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 have dominated the field in the basic research arena for many years. Recently, however, compelling data suggesting that adaptive immune cells may also contribute to the progressive nature of lung destruction associated with COPD in smokers have 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.

Keywords: T lymphocytes; adaptive immunity; autoimmunity; emphysema; exacerbation.

Graphical abstract

FIGURE 1.

The loss of peripheral immune tolerance and mediators of autoreactive T lymphocyte differentiation. Most, but not all, autoreactive T cells undergo programmed cell death within the thymus. A few autoreactive T cells leave the thymus but remain anergic when they encounter T regulatory cells, expressing the transcription factor FOXP3. Anergic T cells retain inhibitory signals through T cell immunoglobulin and mucin domain-containing protein (TIM)-3, cytotoxic T-lymphocyte–associated antigen (CTLA)-4, and programmed cell death (PD)-1 from tolerogenic antigen-presenting cells (APCs) that express the respective ligands. In response to cigarette smoke, activated APCs present self-antigens through major histocompatibility complex (MHC) II, which recognizes T cell receptor (TCR) on autoreactive T cells. The transcription factors Tbet and Rorγt induce self-reacting T cells to differentiate into T helper (Th)1 and Th17 cells, respectively. Th1 cells secrete interferon (IFN)-γ and tumor necrosis factor (TNF)-α promoting B cells to differentiate into plasma cells expressing autoreactive antibodies. Th17 cells express interleukin (IL)-17A and IL-22, which exacerbate tissue destruction in autoimmune inflammation. Image created with BioRender.com, with permission.

FIGURE 2.

Environmental exposure in the lungs linked to induction of adaptive immune cells. Right: the most prominent pathophysiological hallmark of cigarette-smoke induced inflammation is the loss of alveoli in the upper lobes (e.g., emphysema). Chronic exposure to cigarette smoke activates expression of proteolytic enzymes from innate immune cells that can release antigens. APCs interdigitating the airways sense antigens and express them in the context of major histocompatibility complex (MHC) II class molecules. MHC II complex presents antigenic peptides that are recognized by specific TCRs and activate T cells into Th1 and Th17 subsets of T helper cells. Activated Th1 and Th17 adaptive immune cells promote B cell differentiation into plasma cells that secrete immunoglobulin (Ig)G autoantibodies. Th1 cells secrete IFN-γ, which increases IP-10 and activates lung macrophages to express matrix metalloproteinase (MMP)12. Together, autoimmune activation of the T and B lymphocytes promotes lung destruction and emphysema development. Left: environmental allergens containing proteinases (e.g., pollens, mold, or yeast) cause lung tissue injury and activate platelets to secrete Dickkopf-related protein (DKK)1. Platelet activation and secretion of DKKI1 is required for Th2 and Th17 differentiation in models of asthma. Elevated levels of IL-13, IL-4, and IL-17A expressed by Th2 and Th17 cells are hallmarks of chronic allergic inflammation that promote IgE expression in B cells. Although IL-17A is also prominent in allergic inflammation in the lungs, alveoli remain intact, whereas goblet cells undergo metaplasia and bronchial walls thicken. See glossary for additional abbreviations. Image created with BioRender.com, with permission.

FIGURE 3.

Cigarette smoke accelerates lung aging. Under normal conditions advanced aging is associated with increased airway obstruction and reduced lung tissue density. However, smokers develop emphysema and decreased lung function at a much younger age. Other features of advanced aging (e.g., increased atherosclerosis, immune senescence, inflammation, and mitochondrial damage) have been associated with smokers at younger age. See glossary for abbreviations. Image created with BioRender.com, with permission.

FIGURE 4.

Innate and adaptive immunity corroborate in emphysema pathogenesis. Cigarette smokers with emphysema harbor exosomes marked by CD63/CD66 in their lungs. Naturally, an abundance of alpha1 anti-trypsin (A1AT) inhibits neutrophil elastase (NE) action in the lungs. However, when NE is bound on exosome surfaces they become resistant to A1AT. CD63/CD66 exosomes decorated with NE bind to the extracellular molecules (ECMs) via Mac-1 and degrade ECM. Intranasal transfer of activated exosomes from human emphysema can cause emphysema in mice. Cigarette smoke can also activate macrophages to release MMP12, which is a potent inhibitor of A1AT, and can degrade ECM (e.g., elastin) in the lungs. Fragments of elastin can be presented by MHC II molecules and promote Th1 and Th17 adaptive immune responses in the lungs. The presence of Th1 and Th17 immune cells in the lungs positively correlate with emphysema in human smokers. See glossary for abbreviations. Image created with BioRender.com, with permission.

FIGURE 5.

Inducible bronchus-associated lymphoid tissue (iBALT) development in the lungs. Cigarette smokers are highly susceptible to viral and bacterial infections causing chronic obstructive pulmonary disease (COPD) exacerbation, which is linked to disease progression. Tissue damage in response to airway infections can activate APCs and innate lymphoid cells (ILCs). iBALT development requires the activation and differentiation of stromal cells, such as podoponin⁺ fibroblasts that form their outer layer. Cytokines and chemokines expressed by ILCs increase B and T lymphocyte recruitment around the activated stroma, leading to maturation of the iBALT structure. iBALT maintenance requires cross talk between innate and adaptive immune cells that recruit naive cells from the lymphatic and blood vessels to further organize and mature iBALTs. See glossary for additional abbreviations. Image created with BioRender.com, with permission.

FIGURE 6.

Experimental models of cigarette smoke validate adaptive immune responses in human emphysema studies. Mice exposed to chronic smoke recruit interstitial macrophages expressing CD11b, and CD11c to the lungs. Activated macrophages increase osteopontin (Spp1) while suppressing PPAR-γ and C1q. Coculture of interstitial macrophages expressing CD11b and CD11c with naive T lymphocytes promotes Th1 and Th17 differentiation in the presence of IL-12 or IL-6, IL-1b, IL-23, respectively. IL-17A is critical for neutrophil recruitment and together with CCL20 induces MMP12 expression, which causes emphysema. Adoptive transfer of interstitial macrophages CD11b and CD11c or activated T lymphocytes isolated from mice exposed to smoke can cause emphysema in naive mice, indicating the critical role of adaptive immunity in emphysema development. See glossary for abbreviations. Image created with BioRender.com, with permission.