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PubMed1999

Immunohistochemical analysis of arterial wall cellular infiltration in Buerger's disease (endarteritis obliterans).

PURPOSE: The diagnosis of Buerger's disease has depended on clinical symptoms and angiographic findings, whereas pathologic findings are considered to be of secondary importance. Arteries from patients with Buerger's tissue were analyzed histologically, including immunophenotyping of the infiltrating cells, to elucidate the nature of Buerger's disease as a vasculitis. METHODS: Thirty-three specimens from nine patients, in whom Buerger's disease was diagnosed on the basis of our clinical and angiographic criteria between 1980 and 1995 at Nagoya University Hospital, were studied. Immunohistochemical studies were performed on paraffin-embedded tissue with a labeled streptoavidin-biotin method. RESULTS: The general architecture of vessel walls was well preserved regardless of the stage of disease, and cell infiltration was observed mainly in the thrombus and the intima. Among infiltrating cells, CD3(+) T cells greatly outnumbered CD20(+) B cells. CD68(+) macrophages or S-100(+) dendritic cells were detected, especially in the intima during acute and subacute stages. All cases except one showed infiltration by the human leukocyte antigen-D region (HLA-DR) antigen-bearing macrophages and dendritic cells in the intima. Immunoglobulins G, A, and M (IgG, IgA, IgM) and complement factors 3d and 4c (C3d, C4c) were deposited along the internal elastic lamina. CONCLUSION: Buerger's disease is strictly an endarteritis that is introduced by T-cell mediated cellular immunity and by B-cell mediated humoral immunity associated with activation of macrophages or dendritic cells in the intima.

Adult↗
PubMed1984

Covalent binding efficiency of the third and fourth complement proteins in relation to pH, nucleophilicity, and availability of hydroxyl groups.

The binding of [3H]glycerol and [3H]putrescine to C3 was studied in a fluid-phase system using trypsin as the C3 convertase. The binding of glycerol showed little variation in the pH range between 6.0 and 10.0. The binding of putrescine (pKa = 9.0) is rather ineffective below pH 7.5 but becomes more efficient as the pH of the reaction mixture increases. These results agree with the contention that the final step of the binding reaction is the transfer of the acyl group of the exposed thio ester of C3 to a nucleophile since the nucleophilicity of hydroxyl groups is rather independent of pH whereas only the unprotonated form of amino groups is nucleophilic. The inefficient reaction of amino groups with the exposed thio ester of C3 is also supported by the study of the inhibitory activity of serine and its two derivatives, N-acetylserine and O-methylserine, to the binding of [3H]glycerol to C3. N-Acetylserine showed an inhibitory activity equivalent to that of serine, whereas O-methylated serine showed only minimal activity. It can be concluded, therefore, that serine reacts with the thio ester of C3 by its hydroxyl group but not by its alpha-amino group. The ability of the alcohol group of various alkanes to inhibit the binding of [3H]glycerol to C3 was also studied. The primary alcohols inhibit the binding reaction with an efficiency that is similar to glycerol, and there are no significant differences in the binding efficiencies of methanol, ethanol, 1-propanol, and 1-butanol.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗
PubMed1993

Capillary deposition of C4d complement fragment and early renal graft loss.

Clinical outcome of kidney grafts that are affected by the complex syndrome of 'early graft dysfunction' is uncertain and rather unpredictable. In this study, an individual prognosis for dysfunctioning allografts (N = 93) is attempted by the immunohistological assessment of vascular classical complement activation in graft biopsies. Thus, capillary deposition of complement fragment C4d was observed in the majority (N = 51) of early dysfunctioning grafts. In 43 biopsies, abundant deposition of fragment C4d was present in all capillaries, whereas in eight specimens a segmental distribution of capillary C4d was observed. In 42 grafts with early dysfunction no capillary C4d was detectable. Eighteen subsequent graft losses within one year (16 early losses) were recorded in the subgroup with C4d in all capillaries, and three early losses in the group with segmentally distributed C4d. Only four graft losses (3 early losses) were recorded in the C4d-negative group (P = 0.0027; Pearson's chi square test). The resulting one-year graft survival rates (72% for the study group) differed markedly between the subgroups. Grafts with generalized or segmental capillary deposition of C4d had 57% and 63% survival, respectively, contrasted by 90% survival in the C4d-negative group. It is of note, however, that also three of the four grafts that were finally lost within the C4d-negative group, showed distinct capillary deposition of C4d in second biopsies. Vascular deposition of complement fragment C4d therefore represents a clinically relevant factor that contributes to early graft dysfunction. Its assessment is helpful for an individual graft prognosis.

Animals↗
PubMed1986

Detection of disulphide bonds and localization of interchain linkages in the third (C3) and the fourth (C4) components of human complement.

Disulphide bonds contribute significantly to the maintenance of structural/functional integrity of many proteins. Therefore it was of interest to study the distribution and the effect of disulphides on conformation of complement components C3 and C4. These proteins are precursors of several fragments with various binding sites and distinct physiological functions. The constituents of C3c (beta, alpha 27, alpha 43) and those of C4c (beta, alpha 27, alpha 16, gamma) were investigated, since other fragments of C3 or C4 do not participate in interchain linkages. Inter-and intra-chain disulphide bonds in C3c and C4c were localized by using a modification of conventional SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis such that the change in mobility of disulphide-bond-containing proteins can be detected throughout the transition from a non-reduced to a fully reduced state. Several forms of the alpha 43 fragment from C3, and of the gamma-chain of C4, with different mobilities can exist, depending on the number of intra-chain disulphide bonds reduced. The intermediates (heterodimers) generated by a partial reduction of C3c or C4c were characterized by two-dimensional SDS/polyacrylamide-gel electrophoresis performed in the absence, then in the presence, of beta-mercaptoethanol. The inter-chain linkages in C3c were determined to be beta-alpha 27 and alpha 27- alpha 43, thus indicating the presence of only one interchain bond in C3. The two interchain bonds in C4c are beta-alpha 27 and alpha 16-gamma. The third interchain bond in C4 (alpha 27-gamma, tentative) remains to be determined.

Complement C3↗
PubMed1998

Immunoglobulin prolongs survival of pig kidneys perfused ex vivo with human blood.

Intravenous immunoglobulin (IVIG) (Octagam), was used to determine the effect on hyperacute rejection in an ex vivo xenograft model. Six pig kidneys were perfused with IVIG and fresh human AB blood, and six control pig kidneys were simultaneously perfused with albumin and blood from the same donation. The survival of the IVIG-perfused xenografts (median, 6.5 h) was significantly (P = 0.03) longer than the albumin-perfused xenografts (median, 3.5 h). Complement was activated in both groups. The administration of IVIG to the perfused blood resulted in immediate and significantly higher complement activation in the fluid phase as compared with the albumin group. At rejection the fluid phase complement activation was higher in the IVIG group than in the albumin group for C1rs/C1inh complexes, C4bc, Bb and TCC. At the time of rejection both the albumin and the IVIG group demonstrated interstitial tubular haemorrhage, vasculitis or necrosis of glomerular capillaries and glomerular microthrombi. IgM, C1q, C3c, C4 and fibrin were located in arteries and glomeruli and IgG in the interstitium in both groups at rejection. The fluid phase findings are consistent with a modulatory effect of IVIG on complement activation by deviating the classical pathway activation towards the fluid phase. The prolonged survival of the IVIG-perfused kidneys suggests that IVIG may be useful to dampen hyperacute rejection.

Animals↗
PubMedDate not supplied

In vivo and in vitro binding of C4 molecules on red cells: a correlation of numbers of molecules and agglutination.

The fourth component of human complement (C4) is one that is essential to the antibody-mediated classical activation pathway. C4d, present on all normal and most patient red cells (RBCs), may be detected by the human antisera anti-Rodgers (Rg) and -Chido (Ch). A study has been made of the Rg/Ch antigens on normal and patient RBCs in an attempt to understand the mechanism by which C4 is bound to normal RBCs in the absence of RBC antibodies (Abs). Because RBCs from C1q-deficient patients express Rg/Ch, it seems that C1q is not essential for C4 binding. Treatment of normal RBCs with proteolytic enzymes, including trypsin, eliminated positive reactions with anti-Rg/Ch even though the C4d fragment is considered to be resistant to cleavage by trypsin. By correlating agglutination reactions with numbers of bound C4d and C3d molecules, it is evident that both C4d and C3d were affected by trypsin treatment and that anti-Rg/Ch were not capable of agglutinating RBCs with less than 50 molecules of bound C4d. It is concluded that trypsin-sensitive and -insensitive RBC membrane structures may both act as acceptors for C4. RBCs with null phenotypes of the major blood group systems all expressed Rg/Ch antigens, so none of the structures that carry these antigens act preferentially as acceptors for C4.

Agglutination Tests↗
PubMed1993

Complement activation in stored platelet concentrates.

Activation of platelets during preparation and/or storage of platelet concentrates in plastic containers at room temperature has recently been recognized. Many different biologic causes of this activation have been postulated. Activated complement, as a multi-enzyme system, is one of the possible sources of molecules leading to platelet activation. To detect complement activation, functional complement activity and the generation of complement-derived ligands were investigated in platelet concentrate supernatant plasma during 5 days of storage at room temperature. Hemolytic tests for functional classical and alternative pathway activity were used, as was the kinetic test for complement-mediated inhibition of immune complex precipitation. The presence of C3 activation products (C3, C3c, C3dg) was investigated in plasma by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting procedures and on platelets by immunofluorescence. Activation of complement was evident during storage, and C3c and C3d fragments were clearly demonstrated in plasma. The amount of C3d fragments on platelets gradually rose during the first 3 days of storage. At the end of 5 days of storage, the platelets became C3d negative. There are two possible mechanisms of C3d disappearance--shedding and/or further degradation of C3d fragments. Those results indicated that complement activation and the generation of complement-dependent ligand-receptor interaction may be mechanisms for platelet activation in concentrates stored at room temperature.

Binding Sites, Antibody↗
PubMedDate not supplied

[In-vivo activation of the 4th component of the complement system (C4) in premature and term infants with generalized bacterial infections].

The concentrations of the complement components C3 and C4 and their activation products C3dg and C4d were determined in EDTA-stabilized serum of 25 premature and term infants. EDTA plasma and EDTA serum obtained from 30 normal blood donors were used as controls. According to clinical, laboratory and/or microbiological findings, six of the 25 children had infections. The mean scatter range of the C3 and C4 values was from 30% (in the 30th week of pregnancy) to 80% (in term infants) of the normal value for adults. In all the children, irrespective of gestational age, the C3dg concentrations were of the same order of magnitude as in healthy adults. As regards the C3, C4, and C3dg values, there was no difference between the newborns with and without infections. The C4d values of the newborns without infections, on the other hand, (range 0.1-1.4 mg/dl, mean 0.8 mg/dl, n = 19) were significantly lower than those of the newborns with infections (range 1.3-2.4 mg/dl, mean 1.95 mg/dl, n = 6). Observation of the course and comparison with CrP showed that elevated C4d values may occur earlier. In the authors' view, these findings indicate that in bacterial infections of premature and term infants the fourth complement component is activated, while the extent to which the third complement component is involved in the activation process is not measurable. Further studies are needed to establish whether early diagnosis of neonatal sepsis can be improved by determining C4d.

Bacterial Infections↗
PubMed1991

Prolonged CD4+ lymphocytopenia and thrombocytopenia in a chimpanzee persistently infected with human immunodeficiency virus type 1.

The immunologic and virologic status of a chimpanzee inoculated with multiple isolates of the human immunodeficiency virus type 1 (HIV-1) were assessed over 57 months to determine whether prolonged thrombocytopenia and CD4+ lymphocytopenia observed in the animal might be associated with long-term HIV infection. Although the chimpanzee showed no signs of disease, it lost both CD4+ (as low as 134 cells/microliter) and CD8+ lymphocytes approximately 30 months after initial infection, followed by thrombocytopenia that has persisted for greater than 2 years. Lymphopenia and thrombocytopenia were preceded by or coincided with the appearance of antibodies cross-reactive with histone H2B and decreased levels of complement component C4; an eightfold decrease in HIV-specific antibody titers; the inability of CD8+ lymphocytes to suppress virus replication; impaired proliferative responses to T cell mitogens; and the isolation of cell-free HIV from plasma. These data suggest that, given sufficient time, HIV-infected chimpanzees may develop disease.

Animals↗
PubMed1995

Elevated levels of iC3b and C4d, but not Bb, complement fragments from plasma of persons infected with human T cell leukemia virus (HTLV) with HTLV-I-associated myelopathy/tropical spastic paraparesis.

Plasma levels of complement (C) fragments iC3b, C4d, and Bb from human T cell leukemia virus (HTLV)-positive subjects with HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) were analyzed by EIA. Both iC3b and C4d levels were significantly elevated in persons with HAM/TSP. These levels were similar to those in patients with human immunodeficiency virus (HIV) infection or rheumatoid arthritis (RA), who are known to have increased C fragments. Bb levels in persons with HAM/TSP wer unaffected, suggesting that C activation occurred only via the classical pathway. This differed from findings in HIV-infected or RA patients, who had elevated levels of Bb. The results showed an increase in C activation in persons with HAM/TSP and activation via the classical pathway, likely mediated by virus or immune complexes. It is possible that the C activation observed in these subjects contributed to the inflammatory pathogenesis of HAM/TSP.

Arthritis, Rheumatoid↗
PubMed1994

HLA-DRB genes and antiribosomal P antibodies in systemic lupus erythematosus.

Antibodies to the ribosomal P protein are specific for SLE but their prevalence varies in different ethnic groups. In a group of Chinese SLE patients from Malaysia who have a high prevalence of this antibody, we have found an increased frequency of an uncharacterized HLA-DRB gene allele, DR16X, in patients who are positive for anti-P antibodies compared to antibody negative patients (31.3% vs 3.2%, P < 0.01, Pcorr not significant, relative risk = 13.6). DR16X has only been found in south east Asian populations and may be a genetic factor which influences the high prevalence of anti-P antibodies in Chinese.

Alleles↗
PubMedDate not supplied

Rapid activation of the alternative pathway of complement by extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) is an effective therapy for patients with severe respiratory distress syndromes. However, an inflammatory response has been observed with the use of this therapy. We measured complement activation in vivo in two adults receiving ECMO for acute respiratory distress syndrome (ARDS). Production of complement activation fragments C4d, Bb, iC3b, and SC5b-9 was determined using commercial ELISA kits. In both patients there was intense activation of complement that peaked 1 hour (mean SC5b-9 increase to 1135% of baseline) after the start of ECMO and occurred predominantly via the alternative pathway (Bb production). Early and acute complement activation may be responsible for the initiation of the inflammatory response that has been observed in patients treated with ECMO.

Adult↗
PubMed1991

Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection.

Complement activation in 73 renal transplant biopsies was investigated by indirect immunoperoxidase staining using MoAbs reactive with complement-split products. Intense deposition of complement fragments C4d and C3d in peritubular capillaries, indicating activation of the classical pathway, could be detected in the majority of transplanted kidneys with cell-mediated rejections. Abundant deposition of complement-split products was observed in 22 early biopsies from patients with high 'immunological risk' (i.e. previous, rejected transplants and/or circulating antibodies against HLA-antigens). Despite negative results in the crossmatch before transplantation and paucity of immunoglobulins in transplant biopsies, antibodies directed against endothelial cell antigens should be considered as a possible cause of classical complement activation.

Antibodies, Monoclonal↗
PubMed1994

Reactive oxygen product formation by human neutrophils as an early marker for biocompatibility of dialysis membranes.

Production of reactive oxygen intermediates (ROI) by neutrophils (PMN) in vivo was examined by a whole blood assay using dichlorofluorescein-diacetate (DCFH-DA) in 10 patients each dialysed consecutively with two different dialyser membranes. Haemodialysis (HD) with cuprophan membrane (CM) led to a significantly (P < 0.001) more pronounced ROI production by PMN (2.4 +/- 0.5-fold increase in intracellular oxidation of DCFH-DA) compared with HD with polysulfone membranes (PM; 1.5 +/- 0.2-fold). HD with CM induced a decrease in PMN count by about 90%, whereas PM induced a decrease by only 25% (P < 0.001). In CM patients maximal ROI production coincided with the nadir in PMN count. All patients dialysed with CM showed a clear increase in serum levels of Bb fragments, whereas PM-dialysed patients did not. In this respect, however, no clear time relationship was seen to the kinetics of ROI production, nor to the disappearance of neutrophils from the circulation. Evaluating a direct effect of the dialysis membranes on PMN demonstrated that incubation of neutrophils with hollow fibres of the CM but not of the PM in the absence of plasma induces significant ROI production by PMN. Our study thus indicates that ROI production by PMN during HD correlates to membrane biocompatibility. Furthermore, one might speculate that also independently from but perhaps in addition to complement activation, reactive oxygen products are critically involved in the generation of haemodialysis-associated neutrophil emigration.

Adult↗
PubMed1989

The absence of 21-OH A and C4 B genes is a constant characteristic of the "Sardinian" HLA extended haplotype A30 Cw5 B18 BfF1 DR3 DRw52 DQw2.

The genomic DNA of 25 unrelated individuals with HLA haplotype A30 Cw5 B18 BfF1 DR3 D w52 DQw2 was digested with the restriction enzyme Taq I and hybridized with cDNA probes for C4 and 21-OH genes. Eighteen individuals and a non-Sardinian reference cell (DUCAF) were homozygous for the entire extended haplotype, six individuals were heterozygous for the HLA-A locus and homozygous for the rest of the same haplotype. All of the 18 homozygous individuals, four of the six heterozygous subjects and the DUCAF cell revealed the absence of two fragments at 3.2 and 2.4 kb corresponding to the 21-OH A gene, and the absence of fragments corresponding to the C4 B "long" or "short" gene. The contemporary absence of the 21-OH A and C4 B genes seems to be a constant characteristic of this extended haplotype in the Sardinian population and suggests that this and other extended haplotypes bearing C4 A or C4 B null alleles could be ancestral haplotypes which never duplicated at these loci.

Alleles↗