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PubMed2005

Confirmation of the association of the C4B null allelle in autism.

The objective of this study was to examine and attempt to confirm our previous findings of an increased frequency of the C4B null allele (C4BQ0) in subjects with autism. Newly identified subjects from Utah and Oregon were studied. Families evaluated included 85 who had a child with autism and 69 control families. Of the subjects with autism studied, 42.4% carried at least one C4BQ0, compared with 14.5% of the control subjects (p = 0.00013), with a relative risk of 4.33. Over half of the C4B null alleles in the subjects with autism involved C4A duplications. A marked increase in the ancestral haplotype 44.1 that lacks a C4B gene and has 2 C4A genes was also observed. The results of this study suggest that the human leukocyte antigen class III C4BQ0 significantly increases the risk for autism.

Autistic Disorder↗

PubMed1996

Investigation of mechanism-based inhibitors of complement targeting the activated thioester of human C3.

An intramolecular thioester bond in complement protein C3 is vital for covalent attachment of C3b (the proteolytically activated form of C3) to biological surfaces and for activation of the complement system. Proteolytic removal of C3a from C3 activates the thioester in the C3b fragment. Activated C3b primarily forms ester bonds with hydroxyl groups of carbohydrates on complement activating surfaces, but it has also been shown to react with the hydroxyl group of tyrosine and with specific Ser and Thr residues on IgG and on complement protein C4b. To examine the reactivity of the thioester, several families of hydroxylated compounds were examined. Reactivity of a series of substituted phenols varied over two orders of magnitude and demonstrated a linear correlation between reactivity and the Hammett substituent constants. Hydroxylated drugs including members of the L-DOPA/epinephrine family and hydroxamic acids also were examined. Compounds were identified that were 20,000 times more reactive than carbohydrates. These compounds were found to inhibit both the classical and alternative pathways of complement activation. Although the specificity of the thioester for its natural biological targets appears to be determined by many structural features, the data presented here demonstrate that increasing the nucleophilic character of the target hydroxyl group can increase the potency of a synthetic inhibitor many orders of magnitude.

Complement C3↗

PubMed1991

The influence of venous occlusion on the status of protein S.

In the present study the effect of perturbation of the vessel wall by venous occlusion on protein S release, was evaluated in 10 healthy male volunteers. A 9% (P less than 0.01) increase in free protein S and a 7% (NS) in total protein S over the baseline were observed 7 min after venous occlusion, whereas von Willebrand factor antigen (vWF:Ag)--a known release product of vascular endothelium--increased by 11% (P less than 0.01). In addition, the possibility of free protein S release from unstimulated platelets was investigated in pre- and post-occlusion samples incubated at room temperature for 24 h as whole blood or platelet-rich plasma. An increase in the mean free protein S was observed in the pre-occlusion samples which peaked after 4 h of incubation--121% at time 0 to 130% (P less than 0.05) of the normal pooled plasma whereas total protein S increased by only 4% (NS). In the post-occlusion samples, a similar peak in mean free protein S levels was observed after 12 h of incubation--132% at time 0 increased to 142% (P less than 0.01) of the normal human plasma pooled and the total protein S was increased by 8.55 (P less than 0.05). Small but significant increases in vWF:Ag levels were observed at 2 h and 6 h for the pre- and post-occlusion samples, respectively. No changes in C4b-binding protein were observed throughout the study. We conclude that, firstly, venous occlusion causes release of protein S in addition to vWF:Ag and, secondly, unstimulated platelets release protein S in addition to vWF:Ag.

Adolescent↗

PubMed2003

Mutation of IVS2 -12A/C>G in combination with 707-714delGAGACTAC in the CYP21 gene is caused by deletion of the C4-CYP21 repeat module with steroid 21-hydroxylase deficiency.

More than 90% of the cases of congenital adrenal hyperplasia are caused by mutations of the CYP21 gene. Approximately 75% of the defective CYP21 genes are generated through intergenic recombination, termed apparent gene conversion, from the neighboring CYP21P pseudogene. Among them, mutation of the aberrant splicing donor site of IVS2 -12A/C>G at nucleotide (nt) 655 is believed to be a result derived from this mechanism and is the most prevalent case among all ethnic groups. However, mutation of 707-714delGAGACTAC rarely exists alone, although this locus is a distance of 53 nt away from IVS2 -12A/C>G. From the molecular characterization of the mutation of IVS2 -12A/C>G combined with 707-714delGAGACTAC in patients with congenital adrenal hyperplasia, we found that it appeared to be in a 3.2-rather than a 3.7-kb fragment generated by Taq I digestion in a PCR product of the CYP21 gene. Interestingly, the 5' end region of such a CYP21 haplotype had CYP21P-specific sequences. Our results indicate that the coexistence of these two mutations is caused by deletion of the CYP21P, XA, RP2, and C4B genes and intergenic recombination in the C4-CYP21 repeat module. Surprisingly, this kind of the haplotype of the mutated CYP21 gene has not been reported as a gene deletion.

Adrenal Hyperplasia, Congenital↗

PubMed1982

A study of a covalent-like interaction between soluble nascent C4b and C4-binding protein.

In the classical pathway of complement, the interaction between C4b and C4bp can be considered as a control of the C3 convertase formation. Purified C4-binding protein (C4bp) interacts with soluble nascent C4b to form covalent-like complexes; the interaction is also possible with nascent C4b-like C4, but not with C4, C4b or C4b-like C4. Formation of the complexes upon incubation of C4bp, C4 and C1s appears to involve a single link between a subunit of C4bp and the alpha' chain of C4b, as observed by SDS-polyacrylamide gel electrophoresis in reducing conditions (160 000 dalton band). In non-reducing conditions, a mixture of C4b-C4bp complexes is observed as a function of the C4b:C4bp molar ratio, with apparent molecular weights differing by a value of 210 000 and reflecting different C4b-C4bp associations. A maximum of five molecules of C4b are bound per molecule of C4bp, which appears to consist of 10 subunits of apparent molecular weight 72 000. The link between C4b and C4bp is partially destroyed by 1 M hydroxylamine at pH 9.0; its formation is strongly inhibited by 3.5 mM hydroxylamine or 60 mM methylamine at pH 9.0. These findings suggest an ester or amide bond between the activated carboxyl group of the thioester bridge in the alpha' or alpha chain of nascent C4b or C4b-like C4 and a hydroxyl or amino group of C4bp. Thus, C4bp might compete with other C4b acceptors such as membranes or IgG.

Carrier Proteins↗

PubMed2002

Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35).

The K/BxN murine model of rheumatoid arthritis (RA) is dependent on the specificity of the KRN alpha beta-TCR, to recognize glucose-6-phosphate-isomerase (GPI) on the NOD MHC class II A(g7) allele and production of GPI-specific autoantibodies. Transfer of K/BxN serum into MHC-unrelated and lymphocyte-deficient mice induces RA. To investigate whether K/BxN serum-induced RA involves complement activation and/or the complement receptors (CR) 1 and 2, we analyzed the role of complement C4 and of CR1 and CR2. For this purpose we used C4(-/-) mice impaired in the classical and the lectin complement pathways; Cr2(-/-) mice lacking CR1 and CR2 and, as control strains, BALB/c, C57BL/6, KRN and NOD. RA was assessed by caliper measurement of ankle thickness, clinical index and joint histology. We found that all mouse strains except NOD developed RA. The lack of protection in C4(-/-) mice suggests that antibody-mediated RA is independent of the classical as well as the lectin complement pathways and the split complement product C4b. The lack of protection in Cr2(-/-) mice suggests that absence of CR1 had no significant affect, considering its role in immune complex clearance, inhibition of C3 and C5 convertase and as receptor for C3b/C4b. Also, CR2 lacks a role in disease as analyzed here, in its possible functions as receptor for C3dg, germinal center reaction and activation of alternative pathway on binding iC3. Hence we conclude that the transmission of K/BxN serum-induced RA is independent of the classical and the lectin complement pathways and CR1 and CR2. The crucial role of complement C5, while neither classical nor lectin pathway is necessary, indicates that the alternative complement pathway may have a role in the K/BxN serum-induced RA model.

Animals↗

PubMed1992

Tumour necrosis factor B gene polymorphism in relation to complotype in couples with spontaneous abortions and in control families.

NcoI restriction fragment length polymorphism (RFLP) of the tumour necrosis factor B (TNFB) gene gives two allelic fragments of 5.5 and 10.5 kb, corresponding to the TNFB*1 and TNFB*2 alleles, respectively. The frequencies of these alleles were analysed in 121 healthy Finns and 56 Finnish couples suffering from recurrent spontaneous abortions (RSA). In the healthy Finns the frequency of TNFB*1 was 37% and that of TNFB*2 63%, of which the frequency of TNFB*1 was significantly increased compared with the Danish population. No deviation was seen between the RSA couples and the Finnish controls. TNF genes are located in major histocompatibility complex class III region close to complement (BF, C4A and C4B) genes. Some complotypes associated most often with the TNFB*1 (S01, S30, S02) and some (S31, F320) with the TNFB*2 allele in the healthy Finns. The combination of the TNFB and the C4 'null' allele differed between the RSA couples and the Finnish controls.

Abortion, Habitual↗

PubMed1990

Marked shortage of C4B DNA polymorphism among insulin-dependent diabetic patients.

TaqI, BamHI and HinddIII polymorphisms of the C4 genes were studied with a 500-bp C4 cDNA probe (pAT-A153) specific for the 5' end of the gene. The restriction patterns obtained were correlated with the C4A and C4B genotypes in 35 patients suffering from insulin-dependent diabetes mellitus (IDDM), and results were compared to those from 40 healthy individuals. The controls, all Caucasian, were genotyped for HLA-A, B, C, DR, Bf, C2 and C4, together with 10 diabetics and their families; haplotypes for the other patients had been deduced using DNA and protein polymorphism, and taking into consideration linkage disequilibrium for neighbouring loci. No significant difference between genotypes at the C4A locus was seen in either population. The C4A gene deletion, associated with a C4B "short" gene (66.7%), was found mainly in the haplotype B8,Cw7,DR3,BfS,C2C, C4AQOB1, and the C4B gene deletion in the haplotype B18,Cw5,DR3,BfF1, C2C,C4A3BQO. When diabetic patients were compared with normal individuals, we observed, at the C4B locus, a decrease in the C4B "long" gene (22% vs. 49% respectively, p less than 0.001). A compensatory increase was observed in patients vs. controls for the frequency of C4BQO, both in the deleted and intact form (26% vs. 10% respectively, p less than 0.03).

Alleles↗

PubMed1993

Genetic, immunologic and biotransformation studies of patients on procainamide.

This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.

Aged↗

PubMed1990

DQw7 and the C4B null allele in rheumatoid arthritis and Felty's syndrome.

DQ beta and C4 null alleles have been defined in patients with rheumatoid arthritis, Felty's syndrome, and in control subjects. Comparison of DR4 positive subjects shows that rheumatoid disease without extra-articular features has no preferential associations with either DQ beta or C4 null variants. In Felty's syndrome there are significant associations with both the class II major histocompatibility complex (MHC) DQw7 allele (86% of DR4 positive patients with Felty's syndrome and 53% of DR4 positive controls) and the class III MHC C4B null allele (50% of patients with Felty's syndrome and 20% of DR4 positive controls). DQw7 and the C4B null allele are in linkage disequilibrium and the B44-Bf *S-C4A*3-C4B*Q0-DR4-DQw7 haplotype accounts for five of 24 DR4 positive haplotypes assigned in subjects with Felty's syndrome. The results were not accounted for by articular disease severity and suggest that articular and extra-articular forms of rheumatoid disease may be immunogenetically heterogeneous.

Alleles↗

PubMed1988

Cardiolipin antibodies and null alleles of C4 in black Americans with systemic lupus erythematosus.

Twelve of 44 black American patients with systemic lupus erythematosus (SLE) (27%) studied during periods of disease activity had increased levels of IgG antibodies against cardiolipin (IgG aCL). IgG aCL occurred almost exclusively in patients who had a partial genetic deficiency of C4A or C4B. Eleven of 29 patients (38%) with a C4A or C4B deficiency allele had IgG aCL, compared with 1/15 patients (7%) who did not have C4A or C4B deficiency allele (p = 0.04). During periods when SLE was less active clinically, IgG aCL levels returned to normal in 10/12 patients. Active SLE, rather than null alleles, appeared to be associated with low C4 levels in patients with IgG aCL.

Adult↗

PubMed2002

Determining the one, two, three, or four long and short loci of human complement C4 in a major histocompatibility complex haplotype encoding C4A or C4B proteins.

The complex genetics of human complement C4 with unusually frequent variations in the size and number of C4A and C4B, as well as their neighboring genes, in the major histocompatibility complex has been a hurdle for accurate epidemiological studies of diseases associated with C4. A comprehensive series of novel or improved techniques has been developed to determine the total gene number of C4 and the relative dosages of C4A and C4B in a diploid genome. These techniques include (1) definitive genomic restriction-fragment-length polymorphisms (RFLPs) based on the discrete duplication patterns of the RCCX (RP-C4-CYP21-TNX) modules and on the specific nucleotide changes for C4A and C4B isotypes; (2) module-specific PCR to give information on the total number of C4 genes by comparing the relative quantities of RP1- or TNXB-specific fragments with TNXA-RP2 fragments; (3) labeled-primer single-cycle DNA polymerization procedure of amplified C4d genomic DNA for diagnostic RFLP analysis of C4A and C4B; and (4) a highly reproducible long-range-mapping method that employs PmeI-digested genomic DNA for pulsed-field gel electrophoresis, to yield precise information on the number of long and short C4 genes in a haplotype. Applications of these vigorously tested techniques may clarify the roles that human C4A and C4B gene-dosage variations play in infectious and autoimmune diseases.

Alleles↗

PubMedDate not supplied

Immunogenetic studies in autism and related disorders.

The major histocompatibility complex comprises a number of genes that control the function and regulation of the immune system. One of these genes, the C4B gene, encodes a product that is involved in eliminating pathogens such as viruses and bacteria from the body. We previously reported that a deficient form of the C4B gene, termed the C4B null allele (no C4B protein produced) had an increased frequently in autism. In this study we attempted to confirm the increased incidence of the C4B null allele in autism and investigated the presence of a C4B null allele in two other childhood disorders, attention-deficit hyperactivity disorder and dyslexia (reading disability). In addition, we explored the relationship of autism to the DR beta 1 gene, a gene located close to the C4B in autism. We confirmed the finding of an increased frequency of the C4B null allele in autism and found that the related disorders also had an increased frequency of this null allele. In addition, two alleles of the DR beta 1 gene also had significantly increased representation in the autistic subjects.

Amino Acid Sequence↗

PubMed1995

C4 null alleles in a Swedish population.

The distribution of C4 null alleles (C4Q0) was studied in a Swedish population comprising 410 male individuals from Stockholm County and Uppsala City. The prevalances of homozygous C4A*Q0 and C4B*Q0 determined by analysing the gene products in serum were 5.0 and 5.6%, respectively, in the Stockholm population and 4.0% each in the Uppsala population. These values are higher than those previously reported from other Caucasian populations. The finding reflects a different genetic composition of the Swedish population and may have relevance to the disease spectrum in this population as compared to other Caucasian populations.

Adult↗

PubMed1990

Characterization of two hybrid C4 allotypes (C4A12 and C4B3) by electrophoretic, serological and restriction fragment length polymorphism analyses.

Informative pedigree analysis of two rare C4 allotypes is reported. One proband was C4A deficient as a consequence of having one haplotype with a deleted C4A gene, and the second haplotype with two C4B genes--one encoding the common C4B*1 and one encoding a unique hybrid gene product C4B*3. C4B*3 had approximately normal C4B hemolytic activity, a single alpha-chain of MR 94,000 by SDS-PAGE but was positive for Rg:1,2 by hemagglutination inhibition (HAI) and for Rg:1 by Western blotting. The hybrid nature was confirmed by RFLP analysis with a Rg:1-associated fragment by Eco0109 digestion but no C4A-associated fragments by N1aIV digestion were identified. A gene conversion at Locus I which included just the C4 isotype region could explain the structure of C4B*3. The second pedigree had a Rodgers negative C4A*12 allotype. This C4A gene, which segregated with a single 7.0 kb TaqI fragment, encoded a C4A alpha-chain, which was negative for Rg:1 epitope. The affected haplotype lacked the Rg:1-associated fragment by Eco0109 digestion yet had the C4A specific N1aIV digestion fragment. These studies successfully employed RFLP analyses to confirm serologic and electrophoretic observations.

Adolescent↗

PubMed2000

A Schistosoma protein, Sh-TOR, is a novel inhibitor of complement which binds human C2.

Human complement regulatory (also called inhibitory) proteins control misdirected attack of complement against autologous cells. Trypanosome and schistosome parasites which survive in the host vascular system also possess regulators of human complement. We have shown Sh-TOR, a protein with three predicted transmembrane domains, located on the Schistosoma parasite surface, to be a novel complement regulatory receptor. The N-terminal extracellular domain, Sh-TOR-ed1, binds the complement protein C2 from human serum and specifically interacts with the C2a fragment. As a result Sh-TOR-ed1 pre-incubated with C2 inhibits classical pathway (CP)-mediated haemolysis of sheep erythrocytes in a dose-dependent manner. In CP-mediated complement activation, C2 normally binds to C4b to form the CP C3 convertase and Sh-TOR-ed1 has short regions of sequence identity with a segment of human C4b. We propose the more appropriate name for TOR of CRIT (complement C2 receptor inhibitory trispanning).

Amino Acid Sequence↗

PubMed1984

Human C4 haplotypes with duplicated C4A or C4B.

In the course of study of families for the sixth chromosome markers HLA-A, C, B, D/DR, BF, and C2, the two loci for C4, C4A, and C4B, and glyoxalase I, we encountered five examples of probable duplication of one or the other of the two loci for C4. In one of these, both parents and one sib expressed two different structural genes for C4B, one sib expressed one, and one sib expressed none, suggesting that two C4B alleles were carried on a single haplotype: HLA-A2, B7, DR3, BFS1, C2C, C4A2, C4B1, C4B2, GLO1. In a second case, two siblings inherited C4B*1 and C4B*2 from one parent and C4B*Q0 from the other. This duplication appeared on the chromosome as HLA-AW33, B14, DR1, BFS, C2C, C4A2, C4B1, C4B2, GLO2. In a third, very large family with 3 generations, a duplication of the C4B locus occurred which was followed in 2 generations. In one individual, there were three C4B alleles and two C4A alleles. One of the C4B alleles had a hemolytically active product with electrophoretic mobility near C4B2 and was designated C4B*22. It segregated with C4B1 in the family studied. The complete haplotype was HLA-A11, CW1, BW56, DR5, BFS, C2C, C4A3, C4B22, C4B1, GLO2. In another family with 12 siblings, one parent and eight children expressed two C4A alleles on the haplotype HLA-AW30, BW38, DR1, BFF, C2C, C4A3, C4A2, C4BQ0, GLO1.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗

PubMed1988

Antigenic determinants of human C4, Rodgers and Chido.

The duplicated genes, C4A and C4B, are located within the major histocompatibility complex on chromosome 6 and each exhibits a high degree of polymorphism expressed as both electrophoretic and antigenic variation (Rg/Ch). Eight high-frequency antigens and one low-frequency antigen have been defined by immune human polyspecific antisera in haemagglutination inhibition assays. Close association exists between different C4 allotypes and the antigens they express. Normally, C4A expresses Rg and C4B has Ch but rare reverse associations exist. Nucleotide sequences of the C4d region from C4 allotypes of known antigenic status have demonstrated four polymorphic sites that correlate with the antigens, which, in a structural model, are seen to be conformational or sequential epitopes. The observed interrelationships of the antigens on C4 allotypes accommodated by the model suggest that the electrophoretic variation is located outside the C4d region. The molecular genetics of C4 are also considered as part of the polymorphism.

Amino Acid Sequence↗