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PubMed1988

Restriction fragment length polymorphisms of the complement component C4 loci on chromosome 6: studies with emphasis on the determination of gene number.

Restriction fragment length polymorphisms of the C4 region of human chromosome 6 have been studied in family material where the haplotypes are defined with regard to other genetic markers in this region. Employing one near full-length C4 probe and the combination of BglII and XbaI enzymes, five different C4 genes were characterized. Studies of the segregation of DNA patterns in families made possible the reliable determination of DNA C4 haplotype pattern including gene number. In the total material of 76 haplotypes, 13 different types with regard to number and/or DNA type of C4 gene(s) were encountered. Twelve of the haplotypes had one C4 gene only, 58 had two genes, while 6 had three C4 genes. This fits fairly well with the hypothesis that the one- and three-gene haplotypes have originated through unequal crossing-over between chromosomes carrying duplicated C4 genes.

Blotting, Southern↗
PubMed1978

Response to corticosteroids in the hypereosinophilic syndrome. Association with increased serum IgE levels.

Severe blood eosinophilia (16,500/cu mm and 6,500/cu mm) accompanied by involvement of the lungs, pleura, heart, pericardium, liver, gastrointestinal tract, peripheral nerves, or skin developed in two patients with bronchial asthma. Associated with the eosinophilia were elevated serum IgE levels (1,400 IU/ml and 10,500 IU/ml), depressed serum C4 complement levels (13 mg/100 ml and 6 mg/100 ml), and high titers of rheumatoid factor (1:2560 and 1:640). Symptoms improved after treatment with prednisone and the eosinophil counts and serum IgE and C4 complement levels returned to normal.

Asthma↗
PubMed1982

Storage of the complement components C4, C3, and C 3-activator in the human liver as PAS-negative globular hyaline bodies.

Liver biopsies of a 58-year-old clinically healthy patient with a hepatomegaly and intracisternal PAS-negative globular hyaline bodies were immunofluorescent-optically examined for the content of the complement components C 1 q, C 4, C 9, C 1-inactivator, C 3-activator. Further examinations were performed for fibrinogen, IgG, IgA, IgM, IgD, IgE, L-chain (type chi and lambda), alpha 1-antitrypsin, alpha 1-fetoprotein, alpha 1- and alpha 2-glycoprotein, cholinesterase, ceruloplasmin, myoglobin, hemopexin, HBsAg and HBsAg. Th inclusion bodies reacted with antisera against the complement components C 4, C 3 and C 3-activator, as also identified by double immunofluorescence. Probably this is a disturbance of the protein metabolism of the liver cell with abnormal complement storage in the presence of normal total complement and normal complement components in the serum.

Complement Activating Enzymes↗
PubMed2002

X-ray crystal structure of the C4d fragment of human complement component C4.

C4 fulfills a vital role in the propagation of the classical and lectin pathways of the complement system. Although there are no reports to date of a C4 functional activity that is mediated solely by the C4d region, evidence clearly points to it having a vital role in a number of the properties of native C4 and its major activation fragment, C4b. Contained within the C4d region are the thioester-forming residues, the four isotype-specific residues controlling the C4A/C4B transacylation preferences, a binding site for nascent C3b important in assembling the classical pathway C5 convertase and determinants for the Chido/Rodgers (Ch/Rg) blood group antigens. In view of its functional importance, we undertook to determine the three-dimensional structure of C4d by X-ray crystallography. Here we report the 2.3A resolution structure of C4Ad, the C4d fragment derived from the human C4A isotype. Although the approximately 30% sequence identity between C4Ad and the corresponding fragment of C3 might be expected to establish a general fold similarity between the two molecules, C4Ad in fact displays a fold that is essentially superimposable on the structure of C3d. By contrast, the electrostatic characteristics of the various faces of the C4Ad molecule show marked differences from the corresponding faces of C3d, likely reflecting the differences in function between C3 and C4. Residues previously predicted to form the major Ch/Rg epitopes were proximately located and accessible on the concave surface of C4Ad. In addition to providing further insights on the current models for the covalent binding reaction, the C4Ad structure allows one to rationalize why C4d is not a ligand for complement receptor 2. Finally the structure allows for the visualization of the face of the molecule containing the binding site for C3b utilized in the assembly of classical pathway C5 convertase.

Amino Acid Sequence↗
PubMed2002

Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice.

Mice with a disrupted C4 locus (C4(-/-)) have an impaired immune response to thymus-dependent Ags. To test the role of bone marrow-derived C4 in humoral immunity, we reconstituted deficient animals with wild-type bone marrow or an enriched fraction of bone marrow-derived macrophages. C4 chimeras were immunized with 4-hydroxy-3-nitrophenyl(5) conjugated to keyhole limpet hemocyanin (NP(5)- KLH) or infected with HSV-1, and the Ab response was evaluated. Wild-type bone marrow rescued the humoral immune response to both Ags, i.e., the soluble Ag and HSV-1, demonstrating that local C4 production is sufficient for humoral responses. Although the C4 chimeric animals lacked detectable C4 in their sera, C4 mRNA was identified in splenic sections by in situ hybridization, and C4 protein deposits were identified in the germinal center areas of splenic follicles by immunofluorescence staining. Macrophages derived from bone marrow produced sufficient C4 protein to restore the humoral response to NP(5)-KLH in C4-deficient animals when administered along with Ag. Cell-sorting experiments, followed by C4-specific RT-PCR, identified splenic macrophages (CD11b(+), CD11c(-)) as a cellular source for C4 synthesis within the spleen.

Adoptive Transfer↗
PubMed1989

Plasma kinetics of complement component C4: comparison of three models.

Plasma C4 kinetics were studied in members of a kindred with hereditary incomplete C4 deficiency and in control subjects. Test subjects received iodine 125-labeled C4 intravenously, and plasma disappearance curves for 125I-C4 were plotted. By nonlinear least-squares analysis, we fit two-, three-, and four-exponential models of plasma disappearance to the plasma curves of each subject. Goodness of fit was significantly better for all subjects with the three-exponential versus the two-exponential model (p less than 0.0005). No further improvement in curve fit was accomplished by using a four-exponential model (p greater than 0.5). Metabolic rates and extravascular/plasma ratios calculated from the two- and three-exponential models were significantly different. As judged by extravascular/plasma ratio, the two-exponential model underestimated the amount of extravascular C4. Furthermore, the two-exponential model significantly over-estimated catabolic and synthetic rates. Hence, our results show that C4 kinetics are not optimally described by a conventional, two-exponential model. A possible explanation for our findings is that in previous studies of C4 metabolism, the analysis of plasma radioactivity disappearance curves was done by inspection, whereas we used least-squares analysis, a method that determines the number of exponentials with greater reliability.

Complement C4↗
PubMed1985

Haplotype study on C4 polymorphism in Japanese. Associations with MHC alleles, complotypes, and HLA-complement haplotypes.

Genetic polymorphism of the fourth component of human complement (C4) was investigated in 83 Japanese families which have been typed for HLA-A,-B,-C,-DR, C2, and BF. Four common C4A alleles and four common C4B alleles were observed. The allele frequencies estimated from unrelated parents were as follows: C4A3, 0.686; A4, 0.132; A2, 0.106; AQ0, 0.067; ARares, 0.009; C4B1, 0.587; B2, 0.167; B5, 0.088; and BQ0, 0.158. Eight different C4 haplotypes were observed with frequencies of more than 0.01. The estimated haplotype frequencies were as follows: C4A3-B1, 0.513; A4-B2, 0.114; A2-BQ0, 0.106; A3-B5, 0.088; AQ0-B1, 0.059; A3-BQ0, 0.047; A3-B2, 0.038; A4-B1, 0.015; and Rares, 0.021. Strong positive gametic associations were found in the following C4-HLA haplotypes: C4A2BQ0-A24, C4A2BQ0-Bw52, C4A3B5-Bw54, C4A3B5-Bw59, C4A4B2-Bw46, C4A3B5-Cw1, C4A2BQ0-DR2, and C4A3B5-DR4. Eleven complotypes were observed with frequencies of more than 0.01. C4A2BQ0 and C4A3B5 were exclusively associated with BFS-C2C. BFF was associated with C4A3B1. C2AT, C2B, and C2BH were associated with C4A3B1, A4B2, and C4A3B1, respectively. Eight different HLA-complement haplotypes were found to be characteristic of Japanese. These combinations are considerably different from those reported in Caucasoid populations.

Alleles↗
PubMed1993

The thioester and isotypic sites of complement component C4 in sheep and cattle.

The region inclusive of the thioester and the isotype-determining sites of the sheep C4 genes from a single animal was amplified by polymerase chain reaction (PCR). Two bands, at 880 base pairs (bp) and 1000 bp, were resolved by agarose gel electrophoresis. Four different clones were obtained for the 880 bp (type 1) product and two from the 1000 bp (type 2) product. Two of the type 1 clones (type 1H) and both type 2 clones (type 2H) code for the PCPVIH sequence at the isotypic site whereas the other two type 1 clones (type 1D) code for the PFPVMD sequence. By restriction mapping and Southern blot analysis, there appears to be four C4 gene loci for the sheep: two type 1H, one type 1D, and one type 2H. The type 1H and type 2H genes are likely to code for proteins with C4B-like properties whereas the type 1D genes for proteins with C4A-like properties. The same region of the sheep C4 genes of nine other breeds of sheep are also amplified by PCR and analyzed by restriction mapping and Southern hybridization. Each of the sheep has type 1H, type 2H, and type 1D genes and appears to have four C4 gene loci except for the Orkney, which may have five. A single band of 880 bp was obtained from the PCR product from the genomic DNA of a single cow. Five different clones were identified, two of which code for the PFPVMD sequence and three for the PCPVIH sequence at the isotypic site, which is consistent with previous finding that C4 proteins with A- and B-like activities could be purified from the plasma of the same animal. Comparison of the nucleotide sequences of the isotype-determining region of the sheep and cattle C4 genes with those of the primates and mouse suggests that the C4A-like genes evolved independently in the primates and the ungulates.

Amino Acid Sequence↗
PubMed1989

[The 4th complement factor (C4) and t haplotypes in wild mice].

Five different lines of tailless mice bearing different t recessive haplotypes (tAn, tMo, tRa, tLa and tQu) have been established in our laboratory and maintained in combination with the brachury chromosome (T). These t haplotypes were derived from widely separated Chilean wild mouse populations. The immunoelectrophoretic typing for Ss and Slp isotypic variants of C4 showed that all lines had the Ss-High. Slp-negative phenotype suggesting that the t haplotypes might be associated with similar S regions of the major histocompatibility system of the mouse.

Animals↗
PubMed1987

Role of the fourth complement component (C4) in the regulation of contact sensitivity. I. Analysis in mice with high and low C4 levels.

Lymph node cells collected from CBA/J mice 4 days after painting the skin with picryl chloride are able to immunize naive recipients by hapten-IgM immuno complexes. These cells ("4-day" cells) activate the early components of the classical pathway of complement from mice of the H-2 Sd haplotype (high-C4), but fail to activate the classical pathway of complement from mice of the H-2 Sk haplotype (low-C4). Incubation of "4-day" cells in complement from mice with high-C4 levels abolishes the induction of contact sensitivity, probably as a consequence of the solubilization of membrane-bound immuno complexes caused by complement activation. The presence of "4-day" cells is determined by the levels of C4. In fact, using strains of mice which differ only at the S region of the H-2 complex, we found that mice of the H-2 Sd (and perhaps H-2 Sb) haplotype (high-C4 levels) lack "4-day" cells in their lymph nodes and this is due to the activation of the early components of the classical complement pathway which occurs in vivo in these mice during sensitization with picryl chloride. The finding that contact sensitivity reaction to picryl chloride in H-2 Sk mice lasts about 21 days, whereas H-2 Sd mice show a contact sensitivity reaction until 7 days after sensitization, strongly suggests that the S region, and in particular C4 levels, controls the persistence of "4-day" immunogenic cells, and so play a role in the duration of the contact sensitivity reaction to picryl chloride in the mouse.

Animals↗
PubMedDate not supplied

Immune function in acute stress.

UNLABELLED: The aim of this study was to evaluate immune function in acute stress in medical students before academic examinations. Twenty-five medical students were selected because they presented intense acute stress, evaluated by the presence of the following classic signs: cold hands, intense sudoresis in the extremities, generalized sudoresis, paleness, tachycardia, confused reasoning, nervous irritability, diarrhea, and sleep disorders in the hours preceding the examination (agitated sleep, insomnia). METHODS: Immediately before the examination, peripheral blood was collected from the 25 students presenting acute stress to analyze T and B cells, CD4+ and CD8+ cells, immunoglobulins, and C3 and C4 complement components, as well as phagocytic activity in neutrophils and monocytes. These investigations were repeated in the same students in situations free of acute stress. The results of the two samples collected from each student were compared. RESULTS: The means and standard deviations showed no significant differences for any of the parameters analyzed (p> or =0.01). CONCLUSION: We conclude that acute stress did not cause changes in the lymphocyte subpopulations, phagocytic activity of neutrophils and monocytes, serum immunoglobulins, or C3 and C4 complement components in students participating in the present study. In conditions of basal chronic stress, acute stress may cause alterations in immune function.

Acute Disease↗
PubMed1977

Pleural fluid complement, complement conversion, and immune complexes in immunologic and nonimmunologic diseases.

Forty-four pleural fluids and 41 blood specimens from patients with various diseases were examined for concentration of whole complement, C4, C3, conversion products of C3 and C3PA, and immune complexes. C3 conversion was found in all eight pleural fluids from patients with rheumatoid arthritis, five of seven with lupus erythematosus, two of six with congestive heart failure, and nine of 23 with malignant diseases. Conversion of C3PA correlated closely with C3 conversion and both were significantly inversely related to whole complement, C4, and C3. Concentration of immune complexes was highest in patients with rheumatoid arthritis. Pleural fluid immune complex concentrations correlated positively with conversion of C3 and C3PA. These findings suggest that the reduced levels of pleural fluid complement in rheumatoid arthritis and lupus erythematosus may be secondary to complement conversion by immune complexes.

Antigen-Antibody Complex↗