Mice With Lymphatic Dysfunction Develop Pathogenic Lung Tertiary Lymphoid Organs That Model an Autoimmune Emphysema Phenotype of COPD

Authors

Barbara Summers
Kihwan Kim
Anjali Trivedi
Tyler M Lu
Sean Houghton
Jade Palmer-Johnson
Joselyn Rojas-Quintero
Juan Cala-Garcia
Tania Pannellini
Francesca Polverino
Raphaël Lis
Hasina Outtz Reed

Language

English

Publication Date

1-1-2025

Journal

American Journal of Physiology - Lung Cellular and Molecular Physiology

DOI

10.1152/ajplung.00209.2024

PMID

39437762

PMCID

PMC11905800

PubMedCentral® Posted Date

10-22-2024

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Animals, Pulmonary Disease, Chronic Obstructive, Tertiary Lymphoid Structures, Mice, Lung, Lectins, C-Type, Pulmonary Emphysema, Humans, Autoantibodies, Disease Models, Animal, Phenotype, Mice, Inbred C57BL, Autoimmune Diseases, Male, Mice, Knockout, Female, autoimmunity, COPD, emphysema, lymphatic vasculature, tertiary lymphoid organs

Published Open-Access

yes

Recommended Citation

Summers, Barbara; Kim, Kihwan; Trivedi, Anjali; et al., "Mice With Lymphatic Dysfunction Develop Pathogenic Lung Tertiary Lymphoid Organs That Model an Autoimmune Emphysema Phenotype of COPD" (2025). Faculty and Staff Publications. 4795.
https://digitalcommons.library.tmc.edu/baylor_docs/4795