Complement genetics, deficiencies, and disease associations

Abstract

The complement system is a key component of innate immunity. More than 45 genes encoding the proteins of complement components or their isotypes and subunits, receptors, and regulators have been discovered. These genes are distributed throughout different chromosomes, with 19 genes comprising three significant complement gene clusters in the human genome. Genetic deficiency of any early component of the classical pathway (C1q, C1r/s, C2, C4, and C3) is associated with autoimmune diseases due to the failure of clearance of immune complexes (IC) and apoptotic materials, and the impairment of normal humoral response. Deficiencies of mannan-binding lectin (MBL) and the early components of the alternative (factor D, properdin) and terminal pathways (from C3 onward components: C5, C6, C7, C8, C9) increase susceptibility to infections and their recurrence. While the association of MBL deficiency with a number of autoimmune and infectious disorders has been well established, the effects of the deficiency of other lectin pathway components (ficolins, MASPs) have been less extensively investigated due to our incomplete knowledge of the genetic background of such deficiencies and the functional activity of those components. For complement regulators and receptors, the consequences of their genetic deficiency vary depending on their specific involvement in the regulatory or signalling steps within the complement cascade and beyond. This article reviews current knowledge and concepts about the genetic load of complement component deficiencies and their association with diseases. An integrative presentation of genetic data with the latest updates provides a background to further investigations of the disease association investigations of the complement system from the perspective of systems biology and systems genetics.

Kallikrein Cleaves C3 and Activates Complement

“…Activation of both of these systems (contact and complement) causes signs and symptoms often seen in those with septic shock and hereditary angioedema. Hereditary angioedema is a condition caused by a deficiency or defect in the C1 inhibitor [33,34]. Similar to kallikrein, FXII can activate C1 of the classical pathway [35] and factor B of the alternative pathway [14].…”

Cervicovaginal microbiome dysbiosis is associated with proteome changes related to alterations of the cervicovaginal mucosal barrier

“…Minor modifications were made to GO-term GO:0030414 (excluding complement factor 3 and serpin B5), and GO:0005856 (excluding proteasome subunit beta type-3), because the functions of the excluded proteins are better described by other terms according to the published literature. [53][54][55] An annotated heatmap was drawn using the ''Heatplus'' package in R and hierarchical clustering with Euclidean distance and complete linkage was performed on the range-scaled ion intensities of the differentially abundant proteins.…”

Déficit en fraction terminale du complément révélé dès le premier épisode d’infection invasive à méningocoque

“…Une vaccination avec un vaccin tétravalent conjugué aurait due être proposée à toute la famille du cas décrit [6]. Le risque de développer une IIM est beaucoup plus élevé (jusque 6000 fois) chez les sujets déficitaires en protéine de la fraction terminale du complé-ment C5 à C9, comme cela a été rapporté à plusieurs reprises [2][3][4]. S'ajoute à la gravité du diagnostic, la possibilité de traitements préventifs qui justifie la nécessité d'un dépistage systématique d'un déficit en protéine du complément.…”

“…Nm exprime également plusieurs protéines liant spécifique-ment le facteur H humain qui lui-même inhibe spécifique-ment la voie alterne. Ainsi, les déficits de la voie finale et en properdine exposent les patients à un risque majoré 6000 fois d'infections invasives à méningocoque (IIM) par rapport à la population générale [2][3][4]. Ces déficits en protéines du complément sont rares (une prévalence estimée entre 0,03 et 0,1 %) alors que les IIM représentent un fléau mondial dont les formes les plus fulminantes peuvent rapidement engager le pronostic vital des patients [2].…”