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PubMed1996

Immune alterations in lead-exposed workers.

Peripheral blood lymphocytes, serum immunoglobulins (IgG, IgA and IgM), C3 and C4 complement protein concentrations of 25 male lead-exposed workers from storage-battery plants were examined and compared to 25 healthy male controls. Lead exposure was assessed using blood lead levels measured by atomic absorption spectrophotometry and zinc protoporphyrin (ZPP) levels assayed by hematofluorometry. The absolute number and the percentage of functionally different subsets of peripheral blood mononuclear lymphocytes, i.e. T, T-suppressor, B and natural killer cells, were unchanged. However, T-helper lymphocytes were significantly lower in lead-exposed workers compared to healthy controls (P < 0.05). In addition, lead-exposed workers had a significant reduction in the IgG, IgM and C3, C4 complement levels (P < 0.05). These results suggest that human chronic exposure to lead may be detrimental to the immune system.

Adult↗
PubMed1998

Increased levels of CD8+ and CD4+ 45RA+ lymphocytes in schizophrenic patients.

Peripheral blood (PB) lymphocyte subpopulations, IgG, IgM, IgA and IgE serum immunoglobulins and C3 and C4 complement fractions were evaluated in 29 schizophrenic patients, 31 of their relatives and 20 healthy subjects. The patients fulfilled DSM-III criteria for schizophrenia, and were unmedicated for 3 months prior to the PB sample collection. When compared to healthy controls and their own relatives, the schizophrenic patients showed a lower level of CD4+ cells, while the CD4+ 45RA+ (naive) subset was significantly higher. Conversely, the number of CD4+ 45RA- (memory) lymphocytes was significantly lower in schizophrenic patients in comparison to their relatives and controls, while the CD8+ supressor/cytotoxic T-cell percentage was significantly higher. No significant differences were observed for the IgG, IgM, IgA, IgE and C3 and C4 complement fraction levels among the three groups. The present data confirm the presence of immunological abnormalities in schizophrenic patients and suggest a possible role of environmental factors in the triggering of an autoimmune pathogenic mechanism.

Adult↗
PubMed1990

Rapid and standardized quantitation of hemolytic activity of the fourth component of human complement.

Based on a method that uses the fourth component of complement (C4)-deficient guinea pig serum to quantify the hemolytic activity of C4, we developed an assay that allows the processing of a large number of individual samples with high reproducibility. In contrast to the conventional procedure using titration curves of each sample to be determined, we can show that a single appropriate dilution of the sample allows accurate quantitation of hemolytic activity. The reliability of the procedure is demonstrated using either C4A- or C4B- deficient and normal individual samples.

Complement C4↗
PubMed1994

Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and the C4B genes in the HLA class III region. Molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplication.

The correlation of many HLA-associated autoimmune and genetic diseases with the polymorphic complement C4 genes may be attributed to the presence of disease susceptibility genes in the close proximity of C4. We have cloned and characterized a pair of partially duplicated genes, RP1 and RP2, located 611 base pairs upstream of the human C4A and C4B genes, respectively. The putative RP protein, consisting of 364 amino acid residues, is basic and highly hydrophilic. There is a bipartite nuclear localization signal at residues 114-131 and therefore RP may be a nuclear protein. Northern blot analysis suggested that RP is ubiquitously expressed. The 5' region of the RP1 gene is CpG rich, which is a characteristic of housekeeping genes. The RP1 gene contains nine exons. Located in the fourth intron is a cluster of Alu elements, and a newly defined composite retroposon SVA with a SINE, multiple copies of GC-rich VNTRs and an Alu element altogether enclosed by direct terminal repeats. Members of SVA are also present in the complement C2 gene located about 20 kilobases upstream of RP1 in the HLA and in the cytochrome CYP1A1 gene. Determination of the DNA sequences for RP2 from two different HLA haplotypes revealed identical hybrid sequences which resulted from fusion of RP with the tenascin-like Gene X and truncation of the 5' regions of both genes. Cumulative data suggest that the four tandemly arranged genes RP, complement C4, steroid 21-hydroxylase (CYP21), and Gene X altogether form a modular structure, RCCX. The number of RCCX modules varies from one to three or more in the population. Absence of the truncated genes RP2 and Gene XA have been detected in genomes with single RCCX modules. Duplication of the RCCX modules probably occurred before the speciation of great apes and humans as they contain the same breakpoint region of RP and Gene X gene duplication.

Alleles↗
PubMed1988

Serum protein markers in systemic lupus erythematosus.

Serum protein markers (alpha 1-AT, Bf, C3, C4A, C4B, Hp and Tf) were studied in a series of 36 patients with systemic lupus erythematosus (SLE) and compared to normal blood donors. In agreement with the results of previous investigations a significant increase of complement C4 deficiency was found among the SLE patients. The relative risks for AQ0 and BQ0 homozygosity were 7.2 and 4.1, respectively. Simultaneous occurrence of AQ0 and BQ0 was found in three patients with a calculated relative risk of about 65. A significant increase of the haptoglobin type 2-2 (p less than 0.05) was found among SLE patients. The remaining serum protein systems showed no statistically significant associations with SLE.

Blood Proteins↗
PubMed1991

Association of the complement allele C4AQ0 with primary Sjögren's syndrome in Japanese patients.

We studied allotypes of the fourth component of complement (C4) and factor B in 76 patients with Sjögren's syndrome (SS) and in 63 normal subjects. C4A-null (C4AQ0) was found in 10 of 28 patients who had primary SS, compared with 1 of 63 control subjects (P less than 0.005). In contrast, no significant difference in the frequency of any C4 allotype was observed between patients with secondary SS and control subjects. An association of HLA-DRw53 with primary SS in Japanese patients has been reported. Since there is no linkage disequilibrium between DRw53 and C4AQ0, it is possible that at least 2 genes in the major histocompatibility complex may determine susceptibility to the development of primary SS in the Japanese population.

Autoimmune Diseases↗
PubMed1986

[A study on the location of synthetic sites of the fourth and fifth components of the complement system in allogeneic bone marrow chimeras and hepatocyte transplantation chimeras].

In this study, the tissue sites for synthesis of fourth and fifth components of complement (C4, C5) have been investigated by using allogeneic bone marrow chimeras and bone marrow chimeras which were transplanted in addition with hepatocytes. One group of chimeric mice was prepared by transplanting bone marrow cells from C5-sufficient donor mice into irradiated C5-deficient recipients or vice versa, and another group was prepared by transplanting marrow cells from mice which produced high level of C4 into irradiated recipients which were characterized by having low level of C4 or vice versa. The results showed that C4 or C5 antigens were present in the sera of the chimeras only when recipients were strains which were characterized by having high C4 level or were C5-sufficient mice, respectively. These findings indicate that circulating C4 and C5 in the blood are not synthesized primarily by cells that are descendants of bone marrow cells in these chimeric mice. However, when hepatocytes isolated from the C5-sufficient strain were inoculated into the spleens of C5-deficient bone marrow chimeras, detectable amounts of C5 were present in the sera. These results indicate that C5 protein is synthesized and delivered to the blood in vivo by liver cells.

Animals↗
PubMed2002

Structure-function relationships for human antibodies to pneumococcal capsular polysaccharide from transgenic mice with human immunoglobulin Loci.

To investigate the influence of antibody structure and specificity on antibody efficacy against Streptococcus pneumoniae, human monospecific antibodies (MAbs) to serotype 3 pneumococcal capsular polysaccharide (PPS-3) were generated from transgenic mice reconstituted with human immunoglobulin loci (XenoMouse mice) vaccinated with a PPS-3-tetanus toxoid conjugate and their molecular genetic structures, epitope specificities, and protective efficacies in normal and complement-deficient mice were determined. Nucleic acid sequence analysis of three MAbs (A7, 1A2, and 7C5) revealed that they use two different V(H)3 genes (A7 and 1A2 both use V3-15) and three different V(kappa) gene segments. The MAbs were found to have similar affinities for PPS-3 but different epitope specificities and CDR3 regions. Both A7 and 7C5 had a lysine at the V(H)-D junction, whereas 1A2 had a threonine. Challenge experiments with serotype 3 S. pneumoniae in BALB/c mice revealed that both 10- and 1- micro g doses of A7 and 7C5 were protective, while only a 10- micro g dose of 1A2 was protective. Both A7 and 7C5 were also protective in mice lacking either an intact alternative (FB(-/-)) or classical (C4(-/-)) complement pathway, but 1A2 was not protective in either strain. Our data suggest that PPS-3 consists of epitopes that can elicit both highly protective and less protective antibodies and that the superior efficacies of certain antibodies may be a function of their structures and/or specificities. Further investigation of relationships between structure, specificity, and efficacy for defined MAbs to PPS may identify antibody features that might be useful surrogates for antibody (and vaccine) efficacy.

Animals↗
PubMed1988

Association of complement allotype C4B2 with anterior uveitis.

We have studied allotypes of the fourth component of complement (C4) in 44 patients with inflammatory eye disease in order to define genetic susceptibility factors further. Twenty-six patients had uveitis (18 had anterior uveitis) and 18 patients had retinal vasculitis. There was an increased incidence of the C4B2 allotype in patients with anterior uveitis (pc less than 0.002), especially in HLA B27 positive males. In contrast, there was no increased incidence of specific allotypes in patients with posterior uveitis or retinal vasculitis. This genetic association may form part of a disease susceptibility supratype in patients with anterior uveitis.

Alleles↗
PubMed1985

C4B3 allotype with a novel Ch phenotype.

The fourth component of complement (C4) has two classes of protein, C4A and C4B, both of which have many allelic forms. The serological determinants Rodgers (Rg1, Rg2) and Chido (Ch1, Ch2, Ch3) are generally associated with C4A and C4B, respectively. The C4B3 allotype has been detected in a single Canadian family that expresses a novel Ch phenotype, Ch:-1, 2, -3. There was no information for the Rg determinants, as the C4A*2B*3 haplotype would normally express Rg on the C4A protein. Other C4B3 allotypes in informative families have different Ch phenotypes, and the relationships of these within extended major histocompatibility complex haplotypes are discussed in this paper.

Alleles↗
PubMedDate not supplied

Immune profile of women experiencing recurrent spontaneous abortions of unknown aetiology.

Immunological and immunogenetic investigations are described in a group of 28 women with a history of unexplained recurrent (greater than or equal to 3 consecutive) spontaneous abortions (RSA). Compared with female blood donor controls, recurrent aborters had significantly elevated mean serum complement C4 (p less than 0.05), but not C3, levels. Immunoglobulin levels and T4:T8 ratios showed a similar distribution to the controls. Mixed lymphocyte reactivities to partners' lymphocytes were low in some of the patients, but hyporesponsiveness correlated well with husband-wife HLA-DR compatibility. No individual HLA specificity was significantly increased in the RSA patients, but the combination A3, B7, DR2 was common (p less than 0.02), and general HLA antigen sharing with partners was significantly increased (p less than 0.004) relative to obstetrically normal couples. RSA women who shared two or more HLA antigens with spouses had higher mean serum immunoglobulin concentrations, which for IgM reached statistical significance (p less than 0.05).

Abortion, Habitual↗
PubMed1989

Association of homozygous C4B deficiency with bacterial meningitis.

The fourth component of complement (C4) is encoded by two separate but linked loci (C4A and C4B), each of which produces functionally active C4. Although C4A and C4B share certain antigenic and functional characteristics that identify them as C4, they differ with respect to other structural and functional properties. For example, C4B possesses four times the functional hemolytic activity of C4A. This suggests that homozygous deficiency of C4B might be associated with an increased susceptibility to infection. Forty-six children with bacterial meningitis were examined. Of these, 5 (10.9%) were homozygous deficient for C4B versus 7 (3.1%) of 223 controls (P = 0.038). There was no relation between the prevalence of heterozygous C4B deficiency and meningitis or between the prevalence of either homozygous or heterozygous C4A deficiency and meningitis. These results suggest that homozygous C4B deficiency is a relatively common immunodeficiency disorder that is clinically significant and predisposes children to bacterial meningitis.

Adolescent↗
PubMed1996

Association of complement alleles C4AQ0 and C4B5 with rheumatoid arthritis in Koreans.

OBJECTIVE: To investigate the association of complement C4 allotypes with rheumatoid arthritis in Koreans. METHODS: 65 rheumatoid arthritis patients and 255 controls were typed for C4 allotypes and HLA-A, B, C, DR, and DQ antigens. RESULTS: The frequencies of C4AQ0 (32.3% v 14.9%, P < 0.005) and C4B5 (29.2% v 12.2%, P < 0.005) were significantly increased in rheumatoid arthritis patients compared with healthy control subjects. Among rheumatoid patients, the frequency of C4AQ0 was significantly increased in both the rheumatoid factor (RF) positive (27.3%) and the RF negative (66.7%) subgroups. The frequencies of C4B5 and HLA-DR4 were significantly increased only in RF positive subgroup. C4B5 was strongly associated with HLA-DR4, whereas C4AQ0 did not show association with DR4. CONCLUSIONS: In Koreans, C4AQ0 and C4B5 are associated with susceptibility to rheumatoid arthritis, as in the Japanese. C4B5 is strongly associated with HLA-DR4. C4AQ0 is considered to be a DR4 independent risk factor, and a disease susceptibility allele in linkage disequilibrium with C4AQ0 is suggested in Korean patients with rheumatoid arthritis.

Adult↗
PubMed2006

Use of a PCR-based amplification analysis as a substitute for the Southern blot method to determine the C4A and C4B genes.

The human C4 complement components of the C4 gene are encoded by two genes, C4A and C4B, located on chromosome 6p21.3 of the major histocompatibility complex (MHC) of the human leukocyte antigen (HLA) class III region. Genetic determination of these two genes was by the Southern blot method: the 276- and 191-bp NlaIV fragments represent the C4A gene with the sequence, PCPVLP, at residues 1101-1106; the 467-bp NlaIV fragment represents the C4B gene with the sequence, LSPVIH, at residues 1101-1106. Here, we describe a PCR-based approach for differential amplification of the C4 genes adjacent to the respective CYP21A1P and CYP21A2, followed by NlaIV restriction digestion in a secondary PCR product and direct analysis by electrophoresis on an agarose gel to determine the C4A and C4B genes. From the results of this study, we concluded that 87% and 85% of the C4 genes adjacent to the CYP21A1P and CYP21A2 genes carried the C4A and C4B genes, respectively. The frequencies of the C4A and C4B genes comprising the C4 locus were 51.5 and 49%, respectively in this ethnic Chinese (Taiwanese) cohort. Since no radiolabelling application is involved, the protocol is reliable as a substitute for the Southern blot method for C4A and C4B determination.

Blotting, Southern↗
PubMed1988

Inherited deficiency of the fourth component of human complement.

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes, and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Despite considerable structural homology, the gene products of the two loci differ in hemolytic activities, antigenic reactivities and covalent binding affinities to antigens and antibodies. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. In contrast, partial C4 deficiency is a common immune protein defect in all human populations as a consequence of the high frequency of the C4 half-null haplotypes. Complete C4 deficiency in most cases gives rise to SLE and an increased susceptibility to infections, and partial C4 deficiencies predispose to different auto-immune diseases related to extended HLA haplotypes bearing the C4 half-null haplotypes. Studies at the DNA level have shown that about half of the null alleles are due to deletions involving C4A and 21-OHA, C4B and 21-OHA or C4B and 21-OHB. Larger deletions including both C4A and C4B genes have never been observed. Partial C4 deficiency may be observed in combination with other complement deficiencies or immune defects, and allo- or auto-anti-C4 immunization is also a possible consequence of this genetic abnormality. Although the pathogenesis of the diseases related to complete and partial C4 deficiencies is not yet clearly understood, it is evident that C4 null alleles represent interesting markers and additive risk factors for autoimmune phenomena.

Alleles↗
PubMed2003

Acute upper airway angioedema secondary to acquired C1 esterase inhibitor deficiency: a case report.

PURPOSE: Adverse reactions to local anesthetics are widely reported. We report a case of acute upper airway angioedema presumed to be due to the local anesthetic articaine, which was subsequently diagnosed as acquired C1 esterase inhibitor deficiency. CLINICAL FEATURES: A 54-yr-old woman presented with a history of progressive facial and periorbital edema 24 hr after receiving articaine local anesthetic for a dental procedure. She was in mild respiratory distress but was not stridorous. After inhalational induction with sevoflurane in the operating room, direct laryngoscopy revealed marked edema of supraglottic structures including epiglottis, uvula and aryepiglottic folds and the larynx was not visualized. The patient's trachea was intubated under direct laryngoscopy. Seventy-two hours later, the endotracheal tube was removed and she made an uneventful recovery. Initially, the angioedema was thought to be caused by a hypersensitivity reaction to articaine. Later investigations showed normal C3 complement level, very low C4 complement and C1 esterase inhibitor levels confirming a diagnosis of C1 esterase inhibitor deficiency. Subsequently, the patient was started on androgen therapy. Her C1 esterase inhibitor level normalized and she remained symptom free nine months after initial presentation. CONCLUSION: We report a case of acute upper airway angioedema secondary to C1 esterase inhibitor deficiency requiring emergency airway management. Anesthesiologists should consider C1 esterase inhibitor deficiency in the differential diagnosis of patients with airway edema and be familiar with the acute and prophylactic treatment of patients with this diagnosis.

Acute Disease↗
PubMed1989

Isolation and characterization of a novel plasma protein which binds to activated C4 of the classical complement pathway.

We report here the isolation and partial characterization of a previously unrecognized protease-sensitive plasma protein identified during the development of a novel protocol for the purification of the second component of human complement (C2). This new protein is physicochemically similar to C2. It coprecipitates with C2 on polyethylene glycol fractionation and specifically binds, like C2, to Sepharose-bound iC4/C4b. Binding occurs both in the presence and absence of C2. The purified protein has a chain structure similar to C2 as determined by sodium dodecyl sulfate-gel electrophoresis in the presence or absence of reducing agent and has a molecular mass of 120 kDa, only somewhat greater than C2 at 95 kDa. Both proteins radioiodinate under similar conditions to the same specific activities with each of two different methods that yield 10-fold disparate results. Quantitative Mancini analysis identifies 300 micrograms/ml of the 120-kDa protein in plasma and serum. The protein is present at normal concentrations in serum from individuals genetically deficient in C2, has no C2 functional activity, and is not cleaved as is C2 when serum complement is activated. Potent monospecific polyclonal anti-serum to each do not cross-immunoprecipitate using standard gel techniques. However, these anti-sera identify epitopes in common by Western blotting. The data presented indicate that the 120-kDa protein is a distinct plasma component and suggest that the protein is not an "immature" form of C2. Initial experiments to delineate a functional role for the 120-kDa protein have demonstrated a consistent inhibition of C1 site generation on EAC4b which is dose-dependent and reversible. Thus, this protein appears to be a new complement regulatory factor.

Blood Proteins↗