Antigenic determinants expressed by human C4 allotypes; a study of 325 families provides evidence for the structural antigenic model

Giles, Carolyn M.; Uring‐Lambert, B.; Goetz, Joëlle; Hauptmann, G.; Fielder, A. H. L.; Ollier, William; Rittner, Christian; Robson, Tracy

doi:10.1007/bf00364431

Cited by 51 publications

(35 citation statements)

References 25 publications

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“…The apparently anomalous levels of C4 found in seven members of this family (Table 1} illustrates ihe subtle difference between isotypic and serotypic identity and points to one source of spurious variability in studies of this type. Such alleles are uncommon, occurring in only one of 325 selected families studied by Giles et al [34], ihough similar findings were made by Holme and colleagues [5] in a family carrying a C4B*5 allele and the opposite effect was noted wilh a C4A*I molecule.…”

Section: Discussionsupporting

confidence: 67%

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B

Hammond

Ollier

Walport

1992

Clinical and Experimental Immunology

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SUMMARYThe availability of MoAbs now allows the accurate quantification of the individual C4 isotypes, C4A and C4B. Using a sensitive two-site immunoradiometric technique to measure serum levels of C4A and C4B, we studied the relationship between genotype and phenotype and physiological factors affecting C4 expression in 129 fully gcnotyped healthy subjects. Our results confirm that there is extensive phenotypic overlap between genotypic groups and it was not possible to determine the presenee of single null alleles from total serum C4. Of the factors which may influence C4 expression, we found that age conttibutes a very small influence but that gender has no effect and there was no evidence for the presence of feedback of null alleles on the expression of remaining genes. Potential problems in quantifying C4 arising from the complex relationship between isotypic identity and serotypic recognition were highlighted by ihe finding of reversed antigenic expression ofa C4B*5 molecule which was recognized as C4A by the anti-Rg:

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Section: Discussionsupporting

confidence: 67%

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B

Hammond

Ollier

Walport

1992

Clinical and Experimental Immunology

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“…These alloantibodies can agglutinate the recipient red blood cells containing covalently-bound C4b or C4d fragments. Such observations led to the discovery of the Chido and the Rodgers blood groups (Middleton and Crookston, 1972;Longster and Giles, 1976;Giles et al, 1988). Anti-Chido antibodies were generated in recipients with C4B deficiency, and anti-Rodgers antibodies were generated in recipients with C4A deficiency.…”

Section: Rodgers (Rg) and Chido (Ch) Blood Group Antigensmentioning

confidence: 99%

Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement <i>C4</i> CNVs in European American healthy subjects and those with systemic lupus erythematosus

Wu¹,

Yang²,

Chung³

et al. 2008

Cytogenet Genome Res

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A new paradigm in human genetics is high frequencies of inter-individual variations in copy numbers of specific genomic DNA segments. Such common copy number variation (CNV) loci often contain genes engaged in host-environment interaction including those involved in immune effector functions. DNA sequences within a CNV locus often share a high degree of identity but beneficial or deleterious polymorphic variants are present among different individuals. Thus, common gene CNVs can contribute, both qualitatively and quantitatively, to a spectrum of phenotypic variants. In this review we describe the phenotypic and genotypic diversities of complement C4 created by copy number variations of RCCX modules (RP-C4-CYP21-TNX) and size dichotomy of C4 genes. A direct outcome of C4 CNV is the generation of two classes of polymorphic proteins, C4A and C4B, with differential chemical reactivities towards peptide or carbohydrate antigens, and a range of C4 plasma protein concentrations (from 15 to 70 mg/dl) among healthy subjects. Deliberate molecular genetic studies enabled development of definitive techniques to determine exact patterns of RCCX modular variations, copy numbers of long and short C4A and C4B genes by Southern blot analyses or by real-time quantitative PCR. It is found that in healthy European Americans, the total C4 gene copy number per diploid genome ranges from 2 to 6: 60.8% of people with four copies of C4 genes, 27.2% with less than four copies, and 12% with more than four copies. Such a distribution is skewed towards the low copy number side in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease with complex etiology. In SLE, the frequency of individuals with less than four copies of C4 is significantly increased (42.2%), while the frequency of those with more than four copies is decreased (6%). This decrease in total C4 gene copy number in SLE is due to increases in homozygous and heterozygous deficiencies of C4A but not C4B. Therefore, it is concluded that lower copy number of C4 is a risk factor for and higher gene copy number of C4 is a protective factor against SLE disease susceptibility.

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“…This has been demonstrated by the presence of the C4A-associated amino acid residues in many C4B allotypes, and vice versa. The typical examples are the reverse associations of Ch1 antigenic determinant with C4A1 and C4A13 and of Rg1 antigenic determinant with C4B5 (22,61,62). It was also shown that in a systemic lupus erythematosus patient, there is an acquisition of a 2-bp insertion in exon 29 from C4AQ0 to C4BQ0 (63,64).…”

Section: Discussionmentioning

confidence: 99%

Modular Variations of the Human Major Histocompatibility Complex Class III Genes for Serine/Threonine Kinase RP, Complement Component C4, Steroid 21-Hydroxylase CYP21, and Tenascin TNX (the RCCX Module)

Yang¹,

Mendoza²,

Welch³

et al. 1999

Journal of Biological Chemistry

155

149

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The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module. Duplications of the RCCX modules occurred by the addition of genomic fragments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2. Four major RCCX structures with bimodular L-L, bimodular L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome.Besides the immunoglobulins, complement component C4 is probably the most polymorphic serum protein. There are two isotypes, C4A and C4B, that manifest remarkable differences in chemical reactivities and serological properties (reviewed in Ref. 1). More than 34 allotypes for C4A and C4B have been demonstrated by agarose gel electrophoresis, based on gross differences in electric charge (2). Similar to the protein, the complement C4 genes are unusually complex with frequent variations in gene size and gene number. In addition, the genes surrounding C4A or C4B also exhibit considerable variations. These neighboring genes include RP1 or RP2 at the 5Ј region, CYP21A, or CYP21B and TNXA or TNXB at the 3Ј region ( Fig.

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Antigenic determinants expressed by human C4 allotypes; a study of 325 families provides evidence for the structural antigenic model

Cited by 51 publications

References 25 publications

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B

Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement <i>C4</i> CNVs in European American healthy subjects and those with systemic lupus erythematosus

Modular Variations of the Human Major Histocompatibility Complex Class III Genes for Serine/Threonine Kinase RP, Complement Component C4, Steroid 21-Hydroxylase CYP21, and Tenascin TNX (the RCCX Module)

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