Editorial [Hot Topic: Modulators of the Innate Immune Response (Guest Editor: Suzanne S. Bohlson)]

More than 120 years have passed since Dr. Ilya Ilyich Metchnikoff's first description of phagocytosis, originating from his observation that mobile cells from starfish larvae migrated to and surrounded foreign material (thorns from a tangerine tree in this case). His pioneering work formed the foundation for the discipline of innate immunity, now regarded not only as the first line of host defense, but also the instructor of the adaptive immune response, and regulator of tissue repair and homeostasis. The innate immune system was considered to be a “nonspecific” host defense system when viewed in contrast to the exquisite specificity provided by the billions of monoclonal lymphocyte receptors of the adaptive immune system. However, this view of the innate immune system has been revised with the identification of Toll like receptors (TLR), cytosolic nucleotide binding and oligomerization domain (NOD)-like receptors, and other pattern recognition receptors (PRR), either soluble or expressed on the surface of phagocytic cells, that recognize conserved molecular patterns on microorganisms and dead/dying (apoptotic) cells. In addition, cooperation among pattern recognition receptors and other specialized receptors (e.g. integrins) forms a macromolecular signaling complex that allows a phagocyte to specifically recognize a target particle and respond appropriately; an initial step in the generation of an immune response. In this issue of Current Drug Targets, eight review articles focus on modulators of innate immunity, specifically the receptors and pathways involved in the particle recognition phase by the phagocyte. They address complement, adhesion molecules and non-TLR PRR in innate immunity. Because TLR and NOD-like receptors have been the focus of numerous recent comprehensive reviews, this issue explores alternative pathways and receptors that enable the innate immune system to fine-tune the host response. Specific drug targets and therapies related to inflammation, host defense and autoimmunity are identified and emphasized. The first five articles of this issue focus on receptors (soluble and membrane bound) that modulate innate immunity. In the first article, Torrelles and colleagues (pages 102-112) describe cell-associated C-type lectin PRRs and soluble collectins in the innate immune response to mycobacteria, a pathogen that exploits the phagocytic cell, residing within host macrophages. Fraser and Tenner (pages 113-122) then focus specifically on the soluble PRR with particular emphasis on defense collagens (including collectins) in the regulation of phagocytosis and cytokine synthesis. Lawrence and Schorey (pages 123-129) follow with a review on Dectin-1, a membrane bound non-TLR PRR which can recognize specific pathogens and form a cooperative signaling complex with TLR. Next Greenlee and colleagues (page 130-138) describe a novel family of C-type-lectin-like domain-containing surface glycoproteins involved in innate immunity and phagocytosis. Further examples of specific receptors involved in modulation of innate immunity continue on pages (139-149) where McCall-Culbreath and Zutter describe the role of β1 integrins in host defense and autoimmunity. Briken (pages 150-157) then explores specific drug targets relevant to hostpathogen interactions, focusing on the modulins, bacterial proteins and lipids involved in manipulation of host cells. The final two reviews focus on the complement system, an arm of the innate immune system that leads to opsonization of pathogens for phagocytosis, cell recruitment during inflammation, and direct lysis of pathogens. First Hourcade (pages 158-164) describes a novel complement activation pathway and then Morrison and Heise (pages 165-172) address the role of the complement system in response to arbovirus infection. With the advances in genomics and proteomics seen over the last decade that have identified the critical genes and gene products in the immune system, it now falls to investigators to elucidate the relationships between these products and how together they form the system that recognizes the environment and responds appropriately. A philosophically inclined colleague of mine once suggested that the most interesting things in the universe were invisible. Perhaps this statement could apply to the still undefined (or invisible) relationships and cooperation among proteins and pathways that lead to effective immunity -- the elimination of dangerous non-self and clearance of dead or dying old self. As these molecular relationships become visible through research, we are led to ever more questions about the invisible, and that is precisely why we will continue to develop novel strategies and increasingly effective therapies to promote human health.