The long term consequences of severe COVID-19 in the lungs remain speculative, however interstitial abnormalities in these patients may arise. In this study previously identified fibrotic markers from the BAL were evaluated in Post-COVID-19 patients. 26 patients were referred for evaluation of respiratory symptoms and/or abnormalities on HRCT, on average 5.3 months from the acute disease phase, to the Post COVID-19 clinic. 20 patients showed persistent radiological findings with fibrotic changes and/or altered respiratory function.&nbsp;Bronchoalveolar lavage&nbsp;cellular composition was determined by MGG staining and CD45, CD14, CD11c, CD163 and Osteopontin staining. Airway monocytes were identified by SSClo/CD45+ parameters and surface expression of CD11c, CD14 and CD16 by flow cytometry. FVC% and DLCO% were used as measures of disease severity. Collectively, monocyte percentages in the BAL were associated with lower FVC% (Rs=-0.53,p=0.02). Importantly, patients with DLCO% below 60 showed higher monocyte infiltration (p=0.015). CD14 positivity on monocytes was more pronounced in patients with DLCO% below 60, while CD16 and CD11c were&nbsp;not associated with DLCO. Increased Osteopontin expression in airway macrophages was also linked with lower DLCO% levels (Rs=-0.661, p=0.019), in contrast to CD163 macrophage expression which tended to be higher in patients with higher DLCO%. Neutrophils were negatively associated with DLCO% in Post-COVID-19 patients (Rs=-0.62,p=0.01).&nbsp;Airway immune cell populations from BAL were associated with Post-COVID-19 induced altered respiratory function. 

Increased CD14+ monocytes and OPN+ positive airway macrophages in the BAL are associated with Post-COVID-19 induced altered respiratory function

Idiopathic Pulmonary fibrosis is a devastating, chronic lung disease, characterized by irreversible lung damage. Retinoic acid-related Orphan Receptor alpha (RORa; NR1F1) is a widely distributed nuclear receptor involved in several (patho)physiological functions including, circadian rhythm, lipid metabolism, inflammation and angiogenesis. It is known that TGF-b1 alters circadian rhythmicity. Other members of circadian clock Bmal1 and Rev-erba, both transcriptionally regulated by RORa, have been previously shown to enhance and inhibit respectively myofibroblast activation. However, the role of RORα in fibroblast activation is not elucidated. We examined the role of RORα in human lung fibroblasts (HLF) from controls (n=4) and IPF (n=5). siRNA knockdown of RORα resulted in a significant upregulation of aSMA protein in IPF and control HLFs. Treatment with RORa antagonist R1001 revealed a trend of upregulation of aSMA mRNA, while, an opposite trend was observed with RORa agonist, R1078 in IPF and control HLFs. Furthermore, the induction of aSMA levels in IPF HLFs treated with R1001 was significantly higher&nbsp;compared to treated control HLFs. Next, the effect of TGFb1 treatment on RORa expression was evaluated. Importantly, a significant downregulation of RORα mRNA was detected in control HLFs with a similar trend in IPF following TGFb treatment while aSMA mRNA was significantly induced as expected. Our results suggest that RORa is negatively regulated by TGFb1 and may act as a repressor of aSMA transcription in HLF cultures. We suggest that RORa as other circadian genes may represent potential regulatory switches in IPF pathogenesis and possible therapeutic targets. 

Inhibitory role of retinoic acid-related orphan receptor alpha RORa in human lung fibroblast activation.

Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Foxp3+ Treg cells of thymic (tTreg) and peripheral (pTreg) developmental origin are thought to synergistically act to ensure immune homeostasis, with self-reactive tTreg cells primarily constraining autoimmune responses. We exploited tTreg-specific GFP/Cre recombinase activity to selectively ablate either tTreg (ΔtTreg) or pTreg (ΔpTreg) cell development. In contrast to the tTreg cell behavior in ΔpTreg mice, pTreg cells with a highly activated suppressor phenotype replenished the Treg cell pool of C57BL/6.ΔtTreg mice, preventing early mortality and fatal autoimmunity. Even with advancing age, pTreg cells largely maintained immune tolerance in C57BL/6.ΔtTreg mice. However, only two generations of (C57BL/6>NOD) backcrossing precipitated severe disease lethality associated with a distinct, partially overlapping pattern of organ-specific autoimmunity. Genetic association studies defined a small set of autoimmune risk loci sufficient to unleash a particularly severe form of diabetes, including genes known to impinge on Treg cell biology. Thus, pTreg cells exhibit an unexpectedly high functional adaptability, emphasizing their importance as mediators of bystander effects to ensure self-tolerance. SUMMARY This study in complementary loss-of-function mouse models uncovers an unexpected functional plasticity of pTreg cells in constraining systemic autoimmune responses in the absence of tTreg cells and identifies tTreg cells as primary regulators of β-cell autoimmunity in type 1 diabetes.

Selective ablation of thymic and peripheral Foxp3+ regulatory T cell development

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Increased CD14+ monocytes and OPN+ positive airway macrophages in the BAL are associated with Post-COVID-19 induced altered respiratory function

Inhibitory role of retinoic acid-related orphan receptor alpha RORa in human lung fibroblast activation.

Functional Dichotomy of Developmental Foxp3+ Treg Cell Subsets in the Visceral Adipose Tissue of Lean and Obese Mice

Selective ablation of thymic and peripheral Foxp3+ regulatory T cell development