Lymphatic System Development and Function.

PURPOSE OF REVIEW: This review delves into recent advancements in understanding generalized and organ-specific lymphatic development. It emphasizes the distinct characteristics and critical anomalies that can impair lymphatic function. By exploring developmental mechanisms, the review seeks to illuminate the profound impact of lymphatic malformations on overall health and disease progression. RECENT FINDINGS: The introduction of genome sequencing, single-cell transcriptomic analysis, and advanced imaging technologies has significantly enhanced our ability to identify and characterize developmental defects within the lymphatic system. As a result, a wide range of lymphatic anomalies have been uncovered, spanning from congenital abnormalities present at birth to conditions that can become life-threatening in adulthood. Additionally, recent research highlights the heterogeneity of lymphatics, revealing organ-specific developmental pathways, unique molecular markers, and specialized physiological functions specific to each organ. A deeper understanding of the unique characteristics of lymphatic cell populations in an organ-specific context is essential for guiding future research into lymphatic disease processes. An integrated approach to translational research could revolutionize personalized medicine, where treatments are precisely tailored to individual lymphatic profiles, enhancing effectiveness and minimizing side effects.

IL-7: Comprehensive review.

OVERVIEW: IL-7 is a member of the family of cytokines with four anti-parallel α helixes that bind Type I cytokine receptors. It is produced by stromal cells and is required for development and homeostatic survival of lymphoid cells. GENOMIC ARCHITECTURE: Interleukin 7 (IL7) human IL7: gene ID: 3574 on ch 8; murine Il7 gene ID: 16,196 on ch 3. PROTEIN: Precursor contains a signal sequence, mature human IL-7 peptide 152aa, predicted 17.4kd peptide, glycosylated resulting in 25kd. Crystal structure: http://www.rcsb.org/structure/3DI2. REGULATION OF IL-7 PRODUCTION: Major producers are stromal cells in thymus, bone marrow and lymphoid organs but also reported in other tissues. Production is primarily constitutive but reported to be affected by IFNγ and other factors. IL-7 RECEPTORS: Two chains IL-7Rα (IL-7R) and γc (IL-2RG). Human IL-7R: gene ID 3575 on ch 5; human IL2RG: gene ID 3561 on ch X; mouse IL-7R: gene ID 16,197 on ch 15; murine Il2rg gene ID 16,186 on ch X. Member of γc family of receptors for cytokines IL-2, -4, -9, -15, and -21. Primarily expressed on lymphocytes but reports of other cell types. Expression in T-cells downregulated by IL-7. Low expression on Tregs, no expression on mature B-cells. Crystal structure: http://www.rcsb.org/structure/3DI2. IL-7 RECEPTOR SIGNAL TRANSDUCTION PATHWAYS: Major signals through JAK1, JAK3 to STAT5 and through non-canonical STAT3, STAT1, PI3K/AKT and MEK/ERK pathways. BIOLOGICAL ACTIVITY OF IL-7: Required for survival of immature thymocytes, naïve T-cells, memory T-cells, pro-B-cells and innate lymphocytes. Pharmacological treatment with IL-7 induces expansion of naïve and memory T-cells and pro-B-cells. ABNORMALITIES OF THE IL-7 PATHWAY IN DISEASE: Deficiencies in the IL-7 pathway in humans and mice result in severe combined immunodeficiency due to lymphopenia. Excessive signaling of the pathway in mice drives autoimmune diseases and in humans is associated with autoimmune syndromes including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, sarcoidosis, atopic dermatitis and asthma. Mutations in the IL-7 receptor pathway drive acute lymphoblastic leukemia. CLINICAL APPLICATIONS: IL-7 has been evaluated in patients with cancer and shown to expand lymphocytes. It accelerated lymphocyte recovery after hematopoietic stem cell transfer, and increased lymphocyte counts in AIDS patients and sepsis patients. Monoclonal antibodies blocking the IL-7 receptor are being evaluated in autoimmune diseases. Cytotoxic monoclonals are being evaluated in acute lymphoblastic leukemia. Drugs blocking the signal transduction pathway are being tested in autoimmunity and acute lymphoblastic leukemia.

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

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.