Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD

Richmond, Bradley W.; Mansouri, Samira; Serezani, Ana Paula Moreira; Novitskiy, Sergey V.; Blackburn, Jessica B.; Du, Rui-Hong; Fuseini, Hubaida; Gutor, Sergey; Han, Wei; Schaff, Jacob; Vasiukov, Georgii; Xin, Matthew K.; Newcomb, Dawn C.; Jin, Lei; Blackwell, Timothy S.; Polosukhin, Vasiliy V.

doi:10.1038/s41385-020-00344-9

Cited by 27 publications

(17 citation statements)

References 65 publications

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“…Dysfunctional epithelium leads to bacterial invasion deep into the mucosa and fibrotic airway remodeling( 23 ). Animal models suggest that endogenous bacteria orchestrate a persistent and pathologic adaptive immune response that drives tissue remodeling( 24 ).…”

Section: Disscussionmentioning

confidence: 99%

Idiopathic subglottic stenosis arises at the interface of host and pathogen

Gelbard

Shilts

Strickland

et al. 2022

Preprint

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Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Diverse diseases in divergent organ systems are associated with fibrosis, suggesting common biologic mechanisms. One well characterized pathway is chronic inflammation secondary to pathogen. In the present study, we explored the role of the proximal airway microbiome in iSGS pathogenesis. In human samples, abundant bacteria are detectable in iSGS scar as well as in health subglottic controls or patients that developed subglottic stenosis following endotracheal intubation. Interestingly, the community structure of the iSGS proximal airway microbiome does not appear disrupted. Rather, in iSGS defects in the airway epithelial barrier allow displacement of the native microbiome into the immunoprivileged lamina propria and are associated with adaptive immune activation. Animal models of iSGS confirm both bacteria and an adaptive immune response are necessary for pathologic proximal airway fibrosis. Single cell RNA sequencing of the affected airway in iSGS offers an unbiased characterization of the observed epithelial barrier dysfunction. The airway scar in iSGS patients demonstrates basal cell depletion and epithelial acquisition of a mesenchymal phenotype. The epithelial alterations are associated with the observed microbiome displacement, dysregulated immune activation, and localized fibrosis. These results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases.

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Section: Disscussionmentioning

confidence: 99%

Idiopathic subglottic stenosis arises at the interface of host and pathogen

Gelbard

Shilts

Strickland

et al. 2022

Preprint

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“…Scrutiny of TLS induction in non-tumor bearing animal models has provided with crucial information for the understanding of the complex, tightly regulated, non-redundant mechanisms that lead to initiation, formation and maintenance of these lymphoid ectopic structures (55). Notably, several recent reports have shed new light in the ontogeny of TLS in mouse models of lung disorders (33,(60)(61)(62)(63)(64)(65)(66). In a model of viral infection with respiratory syncytial virus (RSV), Gassen et al reported a RSVdependent down-modulation of both IL-21 and IL-21R expression by lung Tfh cells, accompanied by an up-regulation of PD-L1 expression on resident B cells and DC, resulting in a defective GC formation and anti-RSV antibody response.…”

Section: Learning From Tls Study In Non-tumor Inflammatory Diseases To Better Understand Tls Role In Cancermentioning

confidence: 99%

“…Chronic Obstructive Pulmonary Disease (COPD) is often associated with airway epithelium functional defects, including a lack of secreted IgA (sIgA) and a pathological adaptive immune activation in advanced COPD patients. Richmond et al have reported that TLS-like structures (i.e., accumulation of dense B-cell aggregates surrounded by CD4 + and CD8 + T cells) and myeloid DC are present in the lungs of COPD patients where no sIgA are detected, as observed in sIgA-deficient mice ( 64 ). Thus, airway bacteria induce the migration of monocyte-derived DC in the lungs through a CCR2-dependent mechanism which in turn favor T cell recruitment and TLS formation.…”

Section: Learning From Tls Study In Non-tumor Inflammatory Diseases To Better Understand Tls Role In Cancermentioning

confidence: 99%

Tumor-Associated Tertiary Lymphoid Structures: From Basic and Clinical Knowledge to Therapeutic Manipulation

et al. 2021

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The tumor microenvironment is a complex ecosystem almost unique to each patient. Most of available therapies target tumor cells according to their molecular characteristics, angiogenesis or immune cells involved in tumor immune-surveillance. Unfortunately, only a limited number of patients benefit in the long-term of these treatments that are often associated with relapses, in spite of the remarkable progress obtained with the advent of immune checkpoint inhibitors (ICP). The presence of “hot” tumors is a determining parameter for selecting therapies targeting the patient immunity, even though some of them still do not respond to treatment. In human studies, an in-depth analysis of the organization and interactions of tumor-infiltrating immune cells has revealed the presence of an ectopic lymphoid organization termed tertiary lymphoid structures (TLS) in a large number of tumors. Their marked similarity to secondary lymphoid organs has suggested that TLS are an “anti-tumor school” and an “antibody factory” to fight malignant cells. They are effectively associated with long-term survival in most solid tumors, and their presence has been recently shown to predict response to ICP inhibitors. This review discusses the relationship between TLS and the molecular characteristics of tumors and the presence of oncogenic viruses, as well as their role when targeted therapies are used. Also, we present some aspects of TLS biology in non-tumor inflammatory diseases and discuss the putative common characteristics that they share with tumor-associated TLS. A detailed overview of the different pre-clinical models available to investigate TLS function and neogenesis is also presented. Finally, new approaches aimed at a better understanding of the role and function of TLS such as the use of spheroids and organoids and of artificial intelligence algorithms, are also discussed. In conclusion, increasing our knowledge on TLS will undoubtedly improve prognostic prediction and treatment selection in cancer patients with key consequences for the next generation immunotherapy.

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“…Further, we reported that SIgA-deficient mice spontaneously develop progressive lung inflammation, small airway wall thickening, and emphysema similar to patients with COPD (14)(15)(16), suggesting loss of SIgA immunobarrier directly contributes to COPD pathogenesis.…”

Section: Introductionmentioning

confidence: 85%

“…Loss of SIgA is common in COPD small airways and is an established driver of COPD progression in animal models (10,(12)(13)(14)(15)(16). However, the mechanism of SIgA remains poorly understood, particularly in small airways.…”

Section: Discussionmentioning

confidence: 99%

Secretory cells are the primary source of pIgR in small airways

Blackburn

Schaff

Gutor

et al. 2021

Preprint

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BackgroundLoss of secretory immunoglobulin A (SIgA) is common in COPD small airways and likely contributes to disease progression. We hypothesized loss of SIgA results from reduced expression of pIgR, a chaperone protein needed for SIgA transcytosis, in the COPD small airway epithelium.MethodspIgR-expressing cells were defined and quantified at single-cell resolution in human airways using RNA in-situ hybridization, immunostaining, and single-cell RNA sequencing. Complementary studies in mice utilized immunostaining, primary murine tracheal epithelial cell (MTEC) culture, and transgenic mice with secretory or ciliated cell-specific knockout of pIgR. SIgA degradation by human neutrophil elastase or secreted bacterial proteases from non-typeable Haemophilus influenzae (NTHi) was evaluated in vitro.ResultsWe found that secretory cells are the predominant cell type responsible for pIgR expression in human and murine airways. Loss of SIgA in small airways was not associated with a reduction in secretory cells but rather a reduction in pIgR protein expression despite intact PIGR mRNA expression. Neutrophil elastase and NTHi-secreted proteases are both capable of degrading SIgA in vitro and may also contribute to a deficient SIgA immunobarrier in COPD.InterpretationLoss of the SIgA immunobarrier in small airways of patients severe COPD is complex and likely results from both pIgR-dependent defects in IgA transcytosis and SIgA degradation.Key MessagesWhat is the key question? Localized SIgA deficiency in small airways is an established driver of COPD pathogenesis, but the mechanism of loss remains unclear. We hypothesized loss of SIgA is due to reduced numbers of pIgR-expressing cells in SIgA-deficient small airways.What is the bottom line? pIgR is primarily expressed by secretory cells in human and murine airways. Although numbers of secretory cells are similar between SIgA-deficient and SIgA-replete airways in COPD, there is reduced expression of pIgR protein, but not mRNA, in SIgA-deficient airways. Additionally, host and bacterial proteases degrade SIgA in vitro, suggesting loss of SIgA may relate to both impaired transcytosis and increased degradation.Why read on? This study highlights the complexity of SIgA immunobarrier maintenance and suggests that strategies aimed at restoring the SIgA immunobarrier will need to account for both impaired transcytosis and degradation by host and/or bacterial proteases.

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Monocyte-derived dendritic cells link localized secretory IgA deficiency to adaptive immune activation in COPD

Cited by 27 publications

References 65 publications

Idiopathic subglottic stenosis arises at the interface of host and pathogen

Idiopathic subglottic stenosis arises at the interface of host and pathogen

Tumor-Associated Tertiary Lymphoid Structures: From Basic and Clinical Knowledge to Therapeutic Manipulation

Secretory cells are the primary source of pIgR in small airways

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