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Review
. 2023 Dec 27;14(1):39.
doi: 10.3390/biom14010039.

The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome

Piotr P Avdonin  1 , Maria S Blinova  1 , Galina A Generalova  2   3 , Khadizha M Emirova  2   3 , Pavel V Avdonin  1
Affiliations
Review

The Role of the Complement System in the Pathogenesis of Infectious Forms of Hemolytic Uremic Syndrome

Piotr P Avdonin et al. Biomolecules. .

Abstract

Hemolytic uremic syndrome (HUS) is an acute disease and the most common cause of childhood acute renal failure. HUS is characterized by a triad of symptoms: microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In most of the cases, HUS occurs as a result of infection caused by Shiga toxin-producing microbes: hemorrhagic Escherichia coli and Shigella dysenteriae type 1. They account for up to 90% of all cases of HUS. The remaining 10% of cases grouped under the general term atypical HUS represent a heterogeneous group of diseases with similar clinical signs. Emerging evidence suggests that in addition to E. coli and S. dysenteriae type 1, a variety of bacterial and viral infections can cause the development of HUS. In particular, infectious diseases act as the main cause of aHUS recurrence. The pathogenesis of most cases of atypical HUS is based on congenital or acquired defects of complement system. This review presents summarized data from recent studies, suggesting that complement dysregulation is a key pathogenetic factor in various types of infection-induced HUS. Separate links in the complement system are considered, the damage of which during bacterial and viral infections can lead to complement hyperactivation following by microvascular endothelial injury and development of acute renal failure.

Keywords: Escherichia coli; STEC-HUS; Shiga toxin; acute renal failure; complement system; eculizumab; endothelium; hemolytic anemia; hemolytic uremic syndrome; pathogenesis; thrombocytopenia; thrombotic microangiopathy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Complement activation pathways. The CP and LP are activated via antibody–antigen complexes or by sugar moieties on the surfaces of bacteria, respectively, whereupon C4b is surface deposited in a complex with C2b, forming the LP/CP C3 convertase (C4bC2b). The AP is constitutively activated by spontaneous thioester hydrolysis. Either the LP/CP or AP C3 convertase (C3bBb) may result in deposition of surface C3b [B] and generation of respective C5 convertases. C5b production triggers the assembly of the lytic membrane attack complex [A] by the addition of C6, C7, C8, and multiple C9 molecules. C3a and C5a, the smaller fragments, are referred to as anaphylatoxins. They mediate chemotaxis, inflammation and do not contribute to further downstream complement activation [C]. Under physiological conditions, complement activation is tightly controlled by the regulators of complement activation (FI, FH/FHL-1, CR1, CD59, C4BP, CD55, CI-INH).
Figure 2
Figure 2
The coagulation cascade and its regulators. Coagulation is initiated via the extrinsic or intrinsic pathway. The extrinsic pathway initiates by exposure of tissue factor (FIII) and assembly of the extrinsic tenase, leading to prothrombinase and ultimate thrombin (IIa) production. Thrombin (IIa) is responsible for direct fibrin clot formation, further stabilized by FXIIIa. The intrinsic pathway is initiated by FXII interacting with negatively charged surfaces, autoactivation, and via kallikrein. Activated FXIIa activates FXI (FXIa), which activates FIX (FIXa) that binds FVIIIa, forming the tenase complex, where the intrinsic pathway converges with the extrinsic pathway. There are many interactions between components within this complex system. For example, thrombin can activate FXIII, FV, and FVII. Activation of the coagulation system is finely balanced and controlled through specific regulatory mechanisms, including activity of proteins such as antithrombin (ATIII), activated protein C (APC), heparin cofactor II (HCII), and tissue factor pathway inhibitor (TFPI).
Figure 3
Figure 3
Complement and coagulation crosstalk. The complement and coagulation systems have common evolutionary origins. They exhibit several interactions that can affect activation, amplification and regulatory functions in both systems. Anaphylatoxins C3a and C5a, through their receptors, activate platelets sensitized to C3a and C5a, changing their adhesive properties and stimulating aggregation. Activated platelets secret FV, FVIII and FXI, fibrinogen, vWF, P-selectin, Pg, TFPI, PAI-1, PAF, PF4, as well as regulatory complement factors C1-INH, FH, CD55, CD59, CD46, FD, etc. Exposed P-selectin binds to its ligand C3b to ensure the assembly of alternative pathway C3 convertase. C5a triggers surface expression of TF by endothelial cells, monocytes, and neutrophils. Activated by C3a and C5a, endothelial cells express vWF, which can cause platelets aggregates formation. MASP2 protease, either alone or as part of the activated MBL-MASP2 and L-FCN-MASP2 complexes, is capable of stimulating fibrinogen metabolism and fibrin clot formation by cleaving prothrombin to form thrombin. Combined activity of thrombin and C5 convertase yielded C5a and C5b(T). C5b(T) forms the C5b(T)-9 complex with significantly higher lytic activity compared to C5b-9. Thrombin may also be able to enhance the C3 convertase assembly via activation of FD or, on the other hand, induce PAR1-mediated expression of complement decay accelerating factor (DAF), a membrane complement inhibitor.
Figure 4
Figure 4
Complement system activation in STEC-HUS and aHUS. (A)—C3 level in plasma of aHUS patients was lower than C3 level in plasma of STEC-HUS patients. (B)—C4 levels in plasma of STEC-HUS patients and aHUS patients were within normal limits and did not differ significantly from each other. (C)—sC5b-9 level was increased in plasma of STEC-HUS and aHUS compared to the norm. Results represent the mean  ±  standard error of the mean. (* p < 0.01 by independent-samples t-test).
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