The lymph as a pool of self-antigens

Abstract

Prenodal lymph is generated from the interstitial fluid that surrounds organs, and thus contains products of organ metabolism and catabolism. New proteomic analyses have identified in lymph proteins and peptides that are derived from capillary extravasation and tissue-specific proteins. Many of these peptides are detected at nanomolar concentrations in the lymph prior to passage through a regional lymph node. Before entering the node and once inside proteins and processed peptides are filtered from the lymph by circulating immature DC or non-activated nodal APC (macrophages, B cells and immature DC). Here, we suggest that this process ensures organspecific self-antigens are displayed to circulating and nodal antigen-presenting cells, thus contributing to the maintenance of peripheral tolerance. The lymphatic system: a historical perspectiveHistorically, the first mention of the lymphatic system is found in a medical treaty written by the Greek physician Hippocrates in the V century B.C. whereas Galen (II century A.D.) reported the first dissection of the mesenteric lymph nodes. It was not until the seventeenth century that the lymphatic vessels were described as a separate system that carry aqueous fluid distinct from the blood. Until the early 1900s it was thought that the lymph was a cellfree, protein-free ultrafiltrate of the plasma composed only of electrolytes. In 1925 it was discovered that the prenodal lymph has a cellular component and contains high levels of lipids and proteins [1]. Even though it is generally regarded that the analysis of the pre-nodal lymph could provide a molecular signature of organ-specific "omics" (proteomic, lipidomic and metabolomic) transported to the regional lymph node, the difficulty in collecting primary material has hampered a broader development of the field [2]. Recently, a few studies have been performed on human bovine and goat lymph, collected at different sites, which have provided the first glimpse into the composition of the lymphatic fluid.In this review we will focus on current knowledge of the proteomic and peptidomic composition of the lymph under physiological conditions, with particular emphasis on its

Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for Lymphatic Endothelial Cells

“…Further detailed mechanistic studies must be conducted on the coordination (57) of Ag processing, presentation, and costimulatory/coinhibitory molecule pathways to shape the fate of these cells. Because LECs are situated in one of the prime anatomical sites for immunological sampling, our findings support the idea that organ-draining LECs are the first to sample and present the exogenous peptides (3,58), proteins, and particulates present in lymph. Thus, LECs may play an important role in the context of immunomodulation.…”

Emerging roles of lymphatic endothelium in regulating adaptive immunity

“…The LNs serve as hubs of antigen presentation, where lymphocytes are primed or tolerized against antigens presented by APCs. Lymph fluid drained from the periphery via afferent lymphatic vessels bathes LNs with soluble foreign antigens as well as tissue-specific self-antigens and any other molecules present in the local periphery, such as cytokines from inflamed tissues or tumors (10). Because lymph originates as interstitial fluid surrounding the cells of peripheral tissues, it is enriched in peptides that are processed extracellularly, including those resulting from local catabolism, ECM degradation, apoptosis, and tissue remodeling (9,11).…”

“…Lymph indicated the state of the local interstitial fluid it drained, with Starling forces dictating fluid and solute balance (1)(2)(3). Immunologists recognized the importance of lymphatic vessels as channels for leukocyte trafficking from peripheral sites to their draining LNs (4)(5)(6), and as conduits for soluble antigens that can be taken up directly by LNresident B cells and immature DCs (7)(8)(9)(10), which help regulate the kinetics of antigen presentation.…”

Immunomodulatory Roles of Lymphatic Vessels in Cancer Progression

“…This fluid thus contains not only interstitial solutes and serum proteins that have leaked out of the blood capillaries, but it also carries cytokines, growth factors, and cell debris from this space. During any inflammatory event, blood capillaries rapidly become hyperpermeable and an influx of immune cells induce local extracellular matrix proteolysis; thus, lymph from inflamed or irritated tissues is rich in peptides derived from the extracellular matrix (due to proteolysis by matrix metalloproteinases) or from apoptotic cells and other factors present in the inflamed tissue (17). Therefore, lymph is enriched with local antigens from the tissue it drains, and constantly bathes cells in the lymph node with these antigens.…”