Complement System Dysregulation in Hemolytic Syndromes

The complement system is an intricate network of plasma proteins that defends against pathogens and clears cellular debris. Under normal conditions, activation proceeds through classical, lectin and alternative pathways, converging on the generation of C3 and C5 convertases, release of anaphylatoxins (C3a, C5a) and formation of the membrane attack complex (MAC). Inherited mutations or autoantibodies disrupting regulatory checkpoints can lead to uncontrolled complement activation, driving red-cell destruction, thrombocytopenia and organ injury. In atypical hemolytic uremic syndrome (aHUS), defects in regulators such as factor H, factor I or membrane cofactor protein promote microvascular endothelial damage and thrombotic microangiopathy. In paroxysmal nocturnal hemoglobinuria (PNH), somatic loss of glycosylphosphatidylinositol anchors renders red cells susceptible to terminal complement–mediated lysis. Emerging evidence highlights proximal pathway activation and intracellular complement activity as additional layers influencing haemolytic severity, and has spurred development of targeted inhibitors to limit both intravascular and extravascular haemolysis.

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Structural biology has provided fresh insight into regulation of the C5a receptor. High-resolution cryo-EM structures of the C5aR1–Gi complex bound to native ligand C5a and biased agonists have delineated key conformational changes in transmembrane domains and helix 8, clarifying how selective signalling through G proteins or β-arrestins may be achieved. Such information underpins rational design of receptor modulators aimed at dampening inflammatory sequelae of complement overactivation without globally suppressing innate defence.

A consensus conference on aHUS and C3 glomerulopathy convened experts to evaluate genetic and acquired drivers, renal pathology, clinical phenotype and treatment strategies. It identified the value of standardised assays for complement proteins and regulators, highlighted genotype–phenotype correlations, and endorsed complement blockade as first-line therapy. Remaining knowledge gaps include optimal duration of therapy, management of transplantation, and strategies to restore complement homeostasis in patients with incomplete response to C5 inhibition.

In paroxysmal nocturnal hemoglobinuria, a shift toward proximal complement inhibition has been proposed to overcome limitations of terminal blockade. Detailed analyses distinguish contributions of residual intravascular haemolysis from C3-mediated extravascular clearance of opsonised erythrocytes under anti-C5 therapy. Early-phase trials of factor D, factor B and C3 inhibitors, administered subcutaneously or orally, demonstrate potent suppression of haemolysis, improved transfusion independence and reduced markers of complement activation. These findings suggest combination or monotherapy regimens targeting initial pathway steps may offer superior disease control.

Complement System Dysregulation in Hemolytic Syndromes publication trend

The graph below shows the total number of articles in complement system dysregulation in hemolytic syndromes across all publications each year (not limited to Nature Index journals).

Technical terms

Alternative pathway: A complement activation route spontaneously triggered on microbial surfaces and amplified by properdin, generating C3 convertase without antibodies.

C3 convertase: An enzyme complex (C4b2a in classical/lectin, C3bBb in alternative) that cleaves C3 into effector fragments C3a and C3b.

Anaphylatoxin: Small complement peptides (C3a, C5a) that promote inflammation by recruiting and activating immune cells.

Membrane attack complex (MAC): Terminal assembly of C5b, C6–C9 that forms transmembrane pores, leading to target cell lysis.

Atypical hemolytic uremic syndrome (aHUS): A thrombotic microangiopathy caused by dysregulation of the alternative complement pathway, resulting in haemolysis and kidney injury.

Paroxysmal nocturnal hemoglobinuria (PNH): A clonal haematopoietic stem-cell disorder characterised by absence of GPI-anchored complement regulators on blood cells, causing complement-mediated haemolysis.

References

1. Mechanism of activation and biased signaling in complement receptor C5aR1. Cell Research (2023).
2. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney International (2016).
3. Complement System Part I – Molecular Mechanisms of Activation and Regulation. Frontiers in Immunology (2015).
4. Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation. Immunity (2013).
5. Atypical hemolytic uremic syndrome. Orphanet Journal of Rare Diseases (2011).
6. Anti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT. Frontiers in Immunology (2019).
7. The alternative complement pathway revisited. Journal of Cellular and Molecular Medicine (2008).