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PubMed1982

Separation of Fc-binding serum proteins by preparative flat-bed isotachophoresis.

Preparative flat-bed isotachophoresis with discrete spacers was applied as a single-step procedure to separate 2 Fc-dependent activities of normal chicken serum, i.e., (1) the ability to raise the titre of haemagglutinating allo-antisera which is due to a high molecular weight beta-globulin (HEF), (2) the ability to activate guinea pig complement components in mixed complement reaction. The results demonstrate that the 2 activities can be clearly separated, and HEF must therefore be different from the first complement factor in the chicken. Under the chosen conditions the molecule active in the mixed complement reaction is not stacked in contrast to other serum protein including HEF. The same technique with human serum shows that human Clq behaves in the same was as the chicken complement factor. This means that by selective unstacking, flat-bed isotachophoresis can be used as an efficient single-step purification method for human and chicken Clq.

Animals↗
PubMed1988

Complement activation occurs through both classical and alternative pathways prior to onset and resolution of adult respiratory distress syndrome.

We have previously reported that plasma concentrations of the terminal complement (C) complex (TCC), C5b-9, increased significantly 2 days prior to onset of adult respiratory distress syndrome (ARDS) and also 1 day preceding its resolution. To determine the pathway of complement activation that preceded development and resolution of this acute inflammatory lung injury in septic patients, we quantified the C1rC1s-C1 inhibitor complex and the C3bP complex, which are generated following activation of classical and alternative complement pathways, respectively. Two days prior to diagnosis of ARDS, the plasma C1rC1s-C1 inhibitor complex and C3bP complex levels increased 22 and 14%, respectively. Furthermore, significant correlations were identified between concentrations of the TCC and C1rC1s-C1 inhibitor complex (r = 0.73, P = 0.003) and also with the levels of the TCC and C3bP complex (r = 0.81, P = 0.002) before onset of ARDS. Equally of interest, the C1rC1s-C1 inhibitor complex and C3bP complex concentrations increased 68 and 35%, respectively, 1 day before resolution of ARDS. Similarly, significant elevations of TCC concentrations preceding resolution of ARDS correlated with C1rC1s-C1 inhibitor complex (r = 0.66, P = 0.02) and also with C3bP complex (r = 0.72, P = 0.002) levels. Our results indicate that both the classical and alternative complement pathways are activated prior to onset of ARDS and also before its resolution in septic patients.

Complement Activating Enzymes↗
PubMed1979

Immunologic reactivity in the hypereosinophilic syndrome.

Because previous studies have suggested an important link between eosinophilia and immunologic reactivity, we investigated various components of the immune system in a large number of patients with the idiopathic hypereosinophilic syndrome (HES) to elucidate a possible role for immunologic phenomena in the etiology and pathogenesis of this disease. Immunoglobulin G, A, or M levels were only rarely abnormal. However, in 8 of 21 (38%) patients with HES, IgE levels were markedly elevated suggesting an association of an IgE-mediated mechanism with eosinophilia in this subgroup. Severe dermatographism was present in three fourths of patients, and 2 patients with intermittently elevated histamine levels manifested an unusual form of immediate-pressure urticaria. Serum complement determinations showed elevated C4 and C3 levels in 27% and 77% of patients, respectively. Antigen-antibody complexlike material measured by C1q binding was elevated in the serum of 7 of 22 (32%) patients; this finding may relate to the known ability of eosinophils to avidly phagocytose antigen-antibody complexes. When compared with normals, lymphocytes from patients with HES showed a variety of abnormalities of lymphocyte surface receptors and lymphocyte function. Thus, patients with HES demonstrate a variety of immunologic abnormalities which may be related primarily or secondarily to the pathogenesis of this syndrome.

Antigens, Surface↗
PubMed1992

C1-inhibitor prevents PEG fractionation-induced, EDTA-resistant activation of mouse complement.

Fractionation of mouse serum by precipitation with a critical amount of polyethylene glycol 6000 (PEG; 11% w/v) results in a classical and alternative pathway-independent activation of the terminal complement route. The activation can take place after the separation of an activating principle together with the terminal route components from a natural regulator. The isolation and identification of the regulatory component preventing this activation in serum, is subject of this paper. The regulator was purified by fractionated PEG-precipitation (15-25%), followed by heparin-Sepharose affinity, Mono Q anion-exchange, and Superose 12 gel filtration chromatography. The regulator appeared to be a single-chain protein with a Mr of 96 k. A protein with similar activity purified from human serum had a Mr of 104 k and was functionally and antigenically indistinguishable from C1-INH. The mouse 96 k protein inhibited C1-esterase activity indicating that this protein is indeed C1-INH. Mouse C1-INH regulates the PEG fractionation-induced bypass activation of complement, but does not interfere with the assembly or the lytic activity of membrane attack complexes. alpha 2-Macroglobulin appeared also to be capable of inhibiting the PEG-precipitation-induced activation process, but with lower efficiency.

Animals↗
PubMed2026

Biological Mechanisms Underlying the Cardiovascular Effects of Branched-Chain Amino Acids: A Proteome-Wide Mendelian Randomization Study.

BACKGROUND: Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVES: This study aims to explore these pathways using 2-step proteome-wide Mendelian randomization. METHODS: We examined the associations between genetic proxies for BCAAs and 2922 proteins in the United Kingdom Biobank Pharma Proteomics Project, supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Next, we tested their effects on IHD risk using Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics Consortium (122,733 cases and 424,528 controls) and replicated in FinnGen (31,640 cases and 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS: Genetic proxies for BCAAs were associated with 40 proteins. Among these, 6 proteins showed consistent evidence of mediation, including complement C1s subcomponent, coagulation factor II, granulin, proprotein convertase subtilisin/kexin type 9, sex hormone-binding globulin, and V-set and transmembrane domain-containing protein 2-like. These proteins are involved in inflammation, coagulation, lipid metabolism, and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS: This study identified 6 proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. To our knowledge, these findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.

Amino Acids, Branched-Chain↗
PubMedDate not supplied

Opsonic complement system of the solitary ascidian, Halocynthia roretzi.

To elucidate the molecular architecture and function of the possibly primitive complement system of the solitary ascidian. Halochynthia roretzi, cDNA clones for the third component (C3) and mannose-binding lectin (MBL)-associated serine protease (MASP) were isolated from the hepatopancreas cDNA library. The deduced primary structure of ascidian C3 (AsC3) shows overall similarity to mammalian C3 including a typical thioester site. Two distinct ascidian MASPs, termed AsMASPa and AsMASPb, have the same domain structure as mammalian Clr/ Cls/MASP-1/MASP-2. Both of them show a closer similarity to mammalian MASP-1 than to mammalian Clr/Cls/ MASP-2. Ascidian body fluid contains an opsonic activity which enhances phagocytosis of yeast by ascidian blood cells, and an antibody against AsC3 inhibits this opsonic activity. These results indicate that the lectin-dependent, opsonic complement system was present prior to the emergence of the vertebrates and well ahead of the establishment of adaptive immunity.

Animals↗
PubMed1983

Inherited disorders of complement.

Isolated complement component deficiencies are uncommon. Deficiencies of all eleven components and two inhibitors of the classical pathway have been described. Complete absence of the components of the alternative pathway has not been described. The consequences of a single defect in complement are often predictable from an understanding of the biologic activities associated with activation of the complement system. Deficiency of C1 esterase inhibitor gives rise to the disease, hereditary angioedema; deficiency of the early components of the classical pathway are associated with lupus erythematosus; C3 and C3 inactivator deficiencies with pyogenic infections; C5 dysfunction with Leiner's disease; deficiencies of the terminal components with recurrent Neisseria bacteremia; and C9 deficiency with normal health. The complement system and its associated biologic activities are reviewed. The present knowledge of the inherited complement deficiencies and associated diseases, with particular emphasis on the dermatologic manifestations, genetics, and diagnosis, is summarized.

Angioedema↗
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↗