Preformed mediators of defense—Gatekeepers enter the spotlight

Abstract

2With every cut and bruise, every sore throat and runny nose, in all the numerous challenges our bodies face throughout life, our host defense systems spring into action and prevent escalation of the initial insults. They are essential for maintaining or re-establishing barrier function, for detecting and eliminating microbial intruders, and for restoring homeostasis. Higher species in particular, including humans, have developed elegant and efficient mechanisms that enable them to adapt to threats, raising a highly specific response and conferring immunological memory. Yet, the power of adaptive immunity may do little to protect us during a first encounter with new pathogens, and adaptive mechanisms need time to fully develop. For immediate and less discriminating activity against intruders and insults, our body, therefore, relies on host defense systems composed of preformed mediators that are readily available on cell surfaces and in the circulation. These first responders include pillars of innate immunity such as the complement, Toll-like receptor, and other pattern recognition systems; the cytokine network; the coagulation and contact systems; and antimicrobial peptides. Whereas many of these individual defense pathways have been known for a long time, it has become increasingly evident in recent years that they do not act in an isolated manner, but instead exert a high level of cooperativity and critically shape subsequent adaptive responses. Moreover, we now realize that the intrinsic ability to sense and react to non-self surfaces serves not only to eliminate pathogens but also contributes to other physiological surveillance functions, such as the clearance of cellular debris, tissue repair, and pruning during development. Even though the rapid and indiscriminate action of preformed defense mediators is carefully controlled under normal circumstances to prevent host-cell damage, these mechanisms sometimes become overwhelmed or misled, situations that may lead to a number of serious conditions (Figure 1).With an emphasis on the human complement system and its intricate connections to other mechanisms, this special issue of Immunological Reviews on "Preformed Mediators of Defense" highlights the new perception of first-line host defense systems in health and disease. Thanks to the insightful contributions by opinion leaders and emerging scientists in their fields, the reviews in this issue cover a broad spectrum of topics and perspectives, ranging from evolution-

The renaissance of complement therapeutics

“…Complement is a critical part of the host defence machinery that, together with the contact and coagulation systems and the various branches of innate and adaptive immunity, helps to maintain barrier functions and protect against microbial invasion after injury 11 . The role of complement is to detect, tag and eliminate microbial intruders with almost immediate reactivity but sufficient specificity to avoid damaging host cells 7,12 (FIG.…”

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

“…Innate and adaptive immunity, coagulation and contact systems, pattern recognition molecules (PRMs), and antimicrobial peptides all contribute their share to the generation of a forceful defense response. Preformed mediators of defense are a highly important part of this conglomerate; in contrast to adaptive immune responses, which are tailored to a specific pathogen and need time to develop, preformed mediator systems are available instantaneously and allow an immediate reaction to insults such as injury and infection . However, in view of their limited specificity, such first‐line‐of‐defense systems face a challenging task, given that they have to strike a balance between forceful defense against foreign particles and protection of host cells.…”

“…Indeed, replacement of one , and FI (2XRC) were used in PyMOL. For visualization purposes, the closed form of C3bB was generated by using FB from CVF-FB (3HS0), Ba was extracted from the FB structure, full-length FH was composed of five copies of FH [1][2][3][4], and a hypothetical iC3b model was prepared using the structures of C3d and C3c (2A74). The model of C3 bound to C3bBb was prepared as described in, 93 and the model of C3b-FH[1-4]-bound FI was created according to 107 additional contacts with the MG2 and CUB domains of C3b.…”

“…The N-terminal four domains of the soluble AP regulator FH exert both decay acceleration and CA. Crystallization of the C3b-FH [1][2][3][4] complex at 2.7-Å resolution therefore provided an important starting point for studying the molecular basis of these two major regulatory mechanisms. 92 The structure revealed that FH [1][2][3][4] ing mode suggests that all regulators have evolved from a common origin and that MCP and DAF have enhanced their respective functions at the cost of dual activity.…”

“…Crystallization of the C3b-FH [1][2][3][4] complex at 2.7-Å resolution therefore provided an important starting point for studying the molecular basis of these two major regulatory mechanisms. 92 The structure revealed that FH [1][2][3][4] ing mode suggests that all regulators have evolved from a common origin and that MCP and DAF have enhanced their respective functions at the cost of dual activity. 29 In addition to improving our understanding of the molecular mechanisms of complement regulation, these C3b-RCA structures have already become and will continue to be essential for deciphering the functional consequences of the diseaserelated mutations and polymorphisms of RCA proteins.…”