Mice with lymphatic dysfunction develop pathogenic lung tertiary lymphoid organs that model an autoimmune emphysema phenotype of COPD.

Autor:	Summers B; Division of Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medicine, New York, New York, United States., Kim K; Division of Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medicine, New York, New York, United States., Trivedi A; Division of Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medicine, New York, New York, United States., Lu TM; Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, United States.; Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, New York, United States.; Molecular and Cellular Biology Program, SUNY Downstate School of Graduate Studies, Brooklyn, New York, United States., Houghton S; Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, United States., Palmer-Johnson J; Division of Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medicine, New York, New York, United States., Rojas-Quintero J; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas, United States., Cala-Garcia J; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas, United States., Pannellini T; Department of Pathology, Weill Cornell Medicine, New York, New York, United States., Polverino F; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, Texas, United States., Lis R; Division of Regenerative Medicine, Department of Medicine, Ansary Stem Cell Institute, Weill Cornell Medicine, New York, New York, United States.; Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, New York, United States., Reed HO; Division of Pulmonary and Critical Care, Department of Medicine, Weill Cornell Medicine, New York, New York, United States.; Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, New York, United States.
Jazyk:	angličtina
Zdroj:	American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2025 Jan 01; Vol. 328 (1), pp. L1-L14. Date of Electronic Publication: 2024 Oct 22.
DOI:	10.1152/ajplung.00209.2024
Abstrakt:	We have previously shown that mice with a loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development of emphysema. TLOs in CLEC2-deficient mice were rich in plasma cells and were a source of a broad array of autoantibodies. Chronic cigarette smoke exposure increased the size and number of lung TLOs in CLEC2-deficient mice and was associated with increased markers of antigen presentation and maturation, leading to increased autoantibody deposition. Using lung tissue from patients with COPD, we found an increase in lymphatic markers in patients with an emphysema phenotype and autoreactive TLOs compared with patients with COPD without emphysema that lack prominent TLOs. Taken together, these results demonstrate that emphysema in mice with lymphatic dysfunction can be partially rescued by blocking TLO formation and that these TLOs are the source of autoantibodies that are exacerbated by cigarette smoke. Our work suggests that lymphatic dysfunction in mice may recapitulate some aspects of an autoimmune emphysema phenotype that is seen in a subset of patients with COPD. NEW & NOTEWORTHY The lymphatic vasculature has been implicated in the pathogenesis of lung disease but remains understudied. Here, the authors use a mouse model to show that lymphatic dysfunction leads to a phenotype of emphysema that is characterized by lung tertiary lymphoid organs that are autoreactive and pathogenic. Analysis of human tissue showed increased lymphatic markers in autoimmune emphysema with prominent TLOs, compared with other COPD phenotypes.
Databáze:	MEDLINE
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