ReviewTargeting the complement system in systemic lupus erythematosus and other diseases
Introduction
The complement system as a potential therapeutic target has long been acknowledged, though unraveling its complex, and often divergent effects, has been quite challenging (Fig. 1). When left unregulated, the complement system can result in widespread tissue damage. Indeed, systemic complement activation, with complement fragment generation, local deposition and ensuing inflammation, is the pathologic hallmark of systemic lupus erythematosus (SLE). Paradoxically, genetic deficiencies in the classical components of complement are directly linked to the development of SLE and highlight the importance of this pathway in facilitating apoptotic cell and immune complex clearance [1]. It has become increasingly recognized that complement is not only a vital component of the innate immune system, but it also modulates the adaptive immune response [2] through modification of T cell immunity [3], development of natural antibodies [4], and regulation of autoreactive B-cells [5].
Activation of the complement system can occur through one of three pathways [6]. Initiation of classical pathway activation most notably occurs through interactions between C1q and IgM or IgG. Other triggers include C-reactive protein, endothelial neoepitopes in ischemic tissue, apoptotic bodies, and serum amyloid P [7]. Deficiencies in C1q, C4 and C2 are most consistently linked with autoimmune rheumatic illnesses in both murine models and in man [6], [8], highlighting this pathway's beneficial contribution to regulation of apoptotic cell clearance, the humoral immune system and autoreactive B-cells.
The lectin pathway is activated by the interaction of mannose binding lectin (MBL) to repeating carbohydrate residues on infectious agents. This interaction leads to a classical pathway-like series of cleavage steps of MBL-associated serine proteases (MASP-1, MASP-2 and MASP-3) followed by complement pathway assembly [6]. Deficiencies are associated with both infections [9] and SLE [10].
The third activation pathway is the alternative pathway. Activation of the alternative pathway does not require prior exposure to an antigen. Deposition of cleaved C3 results in amplification of the immune response on the cell surface [7]. Deficiencies of C3 have been linked with infections. Data from C3−/− mice do not indicate a phenotype different from controls, in terms of autoimmunity [11], [12]. However, subsequent support of the alternative pathway in the development of lupus was made with the finding of protection against renal disease in fB−/− MRL/lpr mice [13]. Damage presumably occurs from immune complex processing errors in the C3−/− model and subsequent non-complement-mediated damage [12]. This demonstrates the fine balance between the beneficial effects of immune complex handling and the inflammatory damage of unregulated complement activation [7].
Knowledge gained from murine models has provided greater insights into the relative contributions of each arm of the complement system to host defense and inflammation. Furthermore, the recent approval of eculizumab, an anti-C5 monoclonal antibody, has led to renewed interest in these agents for the treatment of SLE as well as other inflammatory diseases. We next review the experience with complement inhibitors in murine models of SLE.
Section snippets
Pre-clinical models
One of the earliest therapeutic targets examined was C5 [14] (Table 1). Cleavage of C5 following complement activation results in the formation of both C5a, a potent anaphylatoxin, and the lytic terminal complement membrane attack complex, C5–9. The effect of blocking terminal complement activation through the direct inhibition of C5 was examined in NZB/W F1 mice. Although this strain spontaneously develops an autoimmune syndrome marked by high titer antinuclear antibodies and
Conclusions
Although the human clinical experience with complement inhibitors in the rheumatic diseases has been scant, their use in SLE appears scientifically justified. Candidate molecules are plentiful, but selection of a specific target could be confounded by safety concerns. While a reduction in disease activity and prevention of tissue damage are the ultimate goals of therapy, these favorable outcomes must be balanced by a preservation of immune clearance mechanisms and lack of infectious
Conflict of interest statement
The author(s) declare that there are no conflicts of interest.
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