Alternative Complement Pathway Deregulation Is Correlated with Dengue Severity

Abstract

BackgroundThe complement system, a key component that links the innate and adaptive immune responses, has three pathways: the classical, lectin, and alternative pathways. In the present study, we have analyzed the levels of various complement components in blood samples from dengue fever (DF) and dengue hemorrhagic fever (DHF) patients and found that the level of complement activation is associated with disease severity.Methods and ResultsPatients with DHF had lower levels of complement factor 3 (C3; p = 0.002) and increased levels of C3a, C4a and C5a (p<0.0001) when compared to those with the less severe form, DF. There were no significant differences between DF and DHF patients in the levels of C1q, immunocomplexes (CIC-CIq) and CRP. However, small but statistically significant differences were detected in the levels of MBL. In contrast, the levels of two regulatory proteins of the alternative pathway varied widely between DF and DHF patients: DHF patients had higher levels of factor D (p = 0.01), which cleaves factor B to yield the active (C3bBb) C3 convertase, and lower levels of factor H (p = 0.03), which inactivates the (C3bBb) C3 convertase, than did DF patients. When we considered the levels of factors D and H together as an indicator of (C3bBb) C3 convertase regulation, we found that the plasma levels of these regulatory proteins in DHF patients favored the formation of the (C3bBb) C3 convertase, whereas its formation was inhibited in DF patients (p<0.0001).ConclusionThe data suggest that an imbalance in the levels of regulatory factors D and H is associated with an abnormal regulation of complement activity in DHF patients.

Incomplete penetrance of CD46 mutation causing familial atypical hemolytic uremic syndrome

“…However, the occurrence of thrombocytopenia, hemolysis, and acute kidney injury after resolution of the acute illness and presence of normal prothrombin time favors the diagnosis of HUS. Although pathogenesis of dengue involves activation of the classical complement pathway, alternative complement pathway dysregulation is also reported, as evidenced by transient depletion of CFH during the acute phase in patients with severe dengue relative to mild disease [18]. We speculate that unregulated [13] and E. coli O157:H7 [14] b post-transplant recurrence was attributed to endothelial microchimerism in this patient activation of alternative complement pathway due to CD46 deficiency might lead to severe dengue infection with circulatory compromise, acute kidney injury, and thrombotic microangiopathy.…”

Down-Regulation of Complement Receptors on the Surface of Host Monocyte Even as In Vitro Complement Pathway Blocking Interferes in Dengue Infection

“…Early clinical studies demonstrated that DENV-infected patients, especially those with severe DF, show reduced levels of C3, C4 and factor B, together with increased catabolic rates of C3a and C1q [32], [33]. In addition, it has been reported that C3 degradation products and anaphylatoxins accumulate in the circulation of severely ill patients and peak on the day of maximum vascular leakage [34], [35].…”

A Physical Interaction Network of Dengue Virus and Human Proteins

“…DENV proteins inhibit complement activation (94). In addition, the levels of complement proteins, including C4, were altered in patients with severe DENV disease (95).…”