Alternative pathway diagnostics

Abstract

Although the alternative pathway (AP) was first described by Pillemer in 1954, 1 the last 20 years have seen an explosion in our understanding of this arm of the complement cascade. 2,3 It is now clear that uncontrolled AP activation is the primary driver of several diseases, and it contributes to the pathogenesis of many others.These discoveries have spurred the development of new therapies that specifically target this activation pathway. [4][5][6][7] Moreover, several complement proteins are unique to the AP, providing biomarkers of AP activation. In addition, multiple different defects in AP proteins (mutations, autoantibodies, endogenous antagonists) are risk factors for disease, and identification of these molecular causes of AP dysregulation provides important prognostic and mechanistic information. | THE IMP ORTAN CE OF AP DIAG NOS TIC SThe complement system provides a useful source of biomarkers that can aid clinicians in diagnosing AP-mediated diseases and monitoring target coverage in patients treated with complement inhibitory drugs. In clinical trials, complement biomarkers can help in patient stratification and in monitoring target engagement. Complement activation fragments are soluble and can be easily measured in plasma

An ex vivo test to investigate genetic factors conferring susceptibility to atypical haemolytic uremic syndrome

“…Nevertheless, some particularities of complement genes should be considered, including the high sequence homology between CFH and CFHRs genes ( 9 ), and additional techniques, such as MLPA, are often required to correctly identify the generation of structural variations in the Regulators of Complement Activation (RCA) gene cluster ( 27 ). Among the variants identified through genetic analyses in aHUS patients, only a subgroup can be defined as pathogenic with certainty, based on either published functional studies or a clear-cut effect on transcription/translation ( 9 , 28 ). But we do not know the functional significance of a large majority of variants.…”

“…But we do not know the functional significance of a large majority of variants. This is an important issue, because knowing the real functional impact of gene variants is crucial to better understanding the pathogenesis of aHUS in each patient and can help confirm a diagnosis, guide patient management, inform prognosis, and reduce the need for invasive procedures ( 8 , 9 , 28 , 29 ).…”

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

“…In concept, such small-molecule heme neutralizers could be utilized alongside selected AP complement inhibitors aimed at C3 [ 117 , 118 , 119 ], CFB and CFD [ 120 , 121 , 122 ], as well as potentially other APCCs [ 75 ]. Therefore, various potential therapeutic schemes could be custom designed to stabilize disease progression and potentially ameliorate some heme-associated clinical phenotypes ( Table 1 and Table 2 ), if applied relatively early in individuals diagnosed with a predisposition to AP deregulation [ 123 ].…”

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

“…The necessity for reliable and accurate assays for defining complement involvement in disease should not be underestimated—without them there is always the danger that patients will be inappropriately treated, and that treatment outcomes might be misinterpreted. Thurman and Fremeaux‐Bacci 37 give a comprehensive overview of today's armamentarium of AP/AL relevant assays.…”