"The innate immune system consists of humoral and a cellular arm, but attention has largely been focused on cells and their receptors. The humoral innate immune system (HIIS) is generally represented as a collection of diverse molecules (collectins, ficolins, pentraxins). A tenet underlying this application is that in spite of molecular diversity, the HIIS is built on general principles and logic conserved in evolution. This general view will be put to a test capitalizing on the discovery by the applicant of the long pentraxin family, the prototype of which is PTX3. PTX3 is a multifunctional fluid phase pattern recognition receptor, highly conserved in evolution, at the interface between innate immunity/ inflammation and female fertility /matrix remodelling. The specific aims of the studies outlined herein are:1) better define the repertoire of HIIS receptors by identifying new receptor(s) (eg PTX4) and ligands as well as interaction among receptor families (eg Ficolins); 2) pursue the structure and function of PTX3 as well as of newly discovered related molecules; 3) using genetic and cellular approaches define the relative importance of different cellular sources (eg lymphatic tissue); 4) based on 1-3, address fundamental mechanisms and logic in the interplay between cellular and humoral innate immunity; 5) explore the applicative potential of long pentraxins as diagnostics; 6) based on 1), engineer new pentraxins as potential therapeutics. The focus will largely be on unexpected turns, based on preliminary results, including: coupling of members belonging to different molecular classes; mechanisms of regulation of innate immunity (pathways of complement activation; P-selectin and leukocyte trafficking); the role in the extracellular matrix of lymphatic vessels."