Modulation of Immunity by Lymphatic Dysfunction in Lymphedema

Abstract

The debilitating condition known as secondary lymphedema frequently occurs after lymphadenectomy and/or radiotherapy for the treatment of cancer. These therapies can damage lymphatic vessels leading to edema, fibrosis, inflammation and dysregulated adipogenesis, which result in profound swelling of an affected limb. Importantly, lymphedema patients often exhibit impaired immune function which predisposes them to a variety of infections. It is known that lymphadenectomy can compromise the acquisition of adaptive immune responses and antibody production; however the cellular mechanisms involved are poorly understood. Here we discuss recent progress in revealing the cellular and molecular mechanisms underlying poor immune function in secondary lymphedema, which has indicated a key role for regulatory T cells in immunosuppression in this disease. Furthermore, the interaction of CD4+ T cells and macrophages has been shown to play a role in driving proliferation of lymphatic endothelial cells and aberrant lymphangiogenesis, which contribute to interstitial fluid accumulation in lymphedema. These new insights into the interplay between lymphatic vessels and the immune system in lymphedema will likely provide opportunities for novel therapeutic approaches designed to improve clinical outcomes in this problematic disease.

Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases

“…Notably, inflammation and infections have been implicated in the pathogenesis of secondary lymphedema (Yuan et al, 2019). Although how exactly inflammation alters lymphatics structurally and functionally in the context of lymphedema remains to be determined, it is possible that junction zippering, along with other potential lymphatic dysfunctions such as retrograde lymph flow, underlies or contributes to localized fluid retention and tissue swelling in patients with inflammationassociated lymphedema.…”

Cellular Origins of the Lymphatic Endothelium: Implications for Cancer Lymphangiogenesis

“…Absence or malfunction of lymphatic vessels leads to the onset of many pathologies, including lymphedema, an incurable disease characterized by a disabling swelling of the extremities, accompanied by recurrent life-threatening infections (Alitalo and Carmeliet, 2002;Brouillard et al, 2014;Yuan et al, 2019;Azhar et al, 2020). In addition, since lymphatics proliferate under inflammatory conditions (Pullinger and Florey, 1937) and are responsible for immune cell clearance and resolution of inflammation; dysfunctional lymphatics are associated with chronic inflammatory and autoimmune diseases like psoriasis (Kunstfeld et al, 2004) and rheumatoid arthritis (reviewed in Schwartz et al, 2019).…”

Multiplexed gene expression analysis of HLA class II-associated podoconiosis implicates chronic immune activation in its pathogenesis

“…An increased number of tissue-infiltrating CD4 + T cells were observed both in lympheodema mouse models as well as in cancer-related lymphedema, and CD4 + T cell depletion in mice prevented the development of lymphoedema (but not CD8 + T cell or macrophage depletion). 26 Naive CD4 + T cells were shown to be activated in skin-draining lymph nodes following interaction with antigen-presenting cells, after which they migrate to the skin. 27 Expression of vascular endothelial growth factor C was induced by activated CD4 + T cells resulting in dysregulated lymphangiogenesis, whereby the formation of immature and leaky lymphatic vessels led to the accumulation of interstitial fluid.…”