Complementopathies

Abstract

The complement system is an essential part of the innate immune system that requires careful regulation to ensure responses are appropriately directed against harmful pathogens, while preventing collateral damage to normal host cells and tissues. While deficiency in some components of the complement pathway is associated with increased susceptibility to certain infections, it has also become clear that inappropriate activation of complement is an important contributor to human disease. A number of hematologic disorders are driven by complement, and these disorders may be termed "complementopathies". This includes paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), cold agglutinin disease (CAD) and other related disorders, which will be the focus of this review. A better understanding of the central role of the complement system in the pathophysiology of these disorders may allow for application of therapies directed at blocking the complement cascade.

Keywords: Alternative pathway of complement; Atypical hemolytic uremic syndrome; Cold agglutinin disease; Complementopathy; HELLP syndrome; Paroxysmal nocturnal hemoglobinuria.

Figure 1. Schematic of the complement cascade

The three primary routes for activation of complement are: (1) the lectin pathway (LP), (2) the classical pathway (CP), and (3) the alternative pathway (AP). The LP and CP are activated when specific triggers are recognized by host pattern-recognition receptors (PRRs). The AP is constitutively active. Initial activation through the LP or CP generates a shared C3 convertase (C4b•C2a). In the AP, C3b pairs with factor B (FB) to form the AP proconvertase (C3b•B), which is processed by factor D (FD) to form the AP C3 convertase (C3b•Bb). Both types of C3 convertases cleave C3 to generate C3a and C3b. C3a is an anaphylatoxin, a substance that promotes an inflammatory response. C3b that lands on the surface of a healthy host cell is quickly inactivated; C3b that attaches to the surface of a pathogen or altered host cell triggers a rapid amplification loop to generate more C3b, resulting in opsonization. C3b also complexes with the C3 convertases to form the C5 convertases (C4b•C2a•C3b and C3b•Bb•C3b). In the terminal complement cascade, C5 convertases cleave C5 into C5a (an anaphylatoxin) and C5b. C5b combines with C6–9 to form the membrane attack complex (MAC), also referred to as the terminal complement complex (TCC). Regulatory factors (Table 2) act at various stages of the cascade to control complement activation via their decay accelerating activity and/or cofactor activity. Additional abbreviations: PAMPs = pathogen-associated molecular patterns; MBL = mannose-binding lectin; MASPs = mannose-binding lectin-associated serine proteases.

Figure 2. Eculizumab and residual extravascular hemolysis in PNH

PNH erythrocytes lack the GPI-anchored complement regulatory proteins CD55 and CD59. CD55 inhibits the AP C3 convertase and CD59 inhibits formation of the membrane attack complex (MAC), also known as the terminal complement complex (TCC). Patients with PNH primarily manifest with chronic intravascular hemolysis mediated by terminal complement. Eculizumab, a humanized monoclonal antibody, inhibits terminal complement by binding to C5. This effectively corrects for the absence of CD59 and blocks intravascular hemolysis. However, up to 25% of patients PNH patients on eculizumab require continued red cell transfusions, likely due to the fact that PNH erythrocytes protected from intravascular hemolysis by eculizumab, are subject to opsonization by C3b (C3b is shown, but other C3 fragments can also bind to the red cells) and extravascular hemolysis due to absence of CD55.

Figure 3. Peripheral blood smear in aHUS

Characteristic peripheral blood smear in aHUS showing schistocytes (fragmented erythrocytes) and thrombocytopenia, typical of microangiopathic hemolytic anemia.

Figure 4. Mechanisms of alternative pathway of complement dysregulation in aHUS

(A) The AP is constitutively active. If C3b lands on the surface of a pathogen or damaged/altered host cell, the cascade proceeds with rapid amplification, resulting in opsonization by C3b, MAC assembly and generation of other inflammatory mediators. (B) If C3b lands on a healthy host cell, it is normally immediately inactivated by endogenous complement inhibitors. This includes CFH, which binds to the surface of host cells, displaces C3b and prevents formation of the C3 convertase (C3b•Bb). CFI, along with its cofactors, cleaves and inactivates C3b, preventing further downstream activation of the complement cascade and amplification loop. THBD enhances inactivation of C3b by CFH and CFI. CD46 indirectly inhibits assembly of C3 and C5 convertases by cleavage/inactivation of C3b and also serves as a cofactor for CFI. (C) In aHUS, mutations that cause loss-of-function of complement inhibitors (CFH, CFI, CD46 or THBD) or gain-of-function in complement activators (C3 or FB), lead to uncontrolled activation of complement on host surfaces, leading to damage to healthy cells and tissues.

Figure 4. Mechanisms of alternative pathway of complement dysregulation in aHUS

(A) The AP is constitutively active. If C3b lands on the surface of a pathogen or damaged/altered host cell, the cascade proceeds with rapid amplification, resulting in opsonization by C3b, MAC assembly and generation of other inflammatory mediators. (B) If C3b lands on a healthy host cell, it is normally immediately inactivated by endogenous complement inhibitors. This includes CFH, which binds to the surface of host cells, displaces C3b and prevents formation of the C3 convertase (C3b•Bb). CFI, along with its cofactors, cleaves and inactivates C3b, preventing further downstream activation of the complement cascade and amplification loop. THBD enhances inactivation of C3b by CFH and CFI. CD46 indirectly inhibits assembly of C3 and C5 convertases by cleavage/inactivation of C3b and also serves as a cofactor for CFI. (C) In aHUS, mutations that cause loss-of-function of complement inhibitors (CFH, CFI, CD46 or THBD) or gain-of-function in complement activators (C3 or FB), lead to uncontrolled activation of complement on host surfaces, leading to damage to healthy cells and tissues.

Figure 4. Mechanisms of alternative pathway of complement dysregulation in aHUS

(A) The AP is constitutively active. If C3b lands on the surface of a pathogen or damaged/altered host cell, the cascade proceeds with rapid amplification, resulting in opsonization by C3b, MAC assembly and generation of other inflammatory mediators. (B) If C3b lands on a healthy host cell, it is normally immediately inactivated by endogenous complement inhibitors. This includes CFH, which binds to the surface of host cells, displaces C3b and prevents formation of the C3 convertase (C3b•Bb). CFI, along with its cofactors, cleaves and inactivates C3b, preventing further downstream activation of the complement cascade and amplification loop. THBD enhances inactivation of C3b by CFH and CFI. CD46 indirectly inhibits assembly of C3 and C5 convertases by cleavage/inactivation of C3b and also serves as a cofactor for CFI. (C) In aHUS, mutations that cause loss-of-function of complement inhibitors (CFH, CFI, CD46 or THBD) or gain-of-function in complement activators (C3 or FB), lead to uncontrolled activation of complement on host surfaces, leading to damage to healthy cells and tissues.

Figure 5. Peripheral blood smear in CAD

Characteristic peripheral blood smear in CAD showing red blood cell agglutination.