Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the CM4 locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BFloci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.An accurate description of the genetics of the fourth component of complement (C4) is important because the C4 genetic loci appear to be closely linked to the major histocompatibility complex (MHC) in man. This is particularly true if genetic loci for immune responsiveness in man are in this region and if variants of the latter loci are determinants of human disease. A number of diseases show striking linkage disequilibrium with specific HLA types (1), and recent evidence strongly suggests that BF (the locus for factor B of the alternative complement pathway in the MHC) is closely linked to a genetic locus for insulin-dependent diabetes mellitus (2).In their study of structural polymorphism of human C4, Rosenfeld et al. (3) used prolonged agarose gel electrophoresis and antiserum to C4 to define patterns in plasma or serum containing EDTA. They noted differences in patterns from person to person but were unable to construct a simple genetic model to explain these differences in populations or in families.Teisberg et al. (4) used similar electrophoretic methods to define one rare and two common C4 structural alleles at a single genetic locus. Mauff (5) introduced a discontinuous buffer system that produced discrete C4 bands, and this was then used to describe two common and two rare variants at a single locus (5, 6). Teisberg et al. (7) C4F and C4S could not be produced by alleles at a single locus but rather that they represented products of two distinct but closely linked loci. Furthermore, sera from "half-null" homozygotes that lacked C4F were negative for the "blood group" antigen Rodgers [Rg(a-)l and those that lacked C4S were negative for Chido [Ch(a-)]. The 93% of random serum samples that had both C4F and C4S were Ch(a+) and Rg(a+). These workers further postulated (9) that deficiencies or null alleles at either the C4F or C4S locus were common. Simple examination of C4 patterns produced in their system, however, did not reveal the expected number of heterozygotes for the half-null haplotypes and C4FS (10). In subsequent publications, Olaisen et al. (11,12) conceded that some chromosomes carried two C4 loci and others carried on...

The difference in sizes of conserved stretches of DNA sequence within the major histocompatibility complex (MHC) in human individuals constitutes an underappreciated genetic diversity that has many practical implications. We developed a model to describe the variable sizes of stretches of conserved DNA in the MHC using the known frequencies of four different kinds of small (< 0.2 Mb) blocks of relatively conserved DNA sequence: HLA-Cw/B; TNF; complotype; and HLA-DR/DQ. Each of these small blocks is composed of two or more alleles of closely linked loci inherited as one genetic unit. We updated the concept of the conserved extended haplotype (CEH) using HLA allele identification and TNF microsatellites to show that specific combinations of the four blocks form single genetic units (>/= 1.5 Mb) with a total haplotype frequency in the Caucasian population of 0.30. Some CEHs extend to the HLA-A and -DPB1 loci forming fixed genetic units of up to at least 3.2 Mb of DNA. Finally, intermediate fragments of CEHs also exist, which are, nevertheless, larger than any of the four small blocks. This complexity of genetic fixity at various levels should be taken into account in studies of genetic disease association, immune response control, and human diversity. This knowledge could also be used for matching CEHs and their fragments for patients undergoing allotransplantation.

In previous studies of the antibody response to hepatitis B vaccine in 598 subjects who received a full course of vaccination, we observed a bimodal response, with about 14 percent producing less than approximately 1000 radioimmunoassay (RIA) units. An analysis of the major histocompatibility complex (MHC) HLA and complement types of 20 of the subjects with the lowest responses indicated a greater-than-expected number of homozygotes for the extended or fixed MHC haplotype [HLA-B8, SC01, DR3]. This finding suggested that the lack of a normal response was a recessive MHC-linked trait. In this study, we prospectively vaccinated five homozygotes and nine heterozygotes for this haplotype in the expectation that the homozygotes would produce much lower levels of antibody than the heterozygotes. When the antibody response was assessed two months after the third injection, four of the five homozygotes had produced very low levels (approximately 1000 units or less) of antibody (mean, 467 RIA units; range, less than 8 to 1266), whereas all nine heterozygotes produced more than 2500 RIA units (mean, 15,608; range, 2655 to 28,900) (P less than 0.01). We conclude that the usual response to hepatitis B surface antigen is due to the presence of a dominant immune-response gene in the MHC and that a low response is due to the absence of such a gene and the presence on both chromosomes of MHC haplotypes (such as [HLA-B8, SC01, DR3]) that indicate such a response.

Of 26 Ashkenazi Jewish patients with pemphigus vulgaris, 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4, DQw3, of which ilI were of the subtype DR4, DQw8.

The chromosomal distribution ofalleles for HLA-A, -B, -C, and -DR and the serum complement protein alleles of factor B and C2 and C4 was studied in normal Caucasian families. Eight combinations of HLA-B, DR, BF, C2, C4A, and C4B markers were found to occur in haplotypes at frequencies significantly higher than expected. In these combinations, which were defined as extended major histocompatibility complex haplotypes, HLA-A showed limited variation. A possible mechanism for the maintenance of extended haplotypes are human analogs of murine t mutants which are characterized by crossover suppression and male transmission bias. One human 6p haplotype, HLA-B8, DR3,