Immunobiology of the Complement System

An Introduction for Research and Clinical Medicine

Gordon D. Ross

• Publisher: Academic Press
• Year: 2014
• ISBN:
  9781483276397
• Topic: Medicine
• Subtopic: Clinical Medicine

Immunobiology of the Complement System: An Introduction for Research and Clinical Medicine provides an introduction to the complement system. The intention was to create a primer that would provide the basic knowledge of complement required for either research or clinical medicine in diseases involving the complement system. The book begins with a historical background of complement research; it introduces certain key investigators from the past who have made important contributions. Separate chapters on the basic aspects of complement function are followed by chapters on the molecular genetics of complement and the role of complement in different diseases. Key topics discussed include the activation of complement via the classical pathway and the alternative pathway; complement mediators of inflammation; opsonization and membrane complement receptors; assembly and functions of the terminal components; and complement-dependent mechanisms of virus neutralization. This book has been written primarily for students and scientists who have not been specifically trained in complement research.

1

The Classical Pathway

NEVIN C. HUGHES-JONES, Mechanisms in Tumour Immunity Unit, Medical Research Council Centre, Cambridge, England CB2 2QH

Publisher Summary

This chapter describes the classical pathway of the complement system. Two distinct pathways lead to the deposition of C3, namely, the classical and alternative pathways; however, there are similarities in both the structure and function of the proteins involved in each, suggesting that the pathways arose by gene duplication from a common ancestral mechanism. The classical pathway consists of five molecules (C1, C2, C3, C4, and C5), all present in the plasma in an inactive form. C3 is also a component of the alternative pathway and C5 is a part of the terminal component pathway that leads to formation of the membrane attack complex. The C2, C3, C4, and C5 components are present as single molecules, but the C1 component is made up of three noncovalently linked subcomponents: Clq, Clr, and Cls. The activation process consists of the enzymic splitting of the components, the Clr, Cls, and C2 components becoming functional serine proteases, while the activated C3 and C4 molecules are structural components capable of binding covalently to immune complexes and cell surfaces. The chapter discusses the sequence extending from activation of the first component of the classical pathway, C1, up to the splitting of C5, which initiates the formation of the membrane attack complex. Although the classical pathway can be activated by many different factors, for the purpose of simplicity, the discussion is confined almost entirely to the activation of complement through the agency of antibody combined to red cells, the main system used for most of the knowledge concerning the cascade.

I INTRODUCTION

The primary function of the complement system may be broadly defined as the destruction of both foreign organisms and immune complexes. This functional activity is carried out by two mechanisms: 1) coating the particles with the proteins C3 and C4, which results in particle phagocytosis through combination of the C3 and C4 coating with the C3/C4 receptors on macrophages (see Chapter 4); and 2) the lysing of organisms through insertion of a structure composed of polymerized C9 molecules (the membrane attack complex) into cell membranes. This structure has a central “hole” which allows the free entry of water and salt into the cell’s interior, with the subsequent expansion of the internal volume and rupture of the lipid membrane (see Chapter 5). Two distinct pathways lead to the deposition of C3—namely, the “classical” and “alternative” pathways—but there are similarities in both the structure and function of the proteins involved in each, suggesting that the pathways arose by gene duplication from a common ancestral mechanism.

The classical pathway consists of five molecules (C1, C2, C3, C4, and C5), all present in the plasma in an inactive form. C3 is also a component of the alternative pathway, and C5 is part of the terminal component pathway that leads to formation of the membrane attack complex. The C2, C3, C4, and C5 components are present as single molecules, but the C1 component is made up of three noncovalently linked subcomponents: C1q, C1r, and C1s. Unfortunately the components were named before their functional properties were completely elucidated, and it was ultimately found that C4 was misplaced in the sequence of activation, the order being C1, C4, C2, C3, and C5, as shown in Fig. 1. The activation process consists of the enzymic splittingof the components, the C1r, C1s, and C2 components becoming functional serine proteases, while the activated C3 and C4 molecules are structural components capable of binding covalently to immune complexes and cell surfaces. This chapter is confined to a discussion of the sequence extending from activation of the first component of the classical pathway, C1, up to the splitting of C5 which initiates the formation of the membrane attack complex. Although the classical pathway can be activated by many different factors (e.g., antigen–antibody complexes, polyionic compounds, certain bacteria and viruses, mitochondria, myelin), for the purpose of simplicity the discussion here is confined almost entirely to the activation of complement through the agency of antibody combined to red cells, the ma...