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PubMed2004

Risk factors for capillary C4d deposition in kidney allografts: evaluation of a large study cohort.

BACKGROUND: Capillary deposition of the complement split product C4d has turned out to be a valuable marker of antibody-mediated rejection. The impact of pre- and posttransplant variables including particular immunosuppressive regimens on the frequency of C4d deposition has not yet been systematically investigated in a large multivariate analysis. METHODS: In this retrospective study, the authors evaluated the incidence of C4d deposition in 388 kidney transplant recipients subjected to diagnostic biopsy within the first 6 months and analyzed the influence of potential confounders on the rate of C4d-positive graft dysfunction by applying multivariate logistic regression. RESULTS: Sixty-six recipients (17%) developed linear C4d deposits in at least a quarter of peritubular capillaries, a finding associated with inferior 1-year allograft survival (73% vs. 88% in C4d-negative patients, P=0.0003). A 50% reduction in the odds of C4d-positive graft dysfunction was found if calcineurin inhibitor or mycophenolate mofetil (MMF) therapy was started 2 to 4 hr before transplantation when compared with initiation after surgery (adjusted odds ratio [OR], 0.5; P=0.03). No differences with respect to C4d staining results were found for the use of tacrolimus, MMF, or sirolimus, or for cyclosporine C2 monitoring. Retransplantation (OR, 3.6; P<0.001) and presensitization (OR, 3.1; P=0.002) turned out to be strong independent risk factors for C4d deposition. CONCLUSIONS: The authors' results suggest a reduced risk of C4d-positive graft dysfunction for patients receiving immunosuppression before transplantation. Apart from first dose timing, no influence of particular immunosuppressive strategies on C4d staining results was found.

Adult↗
PubMed1989

Factor J: isolation and characterization of a new polypeptide inhibitor of complement C1.

An Mr 20,000 protein inhibitor of C1, the first component of complement, has been purified from human urine and characterized. This inhibitor, tentatively designated factor J, is apparently distinct from known complement inhibitors. During purification on QAE-Sephadex, Mono Q, and heparin-Sepharose, factor J was detected by its ability to inhibit the complement-mediated lysis of sheep erythrocytes bearing antibody, C1, and activated C4 (EAC14). The purity of factor J was documented by the concordant elution from a hydroxylapatite column of functional activity and the UV absorbance as measured at three different wavelengths (220, 254, and 280 nm). The relative Mr of 20,000 was determined by sodium dodecyl sulfate-slab gel electrophoresis of radioiodinated protein. Amino acid analysis indicated a high cysteine content and allowed calculations of a specific activity of 7 functional units/pmol. The target of factor J inhibitory activity on the lysis of EAC14 was localized to C1 by the following criteria: factor J inhibited C1 in a C1 transfer assay, but had no effect on C42 activity or decay, and had no effect on the efficiency of isolated C2 or C3-C9 as provided in serum-EDTA. Factor J inhibition was rapid and not significantly influenced by temperature. In a second functional assay, factor J inhibited the association of the tetrameric complex C1r2s2 with 125I-C1q, and the results, when analyzed graphically by a reciprocal plot, were consistent with noncompetitive inhibition (Ki = 529-760 pM range). Functional and/or antigenic data indicated that factor J is distinct from the other known inhibitors of C1, namely the C1 inhibitor and the C1q inhibitor. Antihuman serum precipitated radioiodinated factor J, indicating that an antigen identical or cross-reacting with factor J exists in serum. In summary, factor J is a newly described potent inhibitor of C1 function.

Animals↗
PubMed2000

Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema.

BACKGROUND: Two genetic forms of hereditary angioedema (HAE) are currently recognized. Both are transmitted in an autosomal dominant manner and are characterized by recurrent episodes of localized angioedema. Involvement of the gut leads to episodes of severe abdominal pain, and laryngeal involvement can lead to airway obstruction and even death. One type results from heterozygosity for a nonexpressed C1 inhibitor allele, and the other results from heterozygosity for a nonfunctional C1 inhibitor allele. OBJECTIVE: This report identifies a third type of HAE, with a unique estrogen-dependent phenotype. METHODS: Detailed medical histories were obtained from family members, and a pedigree was constructed to ascertain the mode of inheritance. Determination of serum complement factors, C1 inhibitor protein, C1 inhibitor function, coagulation factor XII, plasma prekallikrein, high molecular weight kininogen, and selected DNA sequences were performed in affected members by using standard assays. RESULTS: Episodes of angioedema were clinically indistinguishable from those associated with previously described forms of HAE; however, these occurred only during pregnancy or the use of exogenous estrogens. Patients were otherwise asymptomatic, except for one patient who had acetyl salicylic acid/nonsteroidal anti-inflammatory drug-related angioedema later in life. History was available for members spanning 4 generations, and affected individuals were identified in 3 generations. Of 46 family members, phenotype could be determined in 13 members. Seven were affected, and 6 were not. One male of undetermined phenotype was an obligate carrier. The unique estrogen-dependent nature of the phenotype means that the status of several members in the third and fourth generation remains unknown. The disorder appears to be transmitted in an autosomal dominant fashion, although other modes of inheritance cannot be excluded entirely. C1 inhibitor protein, C1 inhibitor function, C2, C4, C1q, coagulation factor XII, prekallikrein, and high molecular kininogen were normal in 3 affected family members during asymptomatic periods. DNA sequencing revealed no abnormality in 3 patients in the coding region of the gene encoding C1 inhibitor or in the 5' flanking regions of the genes encoding C1 inhibitor and factor XII. CONCLUSIONS: This family appears to have a novel form of inherited angioedema that does not result from C1 inhibitor deficiency or dysfunction. The phenotype is uniquely estrogen dependent. Implications for diagnosis and treatment are discussed. Further studies are required to define the exact nature of the genetic abnormality involved.

Adult↗
PubMed1986

Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI.

We report the regional mapping of human chromosome 19 genes for three apolipoproteins and a lipoprotein receptor as well as genes for three other markers. The regional mapping was made possible by the use of a reciprocal whole-arm translocation between the long arm of chromosome 19 and the short arm of chromosome 1. Examination of three separate somatic cell hybrids containing the long arm but not the short arm of chromosome 19 indicated that the genes for apolipoproteins CI, CII, and E (APOC1, APOC2, and APOE, respectively) and glucose-6-phosphate isomerase (GPI) reside on the long arm, whereas genes for the low density lipoprotein receptor (LDLR), complement component 3 (C3), and peptidase D (PEPD) reside on the short arm. When taken together with previous studies, our results suggest the following physical gene map: pter-LDLR-C3-p13.2-PEPD-centromere-(APOE, APOC1, APOC2, GPI)-qter. In addition, we have isolated a single lambda phage carrying both APOC1 and part of APOE. These genes are tandemly oriented and are separated by about 6 kilobases of genomic DNA. Since previous family studies indicate tight linkage of APOE and APOC2, the apolipoprotein genes APOC1, APOC2, and APOE form a tight complex on the long arm of chromosome 19, suggesting the possibility of coordinate regulation.

Apolipoprotein C-I↗
PubMed2003

Single-pollen analysis by laser-induced breakdown spectroscopy and Raman microscopy.

The application of laser-induced breakdown spectroscopy to the analysis of single biological microparticles (bioaerosols) is described, exemplified here for a range of pollens. Spectra were recorded by exposure of the pollen to a single laser pulse from a Nd:YAG laser (lambda = 1064 nm, Ep approximately 30 mJ). The intensities of the single-pulse laser-induced breakdown spectra fluctuated dramatically, but an internal signal calibration procedure was applied that referenced elemental line intensities to the carbon matrix of the sample (represented by molecular bands of CN and C2). This procedure allowed us to determine relative element concentration distributions for the different types of pollen. These pollens exhibited some distinct concentration variations, for both major and minor (trace) elements in the biomatrix, through which ultimately individual pollens might be identified and classified. The same pollen samples were also analyzed by Raman microscopy, which provided molecular compositional data (even with spatial resolution). These data allowed us to distinguish between biological and nonbiological specimens and to obtain additional classification information for the various pollen families, complementing the laser-induced breakdown spectroscopy measurement data.

Aerosols↗
PubMed2002

The quality of MCS+ version C2 double dose platelet concentrate with leucodepletion through a continuous filtration process.

182 full double donations were collected, using 7-9 cycles with an in-house guideline based on donor HCT, and platelet count. 95.6% of donations were within specifications for platelet yield and 100% were leucodepleted. To overcome the potential for red cell spill-over when the platelet peak is too small, automated continuous monitoring of machine performance has been introduced reducing the potential for spill-over. To understand the impact of the continuous exposure of platelets to the filter, the quality of the first and second part of the collection was monitored using a new set of markers for the platelet storage lesion (activation, microvesiculation, cellular injury, complement and response to ADP). The results were equivalent and compared well with routine practice. Our new protocol allows a wide range of donors to be selected and the highest percentage of products to meet the UK specification with consistency. It is recommended that it can be used for double dose platelets with routine SPM.

Blood Platelets↗
PubMed2006

Synthesis and properties of trans-3',4'-bridged nucleic acids having typical S-type sugar conformation.

The synthesis of nucleoside analogues with a conformationally restricted sugar moiety is of great interest. The present research describes the synthesis of BNA (bridged nucleic acid) monomers 1 and 2 bearing a 4,7-dioxabicyclo[4.3.0]nonane skeleton and a methoxy group at the C2' position. Conformational analysis showed that the sugar moiety of these monomers is restricted in a typical S-type conformation. It was difficult to synthesize the phosphoramidite derivative of the ribo-type monomer 1, while the phosphoramidite of the arabino-type monomer 2 was successfully prepared and incorporated into oligodeoxynucleotides (ODNs). The hybridization ability of the obtained ODN derivatives containing 2 with complementary strands was evaluated by melting temperature (T(m)) measurements. As a result, the ODN derivatives hybridized with DNA and RNA complements in a sequence-selective manner, though the stability of the duplexes was lower than that of the corresponding natural DNA/DNA or DNA/RNA duplex.

Amides↗
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↗
PubMed1989

The antiglucocorticoid RU38486 is a potent accelerator of adipose conversion of 3T3-F442A cells.

We examined the effects of RU38486, a potent glucocorticoid and progestin antagonist, upon several aspects of 3T3-F442A adipocyte differentiation. RU38486 accelerated the onset of differentiation, as monitored by cell morphological changes, accumulation of lipid droplets and widespread increases in the rate of expression of several enzyme adipose markers and specific mRNAs. RU38486, at a maximal concentration of 1 microM, dramatically hastened the emergence of both fatty-acid synthetase (FAS) and glycerol-3-phosphate dehydrogenase (G3PDH) enzyme activities (550% and 450% above control values 4 days after confluence, respectively). RU38486 induction of G3PDH-specific activity ran parallel to an increase in G3PDH mRNA content (2.4-fold the control content 4 days after confluence). Moreover, RU38486-treated cells exhibited enhancement of adenylate cyclase sensitivity to both isoproterenol and ACTH (160% and 350% above control activities 8 days after confluence, respectively). While the level of expression of lipogenic markers reached similar values at the mature stage, RU38486 enabled cells to acquire hypersensitivity in terms of ACTH-stimulated adenylate cyclase activity. Similarly, adipsin gene expression was highly potentiated by the drug at day 15 post-confluence (5-fold the control value). RU38486 responsiveness observed in differentiating 3T3-F442A cells is dependent upon their prior developmental activation; none of the studied markers could be induced by the drug in the undifferentiating 3T3-C2 cell subclone. Finally, this antiglucocorticoid appears to be a useful tool for studies on adipose conversion in vitro; it could permit a re-evaluation of the role of glucocorticoids in the understanding of adipocyte development.

Adenylyl Cyclases↗
PubMed1990

Myelin basic protein is affected by reduced synthesis of myelin proteolipid protein in the jimpy mouse.

Myelin basic proteins (MBPs) from 6-day-old, 10-day-old, 20-day-old and adult normal mouse brain were compared with those from 20-day-old jimpy (dysmyelinating mutant) mouse brain to determine the effect of reduced levels of proteolipid protein (PLP) on MBPs. Alkaline-urea-gel electrophoresis showed that 6-day-old and 10-day-old normal and jimpy MBPs lacked charge microheterogeneity, since C8 (the least cationic of the components; not be confused with complement component C8) was the only charge isomer present. In contrast, MBPs from 20-day-old and adult normal mouse brain displayed extensive charge microheterogeneity, having at least eight components. A 32 kDa MBP was the major isoform observed on immunoblots of acid-soluble protein from 6-day-old and 10-day-old normal and 20-day-old jimpy mouse brain. There were eight bands present in 20-day-old and adult normal mouse brain. Purified human MBP charge heteromers C1, C2, C3 and C4 reacted strongly with rat 14 kDa MBP antiserum, whereas the reaction with human C8 was weak. This suggested that MBPs from early-myelinating and jimpy mice did not react to MBP antisera because C8 was the major charge isomer in these animals. Purification of MBPs from normal and jimpy brain by alkaline-gel electrophoresis showed that both normal and jimpy MBPs have size heterogeneity when subjected to SDS/PAGE. However, the size isoforms in normal mouse brain (32, 21, 18.5, 17 and 14 kDa) differed from those in jimpy brain (32, 21, 20, 17, 15 and 14 kDa) in both size and relative amounts. Amino acid analyses of MBPs from jimpy brain showed an increase in glutamic acid, alanine and ornithine, and a decrease in histidine, arginine and proline. The changes in glutamic acid, ornithine and arginine are characteristic of the differences observed in human C8 when compared with C1.

Aging↗
PubMed1995

Phosphatidylserine decarboxylase 2 of Saccharomyces cerevisiáe. Cloning and mapping of the gene, heterologous expression, and creation of the null allele.

The yeast Saccharomyces cerevisiae expresses two phosphatidylserine decarboxylase (PSD) activities which are responsible for conversion of phosphatidylserine to phosphatidylethanolamine, and either enzyme alone is sufficient for normal cellular growth. However, strains containing a PSD1 null allele and a mutation leading to loss of PSD2 activity (psd1-delta 1::TRP1 psd2) are auxotrophic for ethanolamine. This nutritional requirement was utilized to isolate the gene encoding the PSD2 enzyme by complementation. The PSD2 gene encodes a protein of 1138 amino acids with a predicted molecular mass of 130 kDa. The deduced amino acid sequence shows significant identity (34%) to a PSD-like sequence from Clostridium pasteurianum and the yeast PSD1 (19%) at the carboxyl end of the protein. Of particular interest is the presence of a sequence, GGST, which may be involved in post-translational processing and prosthetic group formation similar to other PSD enzymes. The PSD2 amino acid sequence also shows significant homology to the C2 regions of protein kinase C and synaptotagmin. Physical mapping experiments demonstrate that the PSD2 is located on chromosome 7. The PSD2 gene was heterologously expressed by infection of Sf-9 insect cells with recombinant baculovirus, resulting in a 10-fold increase in PSD activity. The null allele of PSD2 was introduced into yeast strains by one-step gene deletion/disruption with a HIS3 marker gene. Strains expressing wild type PSD1 and the psd2-delta 1::HIS3 allele show a small decrease in overall PSD activity, but no noticeable effect upon [3H]serine incorporation into aminophospholipids. Strains containing both the psd1-delta 1::TRP1 and psd2-delta 1::HIS3 null alleles, however, express no detectable PSD activity, are ethanolamine auxotrophs and show a severe deficit in the conversion of [3H]serine-labeled phosphatidylserine to phosphatidylethanolamine. These data indicate that the gene isolated is the structural gene for PSD2 and that the PSD1 and PSD2 enzymes account for all yeast PSD activity.

Alleles↗
PubMed1989

Radiological picture of juvenile rheumatoid arthritis.

Basing on the results of radiological, clinical and laboratory examinations of 200 children with juvenile rheumatoid arthritis, we tried to obtain a comprehensive picture of radiological changes in the joints, the spine and the remaining skeleton caused by JRA. The bulk of data was obtained in the period between 1954 and 1972, but for some of the patients, our follow-up continued until 1987. Our main interest were differences in morphological changes caused by JRA and adult RA. We described initial changes and their progress in childhood, adolescence and adulthood, drawing attention to fundamental differences in radiological changes and their progress in patients with an onset of disease in the first half of childhood (up to the age of 8) and in those with an onset in the second half of childhood, where these changes were similar already to those caused by adult RA. Juvenile rheumatoid arthritis affects mainly skeletal growth by either retarding or accelerating various ossification processes. The skeleton of children has a great regenerative capacity, but this, on the other hand, supports various disturbances of growth brought forth by disease. This, apparently, account for differences of changes in the skeleton of the joints observed in JRA patients during childhood and adulthood. Whenever a case is suspected of JRA, a radiological examination of the joints involved ought to be complemented by a radiological examination of the hands because most of our radiographs showed structural changes in the hands. Particular attention should also be given to the knees and hips of children with active disease over a period of 3-6 years. Synostosis of arches and joints of the cervical spine, a typical feature of JRA, was observed in 20-25% of former JRA patients. Synostoses occurred either in the individual segments or in the whole cervical spine, but were never absent at the level of vertebral bodies C2-C3. There were neither objective nor subjective complaints.

Adolescent↗
PubMed1976

Complement-induced ultrastructural membrane lesions: requirement for terminal components.

The step in the complement (C) sequence at which 8- to 11-nm ring-shaped lesions are formed on antibody-coated erythrocytes (EA) has remained controversial. Some workers have concluded that these lesions appear at the C5 step and are not ultrastructural correlates of lysis; others hold that these lesions are formed only after the action of C8 and C9 in association with lysis. We have re-examined this problem by using sheep EA and human sera genetically lacking C5, C6, C7, or C8. Electron micrographs of negatively stained membranes (x 220,000) were read in blind fashion and the results correlated with 125I-C5 binding. Rare structures resemblind C-induced ring lesions were found on EA exposed to C5-deficient (C5D), C6D, C7D and C8D sera or to heated normal serum, with no significant differences among these sera (lesion density 0 to 0.26/mum2). Fresh normal serum (NHS) produced 140 to 220 ring lesions/mum2. C5 binding to EA in C8D serum was 60% of that observed in an NHS control; in C6D and C7D sera C5 binding was 4 to 11% of the normal value. Iodine treatment of sera (to enhance C5 uptake by C2 oxidation) increased C5 binding in C6D serum to 40 to 65% of that seen in native NHS; in iodine-treated C7D and C8D sera C5 binding was 250 and 440%, respectively, of the native NHS value. No increase in ring lesions was observed, however, except in the iodine-treated NHS. Thus, in whole serum, C5 binding is not sufficient to produce ultrastructural membrane rings in the absence of later-acting C components, at least through C8. The formation of ring lesions appears to have C requirements similar to those necessary for lysis.

Binding Sites↗
PubMed2001

Solution structure of the dodecamer d-(CATGGGCC-CATG)2 is B-DNA. Experimental and molecular dynamics study.

The DNA duplex d-(CATGGGCCCATG)2 has been studied in solution by FTIR, NMR and CD. The experimental approaches have been complemented by series of large-scale unrestrained molecular dynamics simulation with explicit inclusion of solvent and counterions. Typical proton-proton distances extracted from the NMR spectra and the CD spectra are completely in agreement with slightly modified B-DNA. By molecular dynamics simulation, starting from A-type sugar pucker, a spontaneous repuckering to B-type sugar pucker was observed. Both experimental and theoretical approaches suggest for the dodecamer d-(CATGGGCCCATG)2 under solution conditions puckering of all 2'-deoxyribose residues in the south conformation (mostly C2'-endo) and can exclude significant population of sugars in the north conformation (C3'-endo). NMR, FTIR and CD data are in agreement with a B-form of the dodecamer in solution. Furthermore, the duplex shows a cooperative B-A transition in solution induced by addition of trifluorethanol. This contrasts a recently published crystal structure of the same oligonucleotide found as an intermediate between B- and A-DNA where 23 out of 24 sugar residues were reported to adopt the north (N-type) conformation (C3'-endo) like in A-DNA (Ng, H. L., Kopka, M. L. and Dickerson, R. E., Proc. Natl. Acad. Sci. U S A 97, 2035-2039 (2000)). The simulated structures resemble standard B-DNA. They nevertheless show a moderate shift towards A-type stacking similar to that seen in the crystal, despite the striking difference in sugar puckers between the MD and X-ray structures. This is in agreement with preceding MD reports noticing special stacking features of G-tracts exhibiting a tendency towards the A-type stacking supported by the CD spectra also reflecting the G-tract stacking. MD simulations reveal several noticeable local conformational variations, such as redistribution of helical twist and base pair roll between the central GpC steps and the adjacent G-tract segments, as well as a substantial helical twist variability in the CpA(TpG) steps combined with a large positive base pair roll. These local variations are rather different from those seen in the crystal.

Base Sequence↗
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↗
PubMedDate not supplied

C4*A6BQO: a 'new' C4 haplotype.

A C4 haplotype containing C4*A6 without C4*B1 is described. It occurred in the MHC haplotype HLA-A1, Cw5, Bw44, C2*1, BF*S, C4*A6BQO, DR3, GLO 2. This haplotype was observed in five of eight siblings, including the propositus who was in renal failure. The C4A6 was not haemolytically active and this new haplotype is therefore of particular interest since it is functionally equivalent to the rare C4-deficient haplotype C4*AQOBQO.

Alleles↗
PubMed1999

Identification of the Pseudomonas stutzeri OX1 toluene-o-xylene monooxygenase regulatory gene (touR) and of its cognate promoter.

Toluene-o-xylene monooxygenase is an enzymatic complex, encoded by the touABCDEF genes, responsible for the early stages of toluene and o-xylene degradation in Pseudomonas stutzeri OX1. In order to identify the loci involved in the transcriptional regulation of the tou gene cluster, deletion analysis and complementation studies were carried out with Pseudomonas putida PaW340 as a heterologous host harboring pFB1112, a plasmid that allowed regulated expression, inducible by toluene and o-xylene and their corresponding phenols, of the toluene-o-xylene monooxygenase. A locus encoding a positive regulator, designated touR, was mapped downstream from the tou gene cluster. TouR was found to be similar to transcriptional activators of aromatic compound catabolic pathways belonging to the NtrC family and, in particular, to DmpR (83% similarity), which controls phenol catabolism. By using a touA-C2,3O fusion reporter system and by primer extension analysis, a TouR cognate promoter (P(ToMO)) was mapped, which showed the typical -24 TGGC, -12 TTGC sequences characteristic of sigma(54)-dependent promoters and putative upstream activating sequences. By using the reporter system described, we found that TouR responds to mono- and dimethylphenols, but not the corresponding methylbenzenes. In this respect, the regulation of the P. stutzeri system differs from that of other toluene or xylene catabolic systems, in which the hydrocarbons themselves function as effectors. Northern analyses indicated low transcription levels of tou structural genes in the absence of inducers. Basal toluene-o-xylene monooxygenase activity may thus transform these compounds to phenols, which then trigger the TouR-mediated response.

Base Sequence↗
PubMed1983

The active site of human C4a anaphylatoxin.

The human C4 activation peptide C4a has recently been shown to be biologically active and to share common tissue receptors with human C3a anaphylatoxin. Human C3a and C4a each induce contraction and cause cross-desensitization of isolated guinea-pig ileal strips. The essential active site of C3a is comprised in the model peptide containing the five COOH-terminal residues, Leu-Gly-Leu-Ala-Arg. The anaphylatoxic activities of the corresponding C4a pentapeptide, Ala-Gly-Leu-Gln-Arg, and several other synthetic peptides related to the COOH-terminal sequence of human C4a were examined. The C4a pentapeptide induced contraction of guinea-pig ileum at 1 X 10(-3) M and produced a wheal and flare reaction in human or guinea-pig skin when 2-5 mumols were injected intradermally. The corresponding C3a pentapeptide is 500-fold more active, since it induces contraction of guinea-pig ileum at 3-4 X 10(-6) M and only 4-10 nmole induce a visible skin reaction. Although the C4a pentapeptide is relatively inactive compared to the C3a pentapeptide, two analogs of these peptides, Leu-Gly-Leu-Gln-Arg and Ala-Gly-Leu-Ala-Arg, each exhibited significantly greater activity than Ala-Gly-Leu-Gln-Arg and each analog desensitized ileal smooth muscle towards contraction by either C3a or C4a. Thus it is a combination of two amino acid substitutions, the Ala for Leu-73 and Gln for Ala-76, in the COOH-terminal pentapeptide of C3a that accounts for the markedly reduced activity of C4a. The contribution of the COOH-terminal portion of C4a on its activity was further documented by examining the C4a octapeptide, Lys-Gly-Gln-Ala-Gly-Leu-Gln-Arg and a trialanyl analog, Ala-Ala-Ala-Ala-Gly-Leu-Gln-Arg. The C4a octapeptide, C4a (70-77), exhibited 5-fold greater biologic activity than the C4a pentapeptide, while the trialanyl analog was 40-fold more active. Anaphylatoxic activities of the C4a-(73-77) pentapeptide, C4a-(70-77) octapeptide, and the trialanyl octapeptide analog and their ability to specifically block the action of C3a and C4a on smooth muscle tissue support the conclusion that, as in C3a, the essential active site of C4a resides at its COOH terminus. Since C4a functions as an anaphylatoxin and significant quantities of this mediator may be generated in individuals with hereditary angioneurotic edema (HANE), the hypotheses that the kinin-like activity promoting edema in HANE patients is derived solely from component C2 and/or kininogens should be reappraised. The activities previously assigned to C4a and now confirmed by synthetic C4a analog peptides suggest that the kinin-like activity generated in HANE plasma may be derived in part from C4a.

Amino Acid Sequence↗

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