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New developments in clinical aspects of lymphatic disease
Peter S. Mortimer, Stanley G. Rockson
Peter S. Mortimer, Stanley G. Rockson
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(3):915-921. https://doi.org/10.1172/JCI71608.
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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.

Authors

Peter S. Mortimer, Stanley G. Rockson

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The Lymphatic system and Human Viruses: an uncertain relationship

Submitter: Frédéric Morinet | frederic.morinet@sls.aphp.fr

Authors: Céleste Lebbé

CHU Saint-Louis APHP-Université Paris Diderot Paris Sorbonne Cité

Published March 12, 2014

We have read with a great interest the article of Peter Mortimer and Stanley Rockson. As they suggest, effectively the lymphatic system is the most neglected system since as far we know very few papers describe the interactions of human viruses with this tissue. The studies of the pathology of Kaposi sarcoma (KS) have opened the door to explore in depth the relationship of the lymphatic system with human viruses. The main cell type found in KS , an Human Herpes Virus 8 induced tumor,  is the spindle cell.  KS spindle cells display markers of lymphatic endothelium, including vascular endothelial growth factor receptor 3(VEGFR3), podoplanin and Prox-1; VEGFR3 is the receptor for VEGF-C , a cytokine critical for the formation of new lymphatic vessels (1 ,2). Such an activation of lymphangiogenesis was found again with two human viruses , the Herpes simplex virus type 1 (HSV-1) and the human cytomegalovirus (HCMV). Effectively in mice models of HSV-1 keratitis , it was shown that CD8+ T cells contained HSV-1 replication but CD8+ T and epithelial -cells induced lymphangiogenesis via secretion of VEGF-C and VEGF-A respectively(3,4). Consequently addition of VEGF isoforms with monoclonal antibodies would result in reduction of  long-term ocular pathology. For the HCMV the induction of lymphangiogenesis in vitro was through an indirect mechanism that relies on the secretion of IL-6 and GMCSF by the infected lymphatic endothelial cells (5 ). In an in vivo placentation model this stimulation of lymphangiogenesis by the HCMV  induced the formation of aberrant lymphatic vessel contributing perhaps in placenta edema in congenital HCMV infection(6). In fact the relationship of human viruses with the lymphatic system is more complex and ambivalent . Effectively the human herpes virus 6 (HHV-6) inhibits in vitro the lymphangiogenesis due to the expression of HHV-6/rep, a latency-associated gene (7). Such an observation is interesting since inhibition of angiogenesis is an important field of investigation in oncology. Also we are at the beginning of the study of the interactions of human viruses with the lymphatic system, in contrast to the numerous articles describing the regulation of inflammatory lymphangiogenesis during wound healing, chronic bacterial infection and Toll-like receptor ligand administration.

References

  1. Ganem D. KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine. J Clin Invest 2010; 120(4):939-949.
  2. Weninger W, et al. Expression of vascular endothelial growth factor receptor-3 and podoplanin suggests, a lymphatic endothelial cell origin of Kaposi’s sarcoma tumor cells. Lab Invest 1999;79(2):243-251.
  3. Conrady CD, Zheng M, Stone DU, Carr DJJ. CD8+ T cells suppress viral replication in the cornea but contribute to VEGF-C-induced lymphatic vessel genesis. J Immunol 2012;189: 425-432.
  4. Wuest TR, Carr DJJ. VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med 2010; 207(1): 101-115.
  5. Fiorentini S, et al. Human cytomegalovirus productively infects lymphatic endothelial cells and   induces a secretome that promotes angiogenesis and lymphangiogenesis through interleukin-6 and granulocyte-macrophage colony-stimulating factor. J Gen Virol 2011;92:650-660.
  6. Tabata T, et al. Cytomegalovirus impairs cytotrophoblast-induced lymphangiogenesis and vascular remodeling in an in vivo human placentation model. Am J Pathol 2012;181(5):1540-1559.
  7. Caruso A, et al. U94 of human herpesvirus 6 inhibits in vitro angiogenesis and lymphangiogenesis. Proc Natl Acad Sci USA 2009;106(48):20446-20451.

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