The complement alternative pathway in health and disease—activation or amplification?

Targeted genotyping of COVID-19 patients reveals a signature of complement C3 and factor B coding SNPs associated with severe infection

“…Despite the surge in volume of published studies and the significant advances carried out towards the exploration of the molecular basis of pathophysiology, it has been a challenging task to identify potential cornerstones that can rationally explain the population wide impact of the infection on an individual basis. In this study, we stepped on our recent findings ( Gavriilaki et al, 2021 ) and observations ( Tsiftsoglou, 2021 ) and attempted to decipher the patterns and distributions of SNPs encoding amino acid substitutions in Complement components historically associated with the mechanics of the Alternative pathway (AP) ( Sim et al, 2016 )( Liszewski and Atkinson, 2022 )( Harrison et al, 2022 ).…”

“…Some of the encoded amino acid substitutions ( Table 2 ) may alter the functional properties of the encoded Complement components directly or in surface complex formations. Such changes may influence the activation threshold dynamics of the Alternative pathway (AP) and to a further extent the clinical outcome of the infection ( Harrison et al, 2022 ).…”

Heme Interactions as Regulators of the Alternative Pathway Complement Responses and Implications for Heme-Associated Pathologies

“…This effort expands on earlier findings and observations describing interactions of heme with specific complement components [ 51 , 54 , 55 ], and attempts to bridge them with the involvement of complement in inflammation and hemostasis at sites of abnormal cellular damage and vascular injury. As the biochemistry of complement components has been intensely investigated for decades and the majority of its structures have now been solved in high resolution [ 106 , 107 ], this computational evaluation aimed to explore the interactions of heme with all known APCCs, determine their impact in the AP as a system unit [ 88 , 89 ], and eventually uncover potential sources of genetic and epigenetic variability among individuals.…”

“…The AP has recently attracted renewed interest due to its multidimensional involvement in important immune [ 88 , 89 , 90 ] and hemostatic processes [ 74 ]. Interestingly and in terms of the competing biochemical dynamics between the CP and AP, recent data have suggested that the contribution of the AP in complement activation on cell surfaces depends on the strength of CP initiation [ 91 ].…”

“…In such an asynchronous setting, C3a becomes dominant over C5a, as the main complement anaphylatoxin released locally and in circulation (C3a > > > C5a). The AP has multidimensional involvement in important immune [ 88 , 89 , 90 ] and hemostatic responses and associated processes [ 74 ]. Figure 1 is adapted from [ 97 ] with minor modifications.…”