Short analytical reviewThe complement system as a therapeutic target in autoimmunity
Introduction
The complement system is a central component of innate immunity [1] and is functionally linked to both the activation and regulatory as well as the effector arms of adaptive immunity [2], [3], [4], [5], [6]. Although the major function of complement has been thought to be recognition and elimination of pathogens through direct killing [7] or stimulation of phagocytosis [8], complement has also been shown more recently to play a central role in enhancing humoral immunity to T-dependent and T-independent foreign antigens (Ags) [6], [9], [10], [11], modifying cellular immunity [12] and regulating tolerance to certain self Ags [6], [13], [14], [15].
In addition to important roles in normal host responses to self and foreign Ags, the complement system is increasingly recognized to be causally involved in tissue injury during ischemic, inflammatory, and autoimmune diseases. Because of this, complement is an attractive therapeutic target for a wide range of diseases. In addition, the complement system may in some instances act relatively independently of other pro-inflammatory pathways, such as cytokines, which might allow for synergistic or additive therapeutic strategies with this increasingly used class of anti-inflammatory drugs [16]. In some disease settings, complement also exhibits activities in vivo that are independent of, or parallel to, Fc receptors, another important mediator of tissue injury [17], [18]. This article reviews the rationale for the use of therapeutic complement inhibitory strategies as well as the clinical and preclinical evidence supporting the use of complement modifying drugs in autoimmune diseases.
Section snippets
Complement activation mechanisms
Complement is activated by three mechanisms which, in toto, allow the system to respond to inflammatory, infectious, ischemic, or necrotic events as well as foreign and self-antigens (Ags) [5], [19], [20], [21] (Table 1). The first mechanism is the classical pathway, which is activated by IgM and certain IgG isotypes when they bind Ag (Fig. 1), resulting in increased affinity of the Fc domains for the first component of complement C1q [22]. Classical pathway components that are potential
Inhibition of complement activation pathway components as a therapeutic strategy
An attractive idea is to block the activation of soluble complement proteins, such as C3 and C5, or other individual members of the activation pathways. This strategy should allow for the effective blockade not only of the soluble protein that was targeted and receptors for its own activation fragments but also fragments resulting from activation of later proteins in the pathway and is in principle a more robust means of blocking many receptors simultaneously. A major target of this strategy is
Inhibition of complement receptors or the MAC as a therapeutic strategy
There are several complement receptors whose biologic roles strongly suggest that they would be appropriate therapeutic targets in autoimmune diseases. For example, activation of C3 by convertases assembled through any of the three pathways leads to cleavage of C3 with generation of the fragments C3a and C3b (Fig. 1). C3a is a small anaphylotoxin that binds to receptors on leukocytes and other cells, resulting in activation and release of soluble inflammatory mediators (reviewed in [76]). C3b
Examples of autoimmune diseases in which the complement system is a rational therapeutic target
Because many ways to block specific components of the complement system have become available over the last several years, and new tools such as gene-targeted mice have been developed, substantially more is known about the role of complement in the development of autoimmune diseases. This section will review experimental and human clinical studies which indicate that manipulation of complement system activities is a rational approach for the treatment of several types of autoimmune diseases.
Additional therapeutic strategies that modify complement activities
In addition to the inhibitory strategies outlined above, other strategies are either being utilized to modify complement activities or will be assessed in the near future. One strategy seeks to reverse the effects of complete complement deficiencies of classical pathway components that lead to autoimmune disease. The best example of this is the use of replacement doses of early classical pathway components, such as C2, in isolated patients with refractory disease [159]. Although this strategy
Conclusion
The complement system plays an important role in protection from infection with foreign pathogens and in the regulation of self-tolerance through clearance of apoptotic cells. In many inflammatory and autoimmune diseases, the injurious aspects of this system, which should be targeted to foreign pathogens, instead damages self-cells and tissues. This is true of both autoantibody- and cellular immune-mediated autoimmune diseases. The mechanisms of injury by complement are under study in many
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