (p<0.0001), interleukin 5 (IL-5; p<0.0001) and thymus and activation regulated chemokine (p=0.0001) were each increased in BAL by allergen. IL-5, SPD and % eosinophils in BAL were correlated with decreased FEV1. CONCLUSION: Short-term coexposure to aeroallergen and DE alters immune regulatory proteins in lungs; surfactant levels are dependent on particle depletion. TRIAL REGISTRATION NUMBER: NCT02017431.