Abstract
The initiation of adaptive immune responses to protein antigens has to be preceded by their uptake by antigen presenting cells and intracellular proteolytic processing. Paradoxically, endocytic receptors involved in antigen uptake do not bind the majority of proteins, which may be the main reason why purified proteins stimulate at most weak immune responses. A shared feature of different types of adjuvants, capable of boosting immunogenicity of protein vaccines, is their ability to induce acute inflammation, characterized by early influx of activated neutrophils. Neutrophils are also rapidly recruited to sites of tissue injury or infection. These cells are the source of potent oxidants, including hypochlorous acid (HOCl), causing oxidation of proteins present in inflammatory foci. We demonstrate that oxidation of proteins by endogenous, neutrophils-derived HOCl increases their immunogenicity. Upon oxidation, different, randomly chosen simple proteins (yeast alcohol dehydrogenase, human and bovine serum albumin) and glycoproteins (human apo-transferrin, ovalbumin) gain the ability to bind with high affinity to several endocytic receptors on antigen presenting cells, which seems to be the major mechanism of their increased immunogenicity. The mannose receptor (CD206), scavenger receptors A (CD204) and CD36 were responsible for the uptake and presentation of HOCl-modified proteins by murine dendritic cells and macrophages. Other scavenger receptors, SREC-I and LOX-1, as well as RAGE were also able to bind HOCl-modified proteins, but they did not contribute significantly to these ligands uptake by dendritic cells because they were either not expressed or exhibited preference for more heavily oxidised proteins. Our results indicate that oxidation by neutrophils-derived HOCl may be a physiological mechanism of conferring immunogenicity on proteins which in their native forms do not bind to endocytic receptors. This mechanism might enable the immune system to detect infections caused by pathogens not recognized by pattern recognition receptors.
Highlights
Adaptive immune responses are mainly directed against foreign proteins
Our results indicate that modification by neutrophils-derived hypochlorous acid (HOCl) may be a universal, physiological mechanism of conferring immunogenicity on proteins which in their native forms do not bind to endocytic receptors involved in the uptake of antigens
The repertoire of proteins bound to mannose receptor (MR) is limited to collagens and glycoproteins containing oligosaccharides terminated with mannose, fucose or N-acetylglucosamine or modified with sulphuric acid [36,39,40,41,42,44], whereas scavenger receptors (SR)-A binds with high affinity to proteins which, owing to covalent modification, gain a net negative charge [45]
Summary
Adaptive immune responses are mainly directed against foreign (non-self) proteins. Th lymphocytes, which are responsible for the initiation and orchestration of immune responses, are not able to directly recognize native proteins, but require them being presented as complexes of short protein fragments (epitopes) with MHC class II molecules (MHC-II) on surfaces of antigen presenting cells (APC). Protein fragments are the only type of antigens presented in the context of both class I and II MHC molecules, the major endocytic receptors of APC, mediating antigen uptake in non-immune hosts: scavenger receptors (SR) and C-type lectins, do not bind the majority of proteins. This seems to be an important reason why purified proteins are at most weakly immunogenic. Our results indicate that modification by neutrophils-derived HOCl may be a universal, physiological mechanism of conferring immunogenicity on proteins which in their native forms do not bind to endocytic receptors involved in the uptake of antigens
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
