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PubMed1986

Steroid 21-hydroxylase deficiency and the major histocompatibility complex.

Steroid 21-hydroxylase (21-OHase) deficiency is an HLA-linked recessive disorder of cortisol biosynthesis that can occur in several forms which differ in severity. Because they are in genetic linkage disequilibrium with different HLA antigens, the inheritance of these forms is consistent with the existence of several alleles at a single locus. When severe 21-OHase deficiency occurs in association with the HLA haplotype A3;Bw47;DR7, there is a simultaneous null allele at one of the C4 loci. This was hypothesized to result from a single deletion or rearrangement affecting the 21-OHase and C4 loci and perhaps the HLA-B gene as well. To test this hypothesis and identify the 21-OHase gene, a cDNA clone was isolated that encoded the cytochrome P450 specific for steroid 21-hydroxylation in the bovine adrenal gland. This clone hybridized to two genes in normal human DNA, but to only one gene in DNA from an individual homozygous for A3;Bw47;DR7. All individuals heterozygous for A3;Bw47;DR7 carry a heterozygous deletion of a cytochrome P450 gene. Cosmid clones have been used to locate the 21-OHase genes both in man and mouse. In both species, there are two 21-OHase genes each located immediately 3' of one of the two C4 genes, and oriented in the same direction as the C4 genes. In man, the gene located 3' of the C4B gene is deleted in 21-OHase deficiency on the Bw47 haplotype, but the gene 3' of the C4A gene is deleted in hormonally normal individuals on the A1;B8;C4AQ0, C4B1;DR3 haplotype. Thus the 21-OHase B gene is normally active in man, but the 21-OHase A gene is not.

Adrenal Hyperplasia, Congenital↗

PubMed1985

Genetically determined low C4: a predisposing factor to autoimmune chronic active hepatitis.

Of 26 patients with autoimmune chronic active hepatitis (CAH) starting in childhood 18 (69%) had low C4 and 5 (19%) had low C3 serum levels. Impaired hepatic synthesis and immune-consumption were unlikely since transferrin levels were normal in all patients, albumin levels were persistently low in only 3, and only 3 had raised levels of activation fragment C3d. C4d was normal in all patients studied. In the families of 12 probands with low C4, 7 parents had low C4 and 2 had levels which were at the lower limit of normal. 5 of 10 siblings from 5 families had low C4. These results suggest that low C4 levels in CAH are genetically determined. C4 phenotyping in 20 patients and in 26 parents showed that 90% and 81%, respectively, had null allotypes at either the C4A or C4B locus compared with 59% in controls, indicating that defective expression of structural genes may contribute to the observed C4 deficiency.

Adolescent↗

PubMed1999

Biocompatibility of a silicone-coated polypropylene hollow fiber oxygenator in an in vitro model.

BACKGROUND: A silicone-coated microporous hollow-fiber membrane oxygenator has been developed to prevent plasma leakage during long-term use. The objective of this study was to evaluate the biocompatibility of the oxygenator. METHODS: A silicone-coated oxygenator was compared with an uncoated oxygenator in an in vitro model of cardiopulmonary bypass. Simulated circulation was maintained for 6 h at 37 degrees C. RESULTS: Platelet counts decreased significantly (p < 0.05) and leukocyte counts tended to decline; however, the differences between groups were not significant. Concentrations of C3a increased significantly in both groups (p < 0.05), but levels were significantly less in the silicone-coated oxygenator (p = 0.008). In contrast, concentrations of C4a, beta-thromboglobulin, and granulocyte elastase increased significantly (p < 0.05), but the differences between groups were not significant. CONCLUSIONS: Silicone coating over a microporous hollow-fiber membrane may improve biocompatibility by reducing C3a activation.

Coated Materials, Biocompatible↗

PubMed1987

The chemical structure of the C4d fragment of the human complement component C4.

The complete amino acid sequence of the C4d fragment (380 residues long) of the human complement component C4 is presented. Most of the sequence was determined by analysis of CNBr peptides and tryptic peptides obtained from S-carboxymethylated protein. The sequence of the amino terminal 88 residues [Campbell R. D., Gagnon J. and Porter R. R. (1981) Biochem. J. 199, 359-370] and a 106 residue polymorphic segment of C4d [Chakravarti D. N., Campbell R. D. and Gagon J. (1983) FEBS Lett. 154, 387-390] was extended. Some overlaps not provided by the protein sequence analysis were obtained from the amino acid sequence predicted by the nucleotide sequence [Belt K. T., Carroll M. C. and Porter R. R. (1984) Cell 36, 907-914]. The present protein sequence data provide information for the isolation of all the CNBr and succinylated tryptic peptides of C4d. In addition to the polymorphism previously described, two other sets of polymorphic amino acid residues at positions 153 (Ile/Ser) and 154 (Gln/Ala) have been identified. The major site of glycosylation has been shown to be an asparagine residue located in the sequence -Asn-Val-Thr- in the carboxy terminal end of C4d. A remarkable difference in the predicted secondary structure of C4d arising from one set of four polymorphic residues in a stretch of six residues and another single polymorphic residue suggests a structural basis for the origin of the different chemical reactivities of the C4 isotypes (C4A and C4B) and their serological difference in the expression of Rodgers or Chido blood group antigens. Possible non-covalent membrane attachment sites have been suggested from the hydropathy profile. Comparison of the C4d sequence with human C3, C5 and alpha 2-macroglobulin revealed extended stretches of sequence similarity (between 19 and 38% homology) with the corresponding regions of these proteins.

Amino Acid Sequence↗

PubMed1984

Extended haplotypes of chromosome 6 in adult rheumatoid arthritis.

In 46 patients with rheumatoid arthritis (RA) the allele C4B*3 occurred in 6 patients, while among 350 normal controls, it occurred 6 times (P less than 0.00002). Among 9 white and 1 black families, each of which had 2 or more members with RA, there were 36 haplotypes associated with RA. An extended haplotype (specific HLA-B, DR, complotype haplotypes in significant linkage disequilibrium) containing C4B*3: HLA-B15, DR4, BF*S, C2*C, C4A*3, C4B*3, was found twice (P less than 0.001) among whites with the disease-associated chromosomes.

Adult↗

PubMed1990

Early onset sensorineural hearing loss: association studies with major histocompatibility class III (complement) markers.

In 39 families with at least one child suffering from moderate or severe bilateral sensorineural hearing loss (SNHL), major histocompatibility complex (MHC) class III complement phenotypes were retrospectively determined by standard methods; MHC class I segregation data was also available. The families were treated in the Hospital for Communication Disorders and selected for the HLA-B16 and B18 specificities, respectively. Haplotype and allele frequencies were derived from segregation analysis in the families. From 31 unrelated children with random and familiar forms of SNHL significant deviations in the distribution were seen for the following MHC class III alleles using as a control population 60 German healthy individuals: duplicated C4A alleles (C4"DA") p = 0.009, silent C4A alleles (C4A*Q0) p = 0.006, duplicated heavy C4 beta-chain alleles (C4 beta"DHH") p = 0.0003, and silent C4 beta-chain alleles (C4 beta*Q0) p = 0.0075. In serum samples from patients with an assumed genetic disposition according to clinical criteria indications for an association were found for C4"DA" (p = 0.03), C4A*Q0 (p = 0.003), C4B*3 (p = 0.046), C4 beta"DHH" (p = 0.004), and C4 beta*Q0 (p = 0.02). The underrepresentation of C4A*Q0 may be an indicator for aberrant or duplicated C4 alleles on the same haplotype or exhibit a protection mechanism for acquiring the inheritable forms of early onset SNHL.

Adolescent↗

PubMed1996

Incomplete functional deficiencies of the fourth (C4) and second (C2) components of complement in a patient with linear frontoparietal scleroderma and his family. Deficiencies determined by a gene not linked to human leukocyte antigen system.

BACKGROUND: In a previous study, a patient suffering from linear frontoparietal scleroderma and some of his family members were found to have an incomplete functional deficiency of the second component (C2) of complement (C). In this study, the proband and the rest of his family members were investigated for functional deficiencies of C2 and the fourth component of C (C4). A search for null alleles of C2 (C2*Q0) and C4 (C4*Q0) was made to find out whether their occurrence is responsible for incomplete functional deficiencies. HLA analysis was performed to find out whether deficiencies are linked to HLA alleles known to be associated with C4*Q0 and C2*Q0. Possible large deletions at C4 and 21-hydroxylase (21-OH) gene loci were also investigated in some family members. OBSERVATIONS: The proband had a combined functional deficiency of C4 and C2. Some of his family members had a partial functional deficiency of C4, some of C2 and some of C4 and C2; none had null alleles of C2 (C2*Q0), factor B (B*Q0) or C4B (C4B*Q0). C4*Q0 or functional C4 deficiency in this family was not associated with HLA-A1;B8;DR3 alleles. C2 deficiency was also not associated with HLA antigens known to be associated with type I and II C2 deficiencies. No gene deletion or unusual polymorphism at C4A and 21-OHA loci could be seen by restriction fragment length polymorphism (RFLP) studies. CONCLUSIONS: Combined and isolated partial functional deficiencies of C4 and C2 observed in the proband and many of his family members were not caused by C activation or null alleles. They were not linked to HLA system and were reminiscent of those observed previously in a family in which C4 deficiency was determined by a gene not linked to the HLA system.

Alleles↗

PubMed1990

Genetic polymorphisms of HLA class III and GLO1 in Chinese Yao nationality.

Yao is one of the minority nationalities located mainly in the South of China (Guang Xi province). The purpose of this study was to examine HLA class III and GLO1 in Yao nationality to identify the difference between Yao and Han. Han is the major nationality in China. Yao has the lowest C2*C frequency (0.9336) in the world. Before this study the lowest C2*C frequency known was that of the Japanese (0.9386). Gene frequencies in Yao are the following: C2*C = 0.9336, C2*B = 0.0664; BF*S = 0.9071, BF*F = 0.0929; C4A*4 = 0.0253, C4A*3 = 0.6061, C4A*2 = 0.2121, C4A*1 = 0.0152, C4A*Q0 = 0.1414; C4B*3 = 0.0051, C4B*2 = 0.0657, C4B*1 = 0.7071, C4B*92 = 0.0455, C4B*95 = 0.0253, C4B*96 = 0.0253, C4B*12 = 0.0051, C4B*Q0 = 0.1212; GLO1*1 = 0.1161, GLO1*2 = 0.8839. We have compared these data with those reported for Han.

Blood Donors↗

PubMed1990

Molecular modeling of human complement component C4 and its fragments by X-ray and neutron solution scattering.

The solution structures of human complement component C4 and five derived fragments, C4u, C4(a + b), C4b, C4c, and C4d, were analyzed by synchrotron X-ray and neutron scattering. The X-ray radii of gyration RG for C4, C4u, and C4(a + b) in H2O buffers are similar at 5.23-5.28 nm, and likewise the cross-sectional radii of gyration RXS are similar at 2.48-2.52 nm. Molecular mass calculations using X-rays and neutrons show unexpectedly that C4c is dimeric; however, all the other forms are monomeric. C4c2 has an X-ray RG of 5.18 nm and an RXS of 2.89 nm. Neutron contrast variation gives RG values at infinite contrast of 4.87-4.93 nm for C4 and C4u, 4.79 nm for C4b, 4.94 nm for C4c2, and 2.69 nm for C4d. The RXS values at infinite contrast are 2.23-2.25 nm for C4 and C4u, 1.89 nm for C4b, and 2.62 nm for C4c2. These data show that a large conformational change occurs on going from C4 to C4b, but not on going from C4 to C4u, and this is attributed to the presence of the C4a moiety in C4u. Comparisons of the C4 and C4u scattering curves show that these are very similar out to a nominal resolution of 4 nm. Scattering-curve models were developed to account for the neutron scattering curves of C4, C4c2, and C4d in 2H2O buffers. The C4c monomer could be represented by a lamellar ellipsoid of size 8 nm x 2 nm x 18 nm. C4d was found to be 4 nm x 2 nm x 9 nm. The combination of these structures gave good accounts of the neutron data for C4, C4b, and C4c2 to resolutions of 5-6 nm. The C4 model was obtained by placing the long axis of C4d parallel to that of C4c such that the cross section is extended. C4b was best modeled by repositioning C4d relative to C4c such that this cross section becomes more compact. The C4 and C4b models are compared with possible structures for the C1 component of complement to show the importance of the surface accessibility of the protease domains and short consensus repeat domains in C1 for C4 activation.

Blood Donors↗

PubMedDate not supplied

A monoclonal anti-C4d that demonstrates a specificity related to anti-Ch.

A monoclonal anti-C4d reagent, L003, agglutinated untreated and trypsin-treated C4A Rodgers(Rg)- and C4B Chido(Ch)-coated red cells. Inhibition of the agglutination, regardless of the Rg/Ch phenotype of the C4 coat, showed Ch specificity, more precisely, for the Ch1 determinant. C4A allotypes that express Ch1 and Ch3 rather than Rg1 and Rg2, and C4B allotypes that express Rg1 rather than Ch1, Ch2, or Ch3 confirmed that the inhibition specificity in serologic tests was anti-Ch1 and not anti-C4B.

Animals↗

PubMed1988

Major histocompatibility complex markers in patients with nomifensine-induced immune hemolytic anemia.

To evaluate a possible role of major-histocompatibility-complex (MHC)-related immune-response genes for the selective production of drug-induced antibodies, HLA class I (ABC), class II (DR, DQ), class III (BF, C2, C4A, C4B) as well as glyoxalase-1 allotypes were investigated in 26 patients with nomifensine-induced immune hemolytic anemia. No statistically significant deviations of MHC antigen frequencies were noted. The possible implications of these findings are discussed.

Adult↗

PubMed1992

Investigation of allotypes of HLA class III (C2, BF and C4) in patients with schizophrenia.

The allotypes of HLA Class III (C2, BF and C4) in 60 patients with schizophrenia were investigated. Significantly higher frequencies of BF*F, BF*SO7 and C4A*4 in patients were found as compared with those of the normal controls. The relative risks (RR) of the three allotypes to schizophrenia were 1.81, 7.79 and 4.18 and the etiologic fraction (EF) were 0.086, 0.060 and 0.042, respectively. There were no significant changes of C2 allotypes.

Complement C2↗

PubMed1990

C4 null genes in American whites and blacks with myositis.

The frequencies of C4A and C4B alleles were determined in 66 adults with myositis in relation to HLA class I and II. In whites with myositis, the C4A*Q0 allele occurred in 13/31 (47%) as compared to 25/101 (25%) normal controls (p = 0.08, relative risk = 2.7). Only 11/35 (31%) of black patients with myositis had a C4A*Q0 allele compared to 11/55 (20%) of controls (p = NS, RR = 1.8). Thus, the MHC class III genes do not appear to be the primary genetic risk factors for myositis in adults.

Alleles↗

PubMed1995

Influence of host genotype on progression to acquired immunodeficiency syndrome among children infected with human immunodeficiency virus type 1.

OBJECTIVE: To study the role of host genotype in pediatric infection with human immunodeficiency virus type 1 (HIV-1) and progression to acquired immunodeficiency syndrome (AIDS). METHODS: Human leukocyte antigen (HLA) class II and complement C4 genotypes were determined by means of molecular genetic techniques for 243 black children born to HIV-1-infected mothers in New York City and San Francisco. Survival, cumulative incidences of opportunistic infections and encephalopathy, and rates of CD4+ T cell decline were compared in children of different genotypes. RESULTS: Among HIV-1-infected children, the HLA-DR3 haplotype (DRB1*0301-DQA1*0501-DQB1*0201) was associated with increased incidence of encephalopathy, faster rate of CD4+ cell decline, and death before 2 years of age. Deletion of the C4A gene was independently associated with increased incidences of encephalopathy and early death. DPB1*0101 was associated with survival to at least 2 years of age. The presence of DQB1*0604 was associated with increased risk of HIV infection. CONCLUSIONS: These results are consistent with previously reported associations between HLA genotypes and faster progression to AIDS among HIV-infected adults. The DR3 haplotype and C4A deletion may reflect the same underlying mechanism of susceptibility in that the DR3 haplotype is in linkage disequilibrium with other C4A null alleles. In addition, the class II locus DPB1 may have an independent effect on survival.

Acquired Immunodeficiency Syndrome↗

PubMed1986

The HLA system in the Korean population.

The frequencies of HLA-A, B, C, DR, and DQ antigens, HLA-D (HTC-defined) haplotypes, and the HLA-linked genetic markers glyoxalase I (GLO), factor B (Bf), C2 and C4 were studied in 162 healthy unrelated Koreans. Antigens A2, A24, A26, B44, B51, Bw62, B35, Cw1, Cw3, DR2, DR4, DRw6, DR7, and DRw8 were observed at frequencies of 15% or greater, and GLO-2, BfS, C4A*3, C2C, C4A*4, C4B*1, and C4B*2 were also frequently observed. The antigens A23, A25, B18, Bw42, Bw47, and B21 were not observed at all. HLA-DR4 was the most common class II antigen and was associated with a series of HLA-D-defined haplotypes including Dw4, Dw10, Dw13, and Dw15. The HLA-DRw6, DR2,Dw8, and DRw8 haplotypes were also found frequently. DR2 haplotypes were either Dw2 or Dw12, while all DRw8 haplotypes tested corresponded to the DB7 or Dw "8.3" specificity that has been described in other Oriental populations. Significant linkage disequilibrium was found between the alleles A2,Cw1; A30,B13; A30,Cw6; A30,DR7; Cw1,Bw22; Cw5,B12; Cw6,B13; Cw6,DR7; B7,DR1; B12,Dw6; B12,DR7; B12,Dw7; B13,DR7, B17,DR3; Bw22,C4B*6; DRw6,BfF; and C4A*4,C4B*2. A comparison of gene frequencies and commonly observed haplotypes between Koreans, Chinese, Japanese, and Caucasians showed that while Koreans share several characteristics in common with other Oriental populations, there are allelic frequencies and haplotypes in Koreans that are distinct.

Complement C2↗

PubMed1990

Relative electrophoretic migration distances for the classification of C4 allotypes.

For the definition of common C4 allotypes relative electrophoretic migration (RM) values were determined. A set of standard C4 variants were investigated by prolonged agarose gel electrophoresis and subsequent immunofixation with specific antiserum. RM distances were measured by laser densitometry. Using an arbitrary standard of 100 units for the migration distance between the C4B 1 and C4A 3 bands a total deviation of +/- 6.45% in more than 108 single determinations was found. The common C4 alleles used for standardization were C4A*6, C4A*4, C4A*3, C4A*2, C4B*5, C4B*3, C4B*2, C4B*1. In addition, side by side comparison and admixture of known variants will be necessary for the differentiation of some of the closely migrating allotypes. RM values are now available for eight alleles frequently found in all populations for future comparison and designation of newly discovered C4 allotypes.

Complement C4↗

PubMedDate not supplied

C4 and HLA haplotypes associated with partial inhibition of anti-Rg and anti-Ch.

Rg and Ch typing was performed, by serum inhibition, on 145 families that had been typed for HLA/C4/BF/C2 with a view to assessing partial inhibition (p.i.) of anti-Rg/Ch and its haplotype associations. Rg p.i. was found predominantly with the C4A*3A*2,B*QO homoduplicated C4 haplotype and BFF. The original type of Ch p.i. (Nordhagen et al., 1980) was closely associated with the allotype C4B 2, which also occasionally exhibited complete inhibition (c.i.), but this Ch p.i. was also found with the C4A*1,B*QO haplotype (Rittner et al., 1984a). The second type of Ch p.i. (Giles, 1984) was closely associated with the C4B 1 allotype most frequently in the haplotype C4A*6,B*1 but also with C4A*3,B*1. Both types of Ch p.i. are usually found with BF S. The present data indicate that the determinants of Rg and Ch are not directly related to any particular C4 allotype or extended haplotype. Further examples of C4A 1 with Ch and C4B 5 without Ch determinants have been detected and theoretical considerations are discussed as to how they might have arisen from unequal crossovers in homologous regions that result in hybrid protein molecules.

Alleles↗

PubMed1984

Study of alleles of the second complement component (C2) on Canadian HLA haplotypes.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2-1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2*1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B *2 whilst the Bw22 haplotypes mostly carry C4A *4, C4B *4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2 *2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2 *2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.

Alleles↗