Sex-differences in COPD: from biological mechanisms to therapeutic considerations

Milne, Kathryn M.; Mitchell, Reid A.; Ferguson, Olivia N.; Hind, Alanna S.; Guenette, Jordan A.

doi:10.3389/fmed.2024.1289259

Cited by 4 publications

(1 citation statement)

References 77 publications

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“…Age and smoking will affect the expression of PD-L1 in patients with conditions such as obstructive sleep apnea [39] and rheumatoid arthritis [40] but it is not clear whether this affects normal subjects. Secondly, though the prevalence of males with COPD is still higher than that of females [41], the significant difference in the male/female ratio in the COPD and control groups is another limitation, despite the clinical symptoms and biological mechanisms having been reviewed in recent years [42]. Thirdly, normal participants were recruited on the basis of observing no past underlying diseases in their medical history.…”

Section: Discussionmentioning

confidence: 99%

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease

Chen,

Sun,

et al. 2024

Cells

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Background: Chronic obstructive pulmonary disease (COPD) is characterized, at least in part, by autoimmunity through amplified T helper 1 and 17 (Th1 and Th17) immune responses. The loss of immune tolerance controlled by programmed death-ligand 1 (PD-L1) may contribute to this. Objectives: We studied the tolerogenic role of PD-L1+ dendritic cells (DCs) and their subtypes in relation to specific T cell immunity and the clinical phenotypes of COPD. Methods: We used flow cytometry to analyze PD-L1 expression by the DCs and their subtypes in the peripheral blood mononuclear cells (PBMCs) from normal participants and those with COPD. T cell proliferation and the signature cytokines of T cell subtypes stimulated with elastin as autoantigens were measured using flow cytometry and enzyme-linked immunosorbent assays (ELISA), respectively. Measurement and main results: A total of 83 participants were enrolled (normal, n = 29; COPD, n = 54). A reduced PD-L1+ conventional dendritic cell 1 (cDC1) ratio in the PBMCs of the patients with COPD was shown (13.7 ± 13.7%, p = 0.03). The decrease in the PD-L1+ cDC1 ratio was associated with a rapid decline in COPD (p = 0.02) and correlated with the CD4+ T cells (r = −0.33, p = 0.02). This is supported by the NCBI GEO database accession number GSE56766, the researchers of which found that the gene expressions of PD-L1 and CD4, but not CD8 were negatively correlated from PBMC in COPD patients (r = −0.43, p = 0.002). Functionally, the PD-L1 blockade enhanced CD4+ T cell proliferation stimulated by CD3/elastin (31.2 ± 22.3%, p = 0.04) and interleukin (IL)-17A production stimulated by both CD3 (156.3 ± 54.7, p = 0.03) and CD3/elastin (148 ± 64.9, p = 0.03) from the normal PBMCs. The PD-L1 blockade failed to increase IL-17A production in the cDC1-depleted PBMCs. By contrast, there was no significant change in interferon (IFN)-γ, IL-4, or IL-10 after the PD-L1 blockade. Again, these findings were supported by the NCBI GEO database accession number GSE56766, the researchers of which found that only the expression of RORC, a master transcription factor driving the Th17 cells, was significantly negatively correlated to PD-L1 (r = −0.33, p = 0.02). Conclusions: Circulating PD-L1+ cDC1 was reduced in the patients with COPD, and the tolerogenic role was suppressed with susceptibility to self-antigens and linked to rapid decline caused by Th17-skewed chronic inflammation.

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Section: Discussionmentioning

confidence: 99%

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease

Chen,

Sun,

et al. 2024

Cells

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Balance measures for fall risk screening in community-dwelling older adults with COPD: A longitudinal analysis

Nguyen,

Brooks,

Macedo

et al. 2024

Respiratory Medicine

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MAP2K1 dampens cigarette smoke-induced inflammation via suppression of type I interferon pathway activation

Gong,

Brune,

Guo

et al. 2024

American Journal of Physiology-Lung Cellular and Molecular Phys

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Chronic Obstructive Pulmonary Disease (COPD), comprised of chronic bronchitis and emphysema, is a leading cause of morbidity and mortality worldwide. MAP2K (mitogen-activated protein 2 kinase) pathway activation is present in COPD lung tissue and a genetic polymorphism in Map2k1 associates with FEV1 decline in COPD, suggesting it may contribute to disease pathogenesis. To test the functional contribution of Map2k1 in cigarette smoke (CS)-induced lung inflammation, we used a short-term CS exposure model in mice deficient in myeloid Map2k1 ( LysmCre+Mek1fl) and wild-type mice ( Mek1fl). Mice deficient in myeloid Map2k1 had enhanced CS-induced lung inflammation characterized by increased neutrophil recruitment, augmented expression of elastolytic matrix metalloproteinases, and increased type I interferon-stimulated gene expression. The augmented neutrophilic inflammatory response could be abrogated by IFNAR1 blockade. These findings indicate that myeloid Map2k1 regulates the immune response to CS via inhibition of the type I interferon pathway. Overall, these results suggest that Map2k1 is a critical determinant in modulating the severity of CS-induced lung inflammation and its expression is protective.

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Sex-differences in COPD: from biological mechanisms to therapeutic considerations

Cited by 4 publications

References 77 publications

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease

Reduced Tolerogenic Program Death-Ligand 1-Expressing Conventional Type 1 Dendritic Cells Are Associated with Rapid Decline in Chronic Obstructive Pulmonary Disease

Balance measures for fall risk screening in community-dwelling older adults with COPD: A longitudinal analysis

MAP2K1 dampens cigarette smoke-induced inflammation via suppression of type I interferon pathway activation

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