Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity.

Abstract

The human complement components C4A and C4B are highly homologous proteins, but they show markedly different, class‐specific, chemical reactivities. They also differ serologically in that C4A generally expresses the Rodgers (Rg) blood group antigens while C4B generally expresses the Chido (Ch) blood group antigens. C4A 1 and C4B 5 are exceptional variants which possess their class‐specific chemical reactivities, but express essentially the reversed antigenicities. The genes encoding the typical Rg‐positive C4A 3a and Ch‐positive C4B 3 allotypes and the interesting variants C4A 1 and C4B 5 have been cloned. Characterization of the cloned DNA has revealed that the genes encoding the A 3a, A 1 and B 3 allotypes are 22 kb long, but that encoding B 5 is only 16 kb long. Comparison of derived amino acid sequences of the polymorphic C4d fragment has shown that C4A and C4B can be defined by only four isotypic amino acid differences at position 1101‐1106. Over this region C4A has the sequence PCPVLD while C4B has the sequence LSPVIH, and this presumably is the cause of their different chemical reactivities. Moreover, the probable locations of the two Rg and the six Ch antigenic determinants have been deduced. Our structural data on the C4A and C4B polymorphism pattern suggests a gene conversion‐like mechanism is operating in mixing the generally discrete serological phenotypes between C4A and C4B.

Reticulocytes bearing C4d as biomarkers of disease activity for systemic lupus erythematosus

“…In humans, C4 exists in 2 isoforms, C4A and C4B, which are encoded by 2 highly homologous (Ͼ99%) genes (29)(30)(31). Both isoforms exhibit further polymorphism at the protein and DNA levels, with Ͼ40 alleles (including null alleles) identified to date (29)(30)(31)(32).…”

“…In humans, C4 exists in 2 isoforms, C4A and C4B, which are encoded by 2 highly homologous (Ͼ99%) genes (29)(30)(31). Both isoforms exhibit further polymorphism at the protein and DNA levels, with Ͼ40 alleles (including null alleles) identified to date (29)(30)(31)(32). Despite their striking sequence identity, C4A and C4B differ significantly in their functional features with regard to the expression of antigenic determinants, reactivity of the thioester site, hemolytic activity, and ability to bind/solubilize immune complexes (31)(32)(33)(34)(35).…”

“…Both isoforms exhibit further polymorphism at the protein and DNA levels, with Ͼ40 alleles (including null alleles) identified to date (29)(30)(31)(32). Despite their striking sequence identity, C4A and C4B differ significantly in their functional features with regard to the expression of antigenic determinants, reactivity of the thioester site, hemolytic activity, and ability to bind/solubilize immune complexes (31)(32)(33)(34)(35). The activated thioester in C4A reacts predominantly with amino group-containing substrate and binds efficiently to immune complexes, whereas the activated thioester in C4B reacts preferentially with hydroxyl groups on carbohydrate substrates and binds effectively to erythrocytes (31)(32)(33)(34)(35).…”

“…Despite their striking sequence identity, C4A and C4B differ significantly in their functional features with regard to the expression of antigenic determinants, reactivity of the thioester site, hemolytic activity, and ability to bind/solubilize immune complexes (31)(32)(33)(34)(35). The activated thioester in C4A reacts predominantly with amino group-containing substrate and binds efficiently to immune complexes, whereas the activated thioester in C4B reacts preferentially with hydroxyl groups on carbohydrate substrates and binds effectively to erythrocytes (31)(32)(33)(34)(35). However, it should be noted that 2 erythrocyte blood group antigens, Rodgers and Chido, have been shown to correspond to the C4d region of C4A and C4B, respectively (16,28), suggesting that both C4A and C4B can bind to and persist on the surface membranes of normal erythrocytes.…”

Sequence analysis of the mannose-binding lectin (MBL2) gene reveals a high degree of heterozygosity with evidence of selection

“…88 The human C4A and C4B genes are highly polymorphic and the patchwork allelic structure has also been attributed to conversion tracts. 89,90 Gene conversion can lead to homogenization, as shown in the example of CYP21 and its pseudogene CYP21P, 91 and in the introns of some HLA genes. 92 As with the HLA locus, the detection of possible gene conversion events could imply functional consequences of past selective pressure on segments of MBL2.…”