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PubMed1990

Genetic polymorphism of MHC class III and GLO in Chinese Yao nationality.

Yao nationality is one of the minority nationalities living mainly in South China (Guangxi Province). The purpose of this study was to provide data of MHC class III and GLO in Chinese Yao nationality and the different genetic background of Yao and Han nationality, the latter representing the major nationality in China. The genetic polymorphism of MHC class III and GLO in Chinese Yao nationality was determined. Previously the Japanese were considered to have the lowest C2*C frequencies (0.9386), but now we ascertained that the Yao have the lowest C2*C frequencies (0.9336). The data concerning gene frequencies of Yao are presented. They were also compared with the available data of Han.

China↗
PubMed1994

Structure of mouse protein S as determined by PCR amplification and DNA sequencing of cDNA.

The cDNA sequence of mouse protein S was derived by conventional PCR amplification from liver mRNA, initially using primers derived from the human cDNA sequence, followed by direct DNA sequencing. Seven overlapping PCR fragments covering all of the mature protein, part of the propeptide, and the 3' noncoding region were generated and sequenced. In some cases primers based upon the human cDNA sequence were ineffective. Subsequent successful amplification with mouse-derived primers to the same regions and comparison of the mouse and human sequences in these regions suggest that the failure of the human primers was due to insufficient degree of heterospecies identity. The mouse protein S cDNA sequence of the coding region shares 82% identity to human. The 3' noncoding region of mouse protein S cDNA has several small deletions and insertions compared to human protein S cDNA. Mature mouse protein S consists of 634 amino acids in a single polypeptide chain and displays domain organization similar to that for other species. The amino acid sequence of mouse protein S is about 80% identical to that of other species. Eleven glutamic acid residues were found in the amino terminal region and are predicted to be sites of gamma-carboxylation. Amino acid residues #80-244 are defined as four cysteine-rich repeat sequences homologous to epidermal growth factor. The remainder of the molecule is homologous to plasma sex steroid binding protein. The mouse protein S contains two potential N-glycosylation sites at positions #458 and 468 and is lacking the putative glycosylation site at #490 found in human protein S.

Amino Acid Sequence↗
PubMed1990

Complement activation products in idiopathic pulmonary fibrosis: relevance of fragment Ba to disease severity.

Immune complexes have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a chronic inflammatory disease of unknown etiology. Using newly developed techniques to measure complement fragments, we assessed whether complement activation occurs in IPF and its relationship to circulating immune complexes (CIC), disease severity, and prognosis. We measured the fragments C3d, C4d, and Ba of the common, classical, and alternative pathway, respectively, along with the components C3, C4, and Factor B and CIC, in 18 patients and 19 healthy subjects. The fragment to parent molecule ratios C3d/C3, C4d/C4, and Ba/Factor B were derived. Complement determinations were repeated in 14 of the patients on a second occasion separated by 8-33 months (median 17 months) from the first. All parameters were higher in patients than controls, and the difference between the two groups was significant for C3d, C4d/C4, C3, CIC (P less than 0.05) and for C4d and Ba (P less than 0.01). Fragment Ba was found to correlate with disease duration and indices of disease severity, i.e., positively with the dyspnoea score (Rs = 0.44, P less than 0.04), the physiological score (Rs = 0.50, P less than 0.02), the fibrosis score (Rs = 0.45, P less than 0.04), and a composite clinical, radiological, and physiological score (Rs = 0.48, P less than 0.03) and negatively with the forced vital capacity (Rs = -0.47, P less than 0.03). Ba was higher in those patients who deteriorated on follow-up analysis than those who improved or remained unchanged (P less than 0.04). These results show that conversion products of all complement pathways are increased in IPF and demonstrate classical pathway activation. They also show that the measurement of Ba might prove a useful laboratory test of disease severity in this condition.

Adult↗
PubMed1994

Classical pathway complement activation in Kawasaki syndrome.

In this study the complement breakdown products C3d, C4d, Bb and membrane attack complex were measured in plasma of patients with Kawasaki syndrome. The results suggested strong activation of the classical activation pathway. However, there was no significant decrease in hemolytic titer or in the concentrations of the intact proteins C3, C4, and B. The relationship between the serum concentrations of cytokines and complement components was examined; increased interleukin-6 concentration on the fifth day after the onset of fever was found to correlate well with the C3 and B concentrations in serum obtained 5 days later. We conclude that complement activation occurred in Kawasaki syndrome via the classical pathway but that the inflammatory reaction was accompanied by increased production of complement components. As a result, there was increased formation of activation products without changes in the serum complement levels.

Child, Preschool↗
PubMed1989

Activation of the classical complement pathway in brain tissue of Alzheimer patients.

Positive immunohistochemical staining of Alzheimer brain tissue was obtained with antibodies to proteins associated with classical, but not the alternative, complement pathway. Clq, C3d, C4d are fractions of complement proteins that bind to tissue when the classical complement pathway is activated. Antibodies to these fractions stained senile plaques, dystrophic neurites and some neurofibrillary tangles. C5b-9 is the membrane attack complex which promotes cell lysis when assembled on the plasma membrane. An antibody to a neoantigenic site on this complex stained dystrophic neurites and many neurofibrillary tangles, but not extracellular amyloid. Properdin and fraction Bb of factor B, two proteins that bind to tissue when the alternative complement pathway is activated, were not detected immunohistochemically.

Aged↗
PubMed1990

Complement activation before, during and after cardiopulmonary bypass.

Plasma levels of the complement parent molecules C3, C4, and factor B and their split products, C3d, C4d, and Ba were measured in 12 patients undergoing cardiopulmonary bypass for coronary artery surgery. Alternative and common complement pathway activation, demonstrated by statistically significant rising levels of Ba (P less than 0.05), and C3d (P less than 0.05) and by elevated Ba:B (P less than 0.05) and C3d:C3 (P less than 0.05) ratios were found before the institution of cardiopulmonary bypass but following heparin administration suggesting that heparin may itself initiate alternative pathway activation. In addition, significant depletion of parent complement components and elevation of split product concentrations was seen during bypass suggesting classical and alternate pathway activation (P less than 0.01). This study clarifies the pathways of complement activation during bypass and presents evidence that heparin administration may initially activate the complement cascade.

Cardiopulmonary Bypass↗
PubMed2004

Antithymocyte globulin is associated with complement deposition in cardiac transplant biopsies.

Polyclonal antithymocyte globulin preparations contain antibodies with reactivity to endothelial cells. Therefore, we investigated whether treatment with this reagent caused complement deposition in human cardiac transplants. Frozen tissue was available from endomyocardial biopsies of 75 patients, who were transplanted between April 1995 and April 2000. Nine of these patients were converted from cyclosporin A (CsA) to horse antithymocyte globulin (ATGAM) in the first month after transplantation. All of the biopsies were stained by immunofluorescence for C4d as evidence of activation of the classical pathway of complement. In addition, biopsies from patients treated with ATGAM and control patients were stained for deposition of horse immunoglobulin (Ig)G. All nine patients who received ATGAM had deposition of horse IgG and C4d. Two color stains demonstrated that the horse IgG colocalized with the C4d staining. No staining for horse IgG or C4d was evident in biopsies obtained before ATGAM treatment. Likewise, no staining for horse IgG was detected in seven control patients who had C4d staining. Most patients treated with ATGAM had no histologic evidence of rejection, but did have myocyte damage and macrophage infiltration. Thus prophylactic treatment with ATGAM is associated with the deposition of horse IgG and activation of complement in the transplant.

Animals↗
PubMed2007

Cutaneous vascular deposition of C5b-9 and its role as a diagnostic adjunct in the setting of diabetes mellitus and porphyria cutanea tarda.

BACKGROUND: The cutaneous lesions of diabetes mellitus (DM) and porphyria cutanea tarda (PCT) exhibit distinctive microvascular changes including basement membrane zone thickening and lamellation, morphologically appearing as hyaline-like alterations of the vessel wall. Immunofluorescence demonstrates homogeneous mantles of immunoglobulin in the microvasculature. The staining intensity is variable and in some cases can closely approximate those immunofluorescent changes seen in photoaged skin. OBJECTIVE: The purpose of this study was to establish an association between the microvascular changes seen in the skin from patients with DM and PCT and the presence of C5b-9 deposition, potentially defining the C5b-9 assay as an additional diagnostic adjunct. METHODS: Routine light microscopy and immunofluorescence studies were conducted on skin biopsy specimens from 14 patients with cutaneous manifestations of DM and 17 patients with PCT. The immunofluorescence profile included IgG, IgM, IgA, C3, C3d, C4d, and C5b-9. RESULTS: Fourteen of 14 DM and 17 of 17 PCT skin biopsy specimens revealed extensive granular and homogeneous vascular deposition of C5b-9; a similar pattern was observed for C3d and C4d. Control specimens from patients without DM and PCT, where C5b-9 was not an expected immunoreactant, were negative. Positive controls were cases of vasculitis, scleroderma, and dermatomyositis without DM and PCT where C5b-9 deposition was expected. C5b-9 deposition was observed and was of lesser magnitude than that encountered in patients with PCT or DM. LIMITATIONS: We were unable to obtain detailed clinical information on some of the diabetic patients in regards to significant extracutaneous vascular complications. In addition, a correlation between hemoglobin 1 Ac levels and the extent of C5b-9 deposition could not be ascertained as the serum levels for hemoglobin 1 Ac were unknown. CONCLUSION: Granular and homogeneous deposits of C5b-9 in vessels, along with homogeneous deposits of immunoglobulin within the blood vessels, are characteristic immunofluorescence findings in patients with DM and PCT. In regards to potential mechanisms of C5b-9 deposition, decreased metabolism of C5b-9 due to glycosylation of CD59 in the setting of DM and activation of complement by irradiated porphyrins in PCT are proposed. The extent of C5b-9 deposition suggests that this complex may play a pathogenetic role in the evolution of microvascular injury in patients with DM and PCT.

Adult↗
PubMed2004

Early complement activation increases in the brain in some aged normal subjects.

Complement activation is increased in Alzheimer's disease (AD) and may contribute to the development and progression of this disorder. To compare early complement activation between normal and AD brain specimens, C4d and iC3b concentrations were measured in hippocampus, entorhinal cortex, temporal cortex, parietal cortex, and cerebellum from aged normal and AD subjects n=10-14 for both), and in hippocampus and entorhinal cortex from younger normal subjects (n=5-6). C4d and iC3b levels increased 2.3- to 4.6-fold in AD versus aged normal specimens (all P <0.05), with lowest concentrations of these activation proteins generally in cerebellum. No significant differences were present between aged and younger normal C4d and iC3b levels in hippocampus or entorhinal cortex. However, the concentrations of these proteins were markedly increased in several aged normal specimens. Normal subject age was moderately associated with both C4d (r=0.49) and iC3b (r=0.53) concentrations in the hippocampus. Increased brain complement activation in some elderly individuals may promote the subsequent development of AD.

Adult↗
PubMed2005

Activation of early components of complement targets myelin and oligodendrocytes in the aged rhesus monkey brain.

The disruption and loss of myelin in the white matter are some of the major changes that occur in the brain with age. In vitro studies suggest a role of the complement system in the catabolic breakdown of myelin membranes. This study presents findings on activation of the early components of complement cascade in the brains of both young and aged rhesus monkeys with evidence of increased complement activation in aged animals. Complement containing oligodendrocytes (CAOs) containing C3d and C4d complement activation products bound to oligodendrocytes and myelinated fibers were found in the brain of normal young and old animals. The CAOs, which also contained activated microglia, were distributed throughout the whole brain and in significantly greater numbers in the aged monkeys. These findings, together with the demonstration of covalent binding of the C3 fragments to myelin, suggest the initiation of the complement cascade by myelin and oligodendrocytes, which are known classical complement activators. Activation of terminal complement components was not demonstrable in the CAOs. Taken together the findings support the concept that activation of early components of complement in the brain may be a normal biological process that involves the metabolism of myelin and oligodendrocytes and up-regulates with age.

Age Factors↗
PubMed2000

Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease.

The complement system constitutes a series of enzymatic steps involved in the inflammatory response and is activated in Alzheimer's disease (AD). Using Down's syndrome (DS) brains as a temporal model for the progression of AD, we examined components of the complement cascade and their relationship to other principal events in AD pathology: Abeta42 deposition, neuritic changes, neurofibrillary tangles (NFTs), and gliosis (reactive astrocytes, activated microglia). Adjacent sections of frontal cortex from 24 DS subjects ranging in age from 12 to 73 years were immunohistochemically examined for immunoreactivity (IR) of classical complement proteins (Clq and C3), markers indicating activation of complement (C4d and C5b-9), the complement inhibitor apolipoprotein J (apo J), and markers of AD neuropathology. Abeta42-labeled diffuse plaques were first detected in a 12-year-old DS subject and were not labeled by any of the complement antibodies. Colocalization of Abeta42 with Clq, C3, C4d, and/or apo J was first detected in compacted plaques in the brain of a 15-year-old DS patient with features of mature AD pathology, such as reactive astrocytes, activated microglia, dystrophic neurites, and a few NFTs. IR for C4d and C5b-9 (membrane attack complex, MAC) was observed in small numbers of plaque-associated dystrophic neurites and in focal regions of pyramidal neurons in this 15-year-old. The only other young (</=30 years) DS brain to show extensive complement IR was that of a 29-year-old DS subject who also displayed the full range of AD neuropathological features. All middle-aged and old DS brains showed IR for Clq and C3, primarily in compacted plaques. In these cases, C4d IR was found in a subset of Abeta42 plaques and, along with C5b-9 IR, was localized to dystrophic neurites in a subset of neuritic plaques, neurons, and some NFTs. Our data suggest that in AD and DS, the classical complement cascade is activated after compaction of Abeta42 deposits and, in some instances, can progress to the local neuronal expression of the MAC as a response to Abeta plaque maturation.

Adolescent↗
PubMed2003

Studies on the mechanisms of allergen-induced activation of the classical and lectin pathways of complement.

Allergen extracts are efficient activators of the complement system trough the classical pathway. Involvement of the lectin pathway was not previously studied. To further examine the mechanism of complement activation by allergens, in vitro experiments, which covered early steps both of classical and lectin pathways, were performed. Two types of allergens used in these studies: parietaria (PA) and house dust (HD) mite extracts. These allergen extracts bound to the globular head of C1q and interacted with purified mannan-binding lectin (MBL) as measured by solid-phase ELISA. None of the allergen extracts was able to activate human C1 in vitro, as measured by the determination of the split products of C1s in a reconstituted precursor C1 preparation. Neither the HD nor the PA extracts induced C4d generation above background in the serum of three subjects with hypogammaglobulinaemia but normal complement haemolytic activity. After reconstitution to normal level with purified human IgG, allergen extracts induced C4d formation above control at a level comparable to that measured in normal serum incubated with the same amounts of the extracts. HD-induced C4d generation was about the same comparable in MBL-depleted serum and in normal sera. In contrast PA induced no C4d formation in the MBL-depleted serum, whereas reconstitution with purified MBL restored C4d generation. These in vitro findings indicate that although the allergen extracts can bind purified C1q and MBL, they require IgG for efficient complement activation. Depending on the allergens, this activation may be initiated through C1, MBL, or both.

Agammaglobulinemia↗
PubMed1997

Amino acid differences in the N-terminus of C(H)2 influence the relative abilities of IgG2 and IgG3 to activate complement.

The four human IgG isotypes are highly conserved in amino acid sequence, but show differential ability to activate complement (C'): IgG3 and IgG1 are very active, IgG2 is active under certain conditions, and IgG4 is inactive. Although the second constant domain [C(H)2] is critical for C' activation, the individual amino acids that confer isotype-specific activity have not been identified. We have generated a series of mutants between IgG2 and IgG3, resulting in the exchange of the four N-terminal and six C-terminal polymorphic residues within C(H)2. Mutants containing the N-terminus of the C(H)2 of IgG3 were as effective as wildtype IgG3 in C1q binding, C1 activation and terminal complex (MAC) formation, but had reduced ability to effect C'-mediated lysis. IgG2 and mutants containing the N-terminal portion of the C(H)2 of IgG2 were reduced compared to IgG3 in activating C1, binding C1q and inducing assembly of the MAC, and were inactive in mediating lysis of target cells. Thus, the amino acid sequence differences in the N-terminus of C(H)2 play a critical role in determining the relative abilities of IgG2 and IgG3 to bind C1q and activate the C' cascade although additional residues of C(H)2 must be involved in mediating optimal target cells lysis. The sequence of the N-terminus of C(H)2 was less critical in determining C4 and C3 binding. Characterization of domain exchange mutants suggests that intermediate steps may be partly dependent on domains other than C(H)2. IgGs that do not direct target cell lysis nevertheless activate intermediate steps in the pathway, which may contribute to immune complex-associated disorders.

Amino Acid Sequence↗
PubMed1997

Catabolism of the human erythrocyte C3b/C4b receptor (CR1, CD35): vesiculation and/or proteolysis?

Human erythrocytes (E) react by exocytosis of membrane vesicles to various stresses including the fixation of the membrane attack complex of Complement. E from normal individuals loose a notable proportion of their initial number of surface CR1 molecules during the ageing process. An acquired decrease of CR1 on E also occurs in pathological conditions such as Systemic Lupus Erythematosus or AIDS. The present study investigated whether calcium ionophore A23187 (Ca-ion) induced vesicle formation of human E in vitro is responsible for a preferential loss of CR1 as well as whether CR1 molecules at the surface of Ca-ion treated E or vesicles are: (i) functional, (ii) native or protease degraded, or (iii) more clustered than CR1 on native E. A study of E from 137 normal individuals showed that a one-hour Ca-ion induced vesicle formation preferentially removed one third of E surface CR1. Kinetic experiments suggested that all surface CR1 could be removed from E upon longer incubation times. CR1 molecules on vesicles were still able to inhibit Complement activation, and were found in larger clusters than on native E. These data suggest that a significant part of surface CR1 molecules may be removed from E by vesicle formation during the life of E in normal individuals. This phenomenon could be exacerbated in pathological conditions.

Aging↗
PubMed2001

Extended HLA haplotypes in a Carib Amerindian population: the Yucpa of the Perija Range.

Eleven MHC loci haplotypes have been defined among a Carib speaking Amerindian population; the Yucpa, inhabiting the northern section of the Perija Range, on the limits between Colombia and Venezuela. This tribe has been known with the name of "Motilones mansos" and is located close to the Chibcha-Paeze speaking Bari or "Motilones bravos." Seventy-three full blooded Yucpa living at the villages of Aroy, Marewa, and Peraya, were selected using a genealogy previously collected by an anthropologist and tested for Bf-C4AB complement allotypes and by serology, high resolution PCR-SSO and SBT typing for HLA class 1 and class 2 alleles. Combinations of 6 HLA-A, 6 HLA-B, 5 HLA-C, 1 Bf, 3 C4AB, 3 DQA1, 3DQB1 and 2 DPA1 and 2 DPB1 alleles present in this population originate 17 different haplotypes, 3 of which represent 63% of the haplotypic constitution of the tribe. The presence of 13 individuals homozygous for 11-loci haplotypes corroborates the existence of the following allelic combinations: DRB1*0411 DQA1*03011 DQB1*0302 DPA1*01 DPB1*0402 with HLA-A*6801 C*0702 B*3909 BfS C4 32 (f = 0.3372) or with A*0204 C*0702 B*3905 (f = 0.1977) and a third haplotype which differs only in DRB1*0403 and A*2402 (f = 0.0930). The results demonstrate the isolation of the tribe and the existence of high frequencies of a reduced number of "Amerindian" ancestral and novel class 1 and class 2 alleles (B*1522, DRB1*0807) with significant linkage disequilibria. These results will be useful to test the hypothesis that differentiation of Amerindian tribal groups will have to rely on haplotypes and micropolymorphism rather than allelic lineage frequencies due to the uniformity shown thus far by the putative descendants of the original Paleo-Indians.

Colombia↗
PubMed1998

Microbial immunology: a new mechanism for immune subversion.

The number of mechanisms that have evolved in microbes to subvert the immune response seems limitless. Tubercle bacilli have found a novel way to coat themselves with the C3 complement protein and invade macrophages by interactions with complement receptors.

Bacterial Proteins↗