The emerging importance of lymphatics in health and disease: an NIH workshop report

Abstract

The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled "Yet to be Charted: Lymphatic System in Health and Disease," held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field.

Figure 1. Key milestones punctuate the centuries-long pursuit to map the lymphatic system.

Ten important events in the history of lymphatic research that occurred between 500 BCE and the present day. See Supplemental Table 1 for a comprehensive timeline of lymphatic discoveries and NIH-led activities and funding opportunities.

Figure 2. Publications and NIH funding data summarize trends for lymphatic research.

(A–C) Bibliometric analysis from 1944 to 2019 used the PubMed Advanced Search Builder and Medical Subject Headings (MeSH) terms, accessed on March 23, 2023. Blood vasculature search queries included ((“Cardiovascular Diseases”[MeSH Terms] OR (“Cardiovascular System”[MeSH Terms] AND (“Mice”[MeSH Terms] OR “Humans”[MeSH Terms])) OR “Blood Vessels”[MeSH Terms] OR “Blood”[MeSH Terms]) OR “Heart” [MeSH Terms]). Lymphatic system queries included lymphatic anomalies: ((“Lymphatic Diseases”[MeSH Terms] OR (“Lymphatic System”[MeSH Terms] AND (“Mice”[MeSH Terms] OR “Humans”[MeSH Terms])) OR “Lipedema”[MeSH Terms] OR “Lymphedema”[MeSH Terms] OR “Lymphatic Vessels”[MeSH Terms] OR “Lymphoid Tissue”[MeSH Terms])). (B and C) The percentage increase was calculated using the following formula: [(no. publications 2019 – no. publications 2000)/no. publications 2000] × 100. (A) Area graphs showing blood vasculature and lymphatic system from 1944 to 2019. (B) Line graphs correspond to the number of blood vasculature system publications and show the growth across the last 75 years. The number of publications increased by 87.5% in the last 20 years. (C) Comparatively, the number of lymphatic system publications has a growth rate of 51.4% for the last 20 years. (D–F) Portfolio analysis of NIH lymphatic research grant applications and awards from 2012 to 2021 using the RCDC categories “lymphatic research,” “lymphoma,” and “lymphedema” indicates total NIH funding amounts. The analysis was performed by the National Heart, Lung, and Blood Institute’s Office of Planning, Analytics, and Evaluation on August 23, 2022. (D) Total cost of NIH-funded lymphatic research awards; lymphoma (dark green bars) and nonlymphoma (light green bars) lymphatic research awards. (E) Number of all NIH research grant applications (light purple bars) and awards (dark purple bars), including competing applications and awards. The success rate for fiscal year (FY) 2021 of 20%. (F) Number of NIH lymphatic research grant applications (light purple bars) and awards (dark purple bars), including first-time and competing applications. The success rate for awards in FY2021 was 17%.

Figure 3. Lymphatic diseases manifest across the human body.

Changes in normal lymphatic function can alter multiple systems in the body and manifest as different and varied pathologies. There are many conditions related to lymphatic dysfunction within all body systems. Hematological malignancies were not included because the focus of the workshop was on understudied diseases of the lymphatic system. Various NIH Institutes or Centers that currently fund lymphatic research are indicated: NCATS, National Center for Advancing Translational Sciences; NCCIH, National Center for Complementary and Integrative Health; NCI, National Cancer Institute; NEI, National Eye Institute; NHLBI, National Heart, Lung, and Blood Institute; NIA, National Institute on Aging; NIAID, National Institute of Allergy and Infectious Diseases; NIAMS, National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIDCD, National Institute on Deafness and Other Communication Disorders; NIDCR, National Institute of Dental and Craniofacial Research; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIGMS, National Institute of General Medical Sciences; NINDS, National Institute of Neurological Disorders and Stroke.