Contribution of adaptive immunity to human COPD and experimental models of emphysema

Abstract

The pathophysiology of chronic obstructive pulmonary disease (COPD) and the undisputed role of innate immune cells in this condition has dominated the field in the basic research. Recently, however, compelling data suggesting that adaptive immune cells may also contribute to the progressive nature of lung destruction associated with COPD in smokers has gained considerable attention. The histopathological changes in the lungs of smokers can be limited to the large or small airways, but alveolar loss leading to emphysema, which occurs in some individuals, remains its most significant and irreversible outcome. Critically, however, the question of why emphysema progresses in a subset of former smokers remained a mystery for many years. The recognition of activated and organized tertiary T and B lymphoid aggregates in emphysematous lungs provided the first clue that adaptive immune cells may play a crucial role in COPD pathophysiology. Based on these findings from human translational studies, experimental animal models of emphysema were used to determine the mechanisms through which smoke exposure initiates and orchestrates adaptive autoreactive inflammation in the lungs. These models have revealed that T helper (Th)1 and Th17 subsets promote a positive feedback loop that activates innate immune cells, confirming their role in emphysema pathogenesis. Results from genetic studies and immune-based discoveries have further provided strong evidence for autoimmunity induction in smokers with emphysema. These new findings offer a novel opportunity to explore the mechanisms underlying the inflammatory landscape in the COPD lung and offer insights for development of precision-based treatment to halt lung destruction.

Lymphatic Dysfunction Models an Autoimmune Emphysema Phenotype of Chronic Obstructive Pulmonary Disease

“…Autoantibody production is exacerbated by CS (29), and has been implicated in disease progression for patients with autoimmune emphysema (1, 3). Interestingly, these autoantibodies can be to a broad array of antigens, including ones that are not specific to the lung, and those that are more commonly seen in autoimmune diseases such as systemic lupus erythematosus SLE) and rheumatoid arthritis (RA) (30).…”

“…We found that while IgG and IgA autoantibody production was broadly increased in the bronchoalveolar lavage (BAL) fluid of control room air exposed Clec2 pltKO mice (Supplemental Figure 3), chronic CS exposure dramatically increased the presence of IgG autoantibodies within the lung tissue of Clec2 pltKO mice (Figure 5a). CS-exposed Clec2 pltKO mice had increased autoantibodies to a wide variety of antigens, including autoantibodies that are typically seen in autoimmune diseases (Figure 5b-g), such as Sm, SSA-A, Jo-1, Scl-70, and autoantibodies to complement proteins (3, 13, 14). We similarly found an increase in IgA autoantibodies in the lung tissue of CS-exposed Clec2 pltKO mice (Supplemental Figure 4).…”

“…Tertiary lymphoid organs (TLOs) are a prominent histologic finding in a clinical phenotype of COPD that is characterized by emphysema and an adaptive immune signature that promotes autoantibodies and autoreactive T cells (1)(2)(3). Though an 'autoimmune emphysema' phenotype of COPD is present in a subset of patients, it is unclear what are the underlying drivers of their specific disease pathogenesis.…”

Advances in immune response to pulmonary infection: Nonspecificity, specificity and memory

“…Th17 cells as important pro‐inflammatory cells, induce epithelial cells to produce antimicrobial peptides, chemokines, and granulocyte growth factors to promote neutrophil accumulation in airways 76 . Th17 can also promote a positive feedback loop that activates innate immune cells, confirming their role in emphysema pathogenesis 77 . Treg cells play a role in immunosuppression, regulating the intensity of the inflammatory reaction and promoting tissue repair.…”

Downregulation ofLet-7miRNA promotes Tc17 differentiation and emphysema via de-repression of RORγt

“…Aberrant T cells are implicated in impaired host defense, exaggerated inflammation, and loss of self-tolerance in COPD (Williams et al, 2021;Chen et al, 2023;Hogg et al, 2004;Maeno et al, 2007;Xu et al, 2012). In this regard, we and others have demonstrated the role and pathogenicity of activated IFN-γ and IL-17-secreting subsets of CD4 + and CD8 + T lymphocytes including Th1, Th17, and Tc1 cells in clinical isolates and in mice with COPD (W. Lu et al, 2015;You et al, 2015;Shan et al, 2009;S.-H. Lee et al, 2007;Kheradmand et al, 2023). The IL-17-secreting Th17 cells are particularly important as they promote the destruction of lung epithelium and recruitment of macrophages and neutrophils which then release proteolytic enzymes such as matrix metalloproteinases (MMPs) involved in the degradation of the lung structural matrix (Barnes, 2016;Hoenderdos & Condliffe, 2013).…”