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PubMed1984

MHC-linked class III genes. Analysis of C4 gene frequencies, complotypes and associations with distinct HLA haplotypes in German Caucasians.

The class III complement components, C4, C2 and factor B (BF), are encoded in the human major histocompatibility complex (MHC). The two genes determining C4 (C4A and C4B) display considerable polymorphism and, thus, are important markers for HLA. In combination with alleles of C2 and BF they can be grouped into unique complotypes. We have analyzed the C4 alleles in a panel of 204 unrelated German Caucasians and studied their segregation with HLA haplotypes in 24 normal families. Inclusion of the class III markers with the class I and II alleles provides a more refined picture of the genetic structure of the MHC in these families. When charted according to the HLA-B locus specificities the MHCs can be clustered into groups showing distinctly homogenous or heterogenous complotypes. The identification of such groups is valuable for the selection of genetic material to analyze the molecular genetics of the human MHC.

Complement C2↗
PubMed1990

Scleral fibroblasts. Human leukocyte antigen expression and complement production.

The authors investigated the ability of recombinant human gamma-interferon (rhIFN-gamma) to influence production of complement and expression of human leukocyte antigens (HLA) by human scleral fibroblasts in culture. Cell cultures were established by explanting sclera from normal human donor eyes. To study complement production, fibroblasts were treated with 500 units/ml rhIFN-gamma in cell culture, and media were tested for complement components by hemolytic assay after 0, 1, 3, 6, 9, and 11 days. To induce Class II HLAs, fibroblasts were exposed to rhIFN-gamma at concentrations ranging from 10-500 units/ml and incubated for 1, 3, and 6 days. The HLAs were detected by immunofluorescence in conjunction with flow cytometry. Class I antigen was detected using a monoclonal antibody directed against beta 2-microglobulin. Class II histocompatibility antigens were identified using monoclonal antibodies specific for HLA-DR, -DP, and -DQ. Although complement component C1 was produced constitutively in cell culture, the addition of rhIFN-gamma resulted in an increase in production. Complement components C2 and C4 were detected only after treatment with rhIFN-gamma. Complement production was completely inhibited by cycloheximide, and C3, C5, C6, and C7 were not present in cell culture media with or without rhIFN-gamma. Class I antigen was present on all cells before induction, and an increase in expression was noted after exposure to rhIFN-gamma. Class II antigens were absent before induction with rhIFN-gamma. After treatment with rhIFN-gamma, scleral fibroblasts expressed HLA-DR, -DP, and -DQ in a dose-dependent, time-related fashion. These findings suggest that rhIFN-gamma has multiple effects on scleral fibroblasts: (1) increased production of C1, (2) production of C2 and C4, (3) up-regulation of Class I antigen expression, and (4) expression of Class II antigens. They also suggest that scleral fibroblasts have the potential to participate in immunologic diseases of the eye.

Adult↗
PubMed1990

Complotypes in pemphigus vulgaris: differences between Jewish and non-Jewish patients.

Haplotypes of alleles of the major histocompatibility complex (MHC) complement genes BF, C2, C4A, and C4B are inherited as single highly polymorphic genetic units called complotypes. There are about a dozen complotypes with frequencies above about 0.01 in Caucasians. In the blistering disease pemphigus vulgaris, the complotypes SC21 and SB45 were found to be markedly elevated in patients compared with general Caucasian controls. The SC21 increase was in Ashkenazi Jewish patients exclusively (relative risk = 17 in that population), whereas SB45 was found solely in non-Jewish Caucasians (specific population relative risk = 57). Although these are unusually high relative risks, it is most unlikely that these complotypes represent susceptibility genes for pemphigus vulgaris. Rather, it is probable that they mark extended major histocompatibility complex haplotypes with fixed DNA so that independent examples in the population have the same alleles. It is likely that it is the class II genes on these haplotypes that confer susceptibility.

Complement C2↗
PubMed1986

HLA antigens and complement types in patients with intracranial saccular aneurysms.

The occurrence of HLA-A, -B, -C antigens and the HLA controlled complement factors (Bf, C2, C4) was investigated in an unselected group of 116 consecutively admitted patients with intracranial saccular aneurysms, and compared to that of healthy controls (blood donors). When multiplying the p-values with the number of comparisons made, none remained significant. However, a rather high etiologic fraction of the BfS gene (0.59) was obtained. Moreover, for HLA -B7 a significant deviation from the Hardy-Weinberg equilibrium with an increase of homozygotes was found. Due to linkage disequilibria this could indicate a strong association between HLA-DR2 and saccular aneurysms. The presence of HLA-DR2 was therefore investigated in a series of 15 aneurysm patients used as cadaver kidney donors and not included among the 116 consecutively admitted patients. In this group the HLA-DR2 antigen frequency was significantly increased (66.7% vs. 29.7%, p less than 0.01). The present study thus demonstrates an association of saccular aneurysm and the major histocompatibility complex and shows the existence of a genetic predisposition to saccular aneurysm.

Complement C2↗
PubMed2000

Phylogenetic analysis of a retroposon family as represented on the human X chromosome.

SINE-R elements constitute a class of retroposons derived from the long terminal repeat (LTR) of the human endogenous retrovirus HERV-K family that are present in hominoid primates and active in the human genome. In an investigation of the X chromosome, we identified twenty-five SINE-R elements with between 89.6 and 97.7% homology with the SINE-R.C2 element that is human specific, originally identified in the gene for the C2 component of complement. SINE-R.C2 and a sequence HS307 that we previously identified in a region of Xq21.3 that has a recently created homology with a 4 Mb block in Yp11.2 are amongst the group of elements that have diverged furthest from the parent HERV-K10 sequence. The sequence on the X chromosome resemble those that we previously described on chromosomes 7 and 17 and the Y chromosome, with a similar range of variation. Phylogenetic analysis from the retroposon family including those of African great apes using the neighbor-joining method suggests that the SINE-R retroposon family have evolved independently during primate evolution. Further investigation of SINE-R elements on the sex chromosomes, particularly in recently created regions of X-Y homology, may cast light on the timing of the retroposition process and its possible relevance to recent evolutionary change.

Animals↗
PubMed1975

Deficiencies of the complement system in man.

Deficiencies of components of the complement system in man are described. Clq was reconstituted in patients with severe combined immunodeficiency after bone marrow transplantation. Clr deficiency is associated with vascular disease and upper respiratory infections. Reconstitution of complement occurred in one patient with Clr deficiency after kidney transplantation. Our C2-deficient patient who developed systemic lupus erythematosus had elevated levels of C3. Following blood transfusion, ie by providing C2, dramatic activation of complement occurred in vivo.

Blood Bactericidal Activity↗
PubMed1979

Inhibition of in vitro synthesis of the second (C2) and fourth (C4) components of complement in guinea pig peritoneal macrophages by a soybean oil emulsion.

Recently a soybean oil emulsion (Intralipid) (IL) has been released in the United States for use as a parenteral nutrient. The study reported here was undertaken to determine the effect of ingestion of IL on the synthesis and secretion of the second (C2) and fourth (C4) components of complement by guinea pig peritoneal macrophages in vitro. Cells exposed to IL had extensive Oil Red 0-positive granular-appearing accumulations of neutral lipid within the cytoplasm. Control cells did not stain with Oil Red 0. Incubation of the cells with concentrations of IL from 2.3--37.5 mg/100 ml resulted in a significant decrease in the production of both C2 and C4, which could not be explained by variability between plates. The decrease in total C2 or C4 production by cells incubated with IL for 4 hr was similar to the decrease in production by cells incubated with IL for 48 hr. Several lines of evidence indicated that the decrease of C2 or C4 was the result of decreased synthesis of these proteins and not interference of IL with the detection of the proteins or their secretion from the cells. Exposure of the cells to IL at all concentrations caused reduction of the number of cells having pseudopodia and a rounding-up of the cells. IL did not affect the rate of detachment of the cells from the plates through the 48-hr incubation period or the ability of the cells to exclude trypan blue. Total protein synthesis and total lysozyme production by control and IL-treated cells was similar.

Animals↗
PubMed1987

Vasculitis simulating eczematous dermatitis due to C2 deficiency.

In a patient with total C2 deficiency and repeated respiratory infections a papulovesicular rash showed to be due to leukocytoclastic vasculitis. The patient's brother also had a total deficiency of C2 but no clinical symptoms. HLA-investigation in both him and the proband showed the genotype commonly reported in cases with homozygous C2 deficiency. Their heterozygous mother and sister had slightly decreased C2 levels.

Adult↗
PubMed2007

Molecular interactions between MASP-2, C4, and C2 and their activation fragments leading to complement activation via the lectin pathway.

Activation of component C3 is central to the pathways of complement and leads directly to neutralization of pathogens and stimulation of adaptive immune responses. The convertases that catalyze this reaction assemble from fragments of complement components via multistep reactions. In the lectin pathway, mannose-binding lectin (MBL) and ficolins bind to pathogens and activate MBL-associated serine protease-2 (MASP-2). MASP-2 cleaves C4 releasing C4a and generating C4b, which attaches covalently to the pathogen surface upon exposure of its reactive thioester. C2 binds to C4b and is also cleaved by MASP-2 to form the C3 convertase (C4b2a). To understand how this complex process is coordinated, we have analyzed the interactions between MASP-2, C4, C2, and their activation fragments and have compared MASP-2-catalyzed cleavage of C4b2 and C2. The data show that C2 binds tightly to C4b but not to C4, implying that C4 and C2 do not circulate as preformed complexes but that C2 is recruited only after prior activation of C4. Following cleavage of C4, C4b still binds to MASP-2 (KD approximately 0.6 microM) and dissociates relatively slowly (koff approximately 0.06 s-1) compared with the half-life of the thioester (<or=0.7 s) (Sepp, A., Dodds, A. W., Anderson, M. J., Campbell, R. D., Willis, A. C., and Law, S. K. (1993) Protein Sci. 2, 706-716). We propose that the C4b.MASP-2 interaction favors attachment of C4b near to the activating MBL.MASP complex on the bacterial surface so that, following recruitment of C2, the proximity of enzyme and substrate (C4b2) combined with more favorable reaction kinetics drive the formation of the C3 convertase, promoting complement activation.

Animals↗
PubMed1998

Independent duplications of Bf and C3 complement genes in the zebrafish.

As part of an ongoing project aimed at the characterization of the MHC system in bony fishes, we have attempted to identify the class III region in the zebrafish (a teleost), a region that in higher vertebrates contains genes coding for complement proteins C2, Bf and C4. We obtained several genomic PAC clones by hybridization with a zebrafish Bf probe, previously identified in our laboratory, and searched these for the presence of other class III genes. We were able to obtain a second Bf-like gene, however, we were unable to detect any C2- or C4-like genes. By using highly degenerated primers, we extended our search to a hepatopancreas cDNA library and amplified from it clones corresponding to three different C3-like genes, and also the Bf genes, but not any C2- or C4-like genes. The zebrafish therefore contains two Bf and three C3 loci but apparently no C2 and C4 loci. Independent duplications of the Bf and C3 genes in bony fishes suggest that complement plays a prominent part in the immune response of this class of vertebrates.

Amino Acid Sequence↗
PubMed1988

The mechanism of discordant xenograft rejection.

The mechanism of discordant xenograft rejection using the guinea pig-to-rat heart graft model was studied. In this model, we found that (A) Rejection occurred rapidly, in 17.5 +/- 8.3 min (mean +/- SD) (n = 8). (B) The graft survived longer when the recipient rat was pretreated with cobra venom facter (CVF). (C) Complement hemolytic titers in serum showed significant reduction of C3 in rejection without consumption of C4 and C2, suggesting complement activation through the alternative pathway. (D) No natural antibodies were detected in this combination. Complement-dependent cytotoxicity (CDC) titer, and hemagglutination (HA) titer were lower than x1. (E) Histological examination of the rejected heart xenograft revealed a large area of myocytolysis without interstitial cellular infiltration. (F) In vitro experiments showed that rat complement attacked guinea pig erythrocytes (Egp) via the alternative pathway. These findings indicate that rejection in this discordant xenograft model of guinea pig-to-rat was caused by primary activation of complement via the alternative pathway.

Animals↗