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 of lymph have identified 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 before 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 dendritic cells (DCs) or non-activated nodal antigen-presenting cells (APCs) (macrophages, B cells and immature DCs). Here, we suggest that this process ensures organ-specific self-antigens are displayed to circulating and nodal APCs, thus contributing to the maintenance of peripheral tolerance.

Figure 1. Anatomical structure of a lymph node and circulation of lymph

a) H & E staining of a human lymph node. The capsule, cortex and medulla are indicated. * designates subcapsular and medullary sinuses. T and B cell areas are indicated as T and B respectively. The large arrowheads point to the lymphatic circulation of particulate material and high molecular weight proteins (>80 kDa), which bypass the nodal cortex, and will exit the node through efferent lymphatics. The smaller arrows illustrate the lymph flux into the conduit system and its exit through the high endothelial venule (HEV). b) A schematic drawing of a lymph node and nodal lymph circulation.

Figure 2. Conformational MHC class II variations and differential MHC class II peptidome on the surface of immature and mature DCs

a) Immature DCs and non-activated APCs are particularly competent for surface MHC II loading compared with mature or activated APCs [42]. Becasue DO expression is higher on immature DCs and non-activated APC the inhibitory function of DO on DM catalytic activity, favors a broader, less stable and more easily exchanged MHC II/peptide repertoire [50,51]. b) Immature DCs (left) present a broader peptide repertoire as well as a less stable and empty (peptide non-receptive and receptive) MHC class II complexes. Mature DCs express a more focused peptidome and more stable MHC class II complexes [–, –56]. c) Schematic showing surface peptide loading events on MHC class II molecules in immature DCs. Five possibleMHC class II molecule conformations are shown: peptide non-receptive (P1 pocket collapsed), peptide-receptive (P1 pocket open or filled) and peptide-loaded (binding groove occupied by the loaded peptide).