The non-classical functions of the classical complement pathway recognition subcomponent C1q

Abstract

C1q, the ligand recognition subcomponent of the classical complement pathway has steadily been gaining recognition as a bridge between innate and adaptive immunity. C1q has been shown to be involved in the modulation of various immune cells (such as dendritic cells, platelets, microglia cells and lymphocytes), clearance of apoptotic cells, a range of cell processes such as differentiation, chemotaxis, aggregation and adhesion, and pathogenesis of neurodegenerative diseases and systemic lupus erythematosus. Recent studies have highlighted the importance of C1q during pregnancy, coagulation process and embryonic development including neurological synapse function. It is intriguing to note that a prototypical defence molecule has so many diverse functions that probably have its origin in its versatility as a potent charge pattern recognition molecule, modularity within the ligand-recognising globular domain, and the redundancy of putative C1q receptors. The range of function that C1q has been shown to perform also provides clues for the undiscovered functions of a number of C1q family members.

Introduction

The human defence system, comprising of two important processes namely innate immunity and acquired immunity, very efficiently thwarts the numerous threats from pathogens received by the body every single day. Out of the two arms of the immunity, the innate immune system is the most phylogenetically ancient and rapid acting component of host defence against the pathogens. The complement system is a major effector system of this ancient immune response. The importance of complement is mirrored by the fact that the soluble proteins of this system makes up approximately 5% of the total protein content of human blood plasma [1]. The mammalian complement system plays a major role in innate and adaptive immunity. The activation of the complement system takes place through three pathways: the classical complement pathway of which C1q is the main recognition component; the lectin pathway that consists of mannose binding protein as its key recognition component, and the alternative pathway that has C3 as its main key recognition component. [1]. The aim of all three pathways is to activate the central component of the complement system, i.e. the C3 component. The classical pathway of complement activation involves a sequentially acting multistep cascade in which the complement components C1q, C1s, C1r, C4, C2 and C3 play very important roles [2]. C1 is the first component of the classical pathway, comprised of three subcomponents namely C1q, C1r and C1s that associate together in a calcium-dependent macromolecular complex. The activation process is initiated by conformational changes within the collagen region of the C1q molecule induced upon binding of C1q to a wide range of non-self and altered acceptor molecules (Table 1). This conformational change leads to the activation of C1r which in turn activates C1s, which are both serine protease proenzymes, thus leading to the initiation of the classical complement pathway. The activation of the C1 complex consequently leads to the activation of the C2–C9 components of the classical pathway and also aids in the formation of the terminal membrane attack complex (MAC) [3], which can generate pores within the outer membrane of the pathogens and thus cause lysis of the membrane.

C1q is predominantly synthesized by myeloid cells, especially tissue macrophages and cultured monocytes along with dendritic cells (DCs) [4]. It circulates in the blood of normal healthy individuals at a concentration of approximately 150 μg/ml within C1, a calcium-dependent trimolecular complex composed of equimolar ratios of C1q:C1r:C1s [5]. Approximately 10% of this total physiological concentration is circulating free C1q and is limited to peripheral tissues [6]. C1q is known to bind to an array of ligands, both self and non-self, through its C-terminal, heterotrimeric globular (gC1q) domain (Table 1). It is by this binding that it triggers the classical complement pathway eventually culminating in to MAC formation.