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Cited by 77Lymphatic System and DiseasesInflammatory Bowel DiseaseLymphatic Disorders and Treatments

Ileitis-associated tertiary lymphoid organs arise at lymphatic valves and impede mesenteric lymph flow in response to tumor necrosis factor

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Czepielewski, Rafael S., Erlich, Emma C., Onufer, Emily J., Young, Shannon, Saunders, Brian T., Han, Yong-Hyun, Wohltmann, Mary, Wang, Peter L. +8 more·2021·Immunity
DOI 10.1016/j.immuni.2021.10.003PMC PMC8678349
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Abstract

Lymphangitis and the formation of tertiary lymphoid organs (TLOs) in the mesentery are features of Crohn's disease. Here, we examined the genesis of these TLOs and their impact on disease progression. Whole-mount and intravital imaging of the ileum and ileum-draining collecting lymphatic vessels (CLVs) draining to mesenteric lymph nodes from TNF ΔARE mice, a model of ileitis, revealed TLO formation at valves of CLVs. TLOs obstructed cellular and molecular outflow from the gut and were sites of lymph leakage and backflow. Tumor necrosis factor (TNF) neutralization begun at early stages of TLO formation restored lymph transport. However, robustly developed, chronic TLOs resisted regression and restoration of flow after TNF neutralization. TNF stimulation of cultured lymphatic endothelial cells reprogrammed responses to oscillatory shear stress, preventing the induction of valve-associated genes. Disrupted transport of immune cells, driven by loss of valve integrity and TLO formation, may contribute to the pathology of Crohn's disease.

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  • Micropuncture studies in the mesentery and other regions of supine animals show that pressures rise from ∼0 cmH2O in lymphatic capillaries to >10 cmH2O in the collectors that enter the mesenteric lymph node.

    “Micropuncture studies in the mesentery and other regions of supine animals (28) show that pressures rise from ∼0 cmH2O in lymphatic capillaries to >10 cmH2O in the collectors that enter the mesenteric lymph node (28, 47).”

    From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [47]

    The Results section on lymph-flow obstruction (page unavailable) reports micropuncture pressures below 5 cmH2O in wild-type mesenteric collecting lymphatics, not above 10 cmH2O. Pressures near 20 cmH2O occurred specifically upstream of obstructing tertiary lymphoid organs in mice with ileitis. The paper does not report the claimed rise from approximately 0 cmH2O in capillaries. (LLM, conf=0.88)

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Authors
Czepielewski, R. S., Erlich, E. C., Onufer, E. J., Young, S., Saunders, B. T., Han, Y.-H., Wohltmann, M., Wang, P. L., Kim, K.-W., Kumar, S., Hsieh, C.-S., Scallan, J. P., Yang, Y., Zinselmeyer, B. H., Davis, M. J., & Randolph, G. J.
Affiliations
  • Washington University in St. Louis (US)
  • University of South Florida (US)
  • University of Missouri (US)
Corresponding author
Randolph, Gwendalyn J.
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2021-12
Volume
54
Issue
12
Pages
2795-2811.e9
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2021.10.003
PMC
PMC8678349
OpenAlex
W3214330513
Cited by
77
References
82
Citations by year
2026: 10 · 2025: 19 · 2024: 19 · 2023: 19 · 2022: 10
FWCI
4.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (DP1 DK1109668)
  • Kenneth Rainin Foundation (T32 DK077653, P30 DK052574, R01 HL145397, R37 AI0499653, FA-2020-01-IBD-1, R01 HL142905, P30 DK097948)
Topics
  • Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
Keywords
tertiary lymphoid structures, ileitis, Crohn's disease, lymphatic valves, collecting lymphatic vessels, mesenteric lymph nodes, TNF-α, lymphatic leakage, lymphatic endothelial cells, oscillatory shear stress, TNF-alpha neutralization, intravital imaging
MeSH terms
Tertiary Lymphoid Structures, Animals, Cell Movement, Cells, Cultured, Crohn Disease, Disease Models, Animal, Humans, Ileitis, Ileum, Lymph, Lymphangitis, Mesentery, Stress, Mechanical, Tumor Necrosis Factor-alpha, Mice, Knockout, Lymphatic Vessels, Endothelial Cells, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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