New developments in clinical aspects of lymphatic disease

Abstract

The lymphatic system is fundamentally important to cardiovascular disease, infection and immunity, cancer, and probably obesity--the four major challenges in healthcare in the 21st century. This Review will consider the manner in which new knowledge of lymphatic genes and molecular mechanisms has demonstrated that lymphatic dysfunction should no longer be considered a passive bystander in disease but rather an active player in many pathological processes and, therefore, a genuine target for future therapeutic developments. The specific roles of the lymphatic system in edema, genetic aspects of primary lymphedema, infection (cellulitis/erysipelas), Crohn's disease, obesity, cancer, and cancer-related lymphedema are highlighted.

Figure 1. The traditional view of the lymphatic capillaries is that the arteriolar end of the capillary filters, while the venular end of the capillary reabsorbs fluid.

However, if all Starling forces are considered, including interstitial colloid osmotic and hydraulic pressures, there is a net but dwindling filtration along the entire length of the capillary, with no venous reabsorption. (A) In the traditional view, interstitial forces are deemed negligible (the sum of Starling forces opposing filtration [P₀] = 25 mmHg, P_V = 7.7 mmHg). (B) However, interstitial forces are taken into account when using direct measurements (P_i = –2.1 mmHg, π_i = 15.7 mmHg, P₀ = 6.3 mmHg, P_V = 7.7 mmHg). Adapted with permission from Cardiovascular Research (6).

Figure 2. Clinical algorithm for classification of primary lymphoedema according to genotype and, where the gene is not known, phenotypic cohort.

Adapted with permission from Clinical Genetics (24). FH, family history.

Figure 3. The dermal lymphatic sits center stage for the drainage of immune-active cells.

Skin grafts, allergens, or immunization stimulate a variety of immune cells, including T cells, Langerhans cells, dendritic cells, and macrophages, which exit from the skin via the lymphatic system. Antigen-presenting cells cells exit the dermis via the lymphatic postcapillary venules and travel to the dermal lymphatic and then on to the lymph node, in which they activate and expand lymphocytes that secrete antibodies or otherwise target the antigen. Immune cells then travel through the lymphatic vasculature and enter the blood circulation via the thoracic duct. The blood is filtered through the spleen, which can lead to additional activation and expansion of antigen-targeted immune cells.