Fig. 7.

Proposed pathophysiology of secondary lymphedema. 1 After PLND, DCs activate in the area of lymphatic injury with subsequent migration to the nearest skin-draining lymph node(s). 2 DCs interact with and activate CD4⁺ T cells in the skin-draining lymph node(s). Activated CD4⁺ T cells are then released from the lymph node(s) into the systemic circulation. 3 Activated CD4⁺ T cells preferentially migrate to the skin in the area of lymphatic injury by following gradients created by upregulation of leukocyte adhesion molecules on blood and lymphatic vessels (e.g., E-selectin, ICAM-1, and VCAM-1) and chemokines like CCL17 and CCL27, all of which bind skin-homing receptors such as CCR4, CCR10, and CLA. Once in the skin, CD4⁺ T cells promote the development of features such as impaired lymphangiogenesis, fibrosis, and increased iNOS expression. ILN, inguinal lymph node; PLND, popliteal lymph node dissection; S1P, sphingosine-1-phosphate