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[Recurrent post-infectious immune complex glomerulonephritis with persistent activation of the alternative complement pathway].

Recurring upper respiratory tract infections in a previously healthy 4 years old boy led to an acute nephritic syndrome requiring haemodialysis. Renal biopsy showed poststreptococcal like immune complex glomerulonephritis with subepithelial humps, C3 deposition and crescent formation. Renal function improved after methyl-prednisolone pulse therapy. Two relapses occurred in the following six months which responded to immunosuppressive therapy. 21 months following the first presentation the boy has normal glomerular filtration rate but persistent glomerular proteinuria and haematuria. Detailed complement analyses revealed a persistent activation of the alternate pathway.

Child, Preschool↗

Genetic polymorphisms of HLA class III and GLO1 in Chinese Yao nationality.

Yao is one of the minority nationalities located mainly in the South of China (Guang Xi province). The purpose of this study was to examine HLA class III and GLO1 in Yao nationality to identify the difference between Yao and Han. Han is the major nationality in China. Yao has the lowest C2*C frequency (0.9336) in the world. Before this study the lowest C2*C frequency known was that of the Japanese (0.9386). Gene frequencies in Yao are the following: C2*C = 0.9336, C2*B = 0.0664; BF*S = 0.9071, BF*F = 0.0929; C4A*4 = 0.0253, C4A*3 = 0.6061, C4A*2 = 0.2121, C4A*1 = 0.0152, C4A*Q0 = 0.1414; C4B*3 = 0.0051, C4B*2 = 0.0657, C4B*1 = 0.7071, C4B*92 = 0.0455, C4B*95 = 0.0253, C4B*96 = 0.0253, C4B*12 = 0.0051, C4B*Q0 = 0.1212; GLO1*1 = 0.1161, GLO1*2 = 0.8839. We have compared these data with those reported for Han.

Blood Donors↗

Heat labile opsonin system to pneumococcus.

Normal mammalian sera contain the heat labile opsonin system that promotes the phagocytosis of various microorganisms by polymorphonuclear leukocytes. Because the heat labile opsonin system is present in normal nonimmune sera and because it operates against various microorganisms in an apparently nonspecif manner, it is considered to play an important role during the early phase of an acute bacterial infection. The role of various factors participating in the heat labile opsonin system, and its in vivo significance are discussed.

Animals↗

[The immune status of homosexuals ill with different forms of syphilis].

Status of the cell-mediated, humoral immunity, and nonspecific defense factors were examined before and after specific therapy in 40 homosexuals suffering from secondary relapsing and latent early syphilis. The findings evidence that changes in the cell-mediated immunity of homosexual syphilitics essentially differ from those in heterosexuals with syphilis: decreased count of T-helpers and elevated one of T-suppressors evidence impaired ratio of T-lymphocyte subpopulations and immunoregulatory cell imbalance. A significantly increased level of C4 complement component was observed, evidencing a deficiency of the complement system. These data call for the development of a scheme of immunocorrective therapy for homosexuals suffering from syphilis.

Adolescent↗

Differences between the binding sites of the complement regulatory proteins DAF, CR1, and factor H on C3 convertases.

Binding studies using purified decay-accelerating factor (DAF), CR1, and Factor H indicate that the primary interaction of DAF with C3 convertases is with the Bb or C2a subunits, whereas CR1 and Factor H interact primarily with the C3b or C4b subunits. The ability of soluble DAF, CR1, or Factor H to decay C3b,Bb bound to zymosan was inhibited by various concentrations of fluid-phase competitors (C3b, Bb, C3b,Bb, C3b,B, C4b, or C4b,C2a) in 0.1% NP-40 at 22 degrees C. The apparent association constants (appKa) for DAF were 0.045, 0.067, 0.91, 0.71, 0.00045, and 0.53 microM-1, respectively. The appKa for CR1 were 0.50, 0.0040, 1, 1, 1, and 1.1 microM-1, respectively. The appKa for Factor H were 4.3, 0.0005, 2.9, 6.3, 0.27, and 0.29 microM-1, respectively. Thus, C3b binds to DAF with a 10-fold lower affinity than to CR1 and a 100-fold lower affinity than to Factor H. The appKa of C3b,Bb for the three proteins were more similar: DAF (0.91 microM-1), CR1 (1 microM-1), and Factor H (2.9 microM-1). DAF binds to Bb with a 50% higher affinity than to C3b, and to C4b,C2a with a 1000-fold higher affinity than to C4b alone. In contrast, CR1 and Factor H bind almost equally well to the C3 convertases and to their noncatalytic subunits. The affinity of DAF for CVF,Bb was similar to its affinity for Bb alone, suggesting that DAF does not recognize conformational determinants unique to Bb in C3 convertases.

Binding Sites↗

Endogenous association of decay-accelerating factor (DAF) with C4b and C3b on cell membranes.

Decay-accelerating factor (DAF) is a membrane glycoprotein found on various cells that are in contact with complement. It inhibits the formation of the C3 convertases of the complement system, both the classic (C4b2a) and alternative (C3bBb) pathways. In this investigation, we used a homobifunctional cross-linking reagent to search for a DAF ligand on the surface of cells subjected to complement attack. We found that DAF forms complexes with C4b and C3b deposited on the same erythrocytes, but not with the physiologic degradation products of these complement fragments, that is, C4d or C3dg. Taken together with prior observations that DAF action is reversible, and DAF does not affect the structure of C4b or C3b, these findings suggest that DAF functions by competitively inhibiting the uptake of C2 or factor B, and preventing the assembly of the C3 convertases.

Animals↗

[Serum proteins and hormones in vaginal and abdominal hysterectomy].

Postoperative changes in various acute-phase-proteins (alpha 1-Antitrypsin, c-reactive protein), alpha 2-Macroglobulin, haptoglobin, transferrin. c3-c4-complement and myoglobin as well as endocrine parameters were studied in forty healthy women in two groups. Women with malignant neoplasms were excluded. Each group consisted of 20 women who underwent either a vaginal or abdominal hysterectomy. Differences between both collectives could be seen in determinations of alpha 1-antitrypsin, CRP and myoglobin, where decreases were significantly higher in the laparotomy group than in the vaginal operation group.

Acute-Phase Proteins↗

A cytokine-selective defect in interleukin-1 beta-mediated acute phase gene expression in a subclone of the human hepatoma cell line (HEPG2).

Several well-differentiated human hepatoma cell lines (HepG2, Hep3B) have been used to identify factors which regulate hepatic gene expression during the host response to inflammation/tissue injury (acute phase response). Studies in these cell lines, as well as in primary cultures of rat, rabbit, and mouse hepatocytes, have demonstrated that interleukin-1 beta (IL-1 beta), tumor necrosis factor (TNF-alpha), and interferon-beta 2 (IFN-beta 2) each mediate changes in expression of several hepatic acute phase genes. In this study we identify a subclone of the HepG2 cell line in which there is a selective defect in IL-1 beta-mediated acute phase gene expression. Recombinant human IL-1 beta mediates an increase in synthesis of the positive acute phase complement protein factor B and a decrease in synthesis of negative acute phase protein albumin in the parent uncloned HepG2 cell line (HG2Y), but not in the subclone HG2N. Recombinant human IFN-beta 2 and TNF-alpha, however, regulate acute phase protein synthesis in the subclone HG2N; i.e. IFN-beta 2 and TNF-alpha increase synthesis of factor B and decrease synthesis of albumin in both HG2Y and HG2N cells. Equilibrium binding analysis with 125I-rIL-1 beta at 4 degrees C showed that both HG2N and HG2Y cells bind IL-1 beta specifically and saturably. HG2N and HG2Y possess 3.8 and 4.0 x 10(3) plasma membrane receptors/cell with affinities of 0.96 and 1.07 x 10(-9) M, respectively. Thus, the defect in this subclone of the HepG2 cell line is likely to involve the signal transduction pathway for the biological activity of IL-1 beta and will be useful in elucidation of this signal transduction pathway.

Acute-Phase Proteins↗

Hemodialysis and the acute-phase response in chronic uremic patients.

In comparison with healthy persons, chronic uremic patients on regular hemodialysis treatment had significantly higher blood serum concentrations of alpha 1-acid glycoprotein, ceruloplasmin and C4 complement component, while levels of haptoglobin, C3 and transferrin were lower. Serum alpha 2-macroglobulin and alpha 1-antitrypsin levels were similar in both groups. Hemodialysis with cuprophan membrane induced only slight changes in some of these glycoproteins during a 48-hour follow-up period. Seven hours after termination of hemodialysis slight, but significant, decreases in blood serum transferrin and alpha 1-antitrypsin concentrations were observed. Hemodialysis thus does not seem to induce a conspicuous acute-phase reaction.

Acute-Phase Proteins↗

Erythrocyte membrane protein deficiencies in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by intermittent hemolytic anemia. Membrane abnormalities of blood cells from patients with PNH are the reason for the unusual sensitivity to lysis by autologous plasma complement. A patient with typical clinical disease consistent with PNH is described together with a few strategies and pitfalls for treatment. Commonly used in vitro assays are discussed that document the complement-mediated lysis of aberrant PNH erythrocytes. Membrane-associated proteins that are abnormal in PNH cells, the characteristics of these proteins, and their mechanism(s) of action are described; these include the decay accelerating factor that inhibits the C3/C5 convertases of both complement pathways on cell surfaces, the C8 binding protein that modulates a step in terminal complement lysis, and other proteins that regulate complement-mediated lysis at early or late steps of the complement cascade.

Adult↗

The alternate complement pathway in inflammatory bowel disease. Quantitation of the C3 proactivator (factor B) protein.

A component of the complement system's alternate pathway was investigated in ulcerative colitis and Crohn's disease. The mean C3PA (Factor B) titer in normals was 74 +/- 15%; in ulcerative colitis, 92 +/- 18%; and in Crohn's disease, 119+/- 24%. Significance was at the P less than 0.001 level when the mean values for the ulcerative colitis and the Crohn's disease groups were compared to normal subjects. Titers did not change significantly with exacerbation or amelioration of the diseases or when patient groups were analyzed according to the mode of treatment received.

Blood Proteins↗

Characterization of a synthetic peptide that inhibits the interaction between protein S and C4b-binding protein.

Protein S is unique among the vitamin K-dependent proteins found in blood plasma because it is a cofactor rather than a zymogen of a serine protease. Instead of a trypsin-like domain, protein S contains a domain that has sequence homology with steroid binding proteins. In order to understand the function of this structural domain, peptides have been synthesized with amino acid sequences that are homologous between human protein S and rat androgen binding protein. Two peptides, corresponding to amino acids 400-407 (PINPRLDG) and 605-614 (GVQLDLDEAI) of the protein S sequence have been tested for their effects on protein S function. Neither peptide altered the clotting of bovine or human plasma. The peptide GVQLDLDEAI enhanced the anticoagulant activity of human-activated protein C in human plasma while the peptide PINPRLDG had no effect. The peptide GVQLDLDEAI was observed to inhibit the binding of protein S to C4b-binding protein in plasma, resulting in increased concentrations of free protein S. GVQLDLDEAI was also observed to enhance the disassociation of the protein S.C4b-binding protein complex when purified complex was used. Finally, C4b-binding protein was observed to bind to GVQLDLDEAI. These results suggest that the carboxyl-terminal region of protein S, which contains the sequence GVQLDLDEAI, is involved in the interaction between protein S and C4b-binding protein.

Amino Acid Sequence↗

Complement receptors.

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Antigens, Differentiation, B-Lymphocyte↗

Antibody-mediated alternative complement pathway activation resists inhibition by sialoglycolipids.

Although sialoglycolipids on liposome membranes were able to inhibit the activation of the alternative complement pathway (ACP) of guinea pigs mediated by trinitrophenylaminocaproyldipalmitoylphosphatidylethanolamine, they scarcely inhibited the ACP activation mediated by natural antibody to paragloboside (PG) inserted into the liposome membranes. Therefore, ACP activation was able to proceed regardless of the presence of sialoglycolipids on heterologous cell membranes when antibodies to constituents of the membranes were available. On the other hand, sialoglycolipids effectively inhibit undesirable ACP activation on self cell membranes, because little if any antibody is reacting on the self cell surface. Thus, the natural antibody reaction may effectively discriminate between self and non-self cell surface by cooperation with complement inhibitors on cell membranes such as sialoglycolipids.

Absorption↗

Autoantibodies in myotonic dystrophy.

We evaluated some immunological parameters in a group of 24 patients affected with myotonic dystrophy (MD). IgG, IgA, IgM immunoglobulin serum levels resulted decreased in most of the patients. Anti-smooth-muscle antibodies have been found in 10 out of 24 patients (45.5%). Moreover in some of them decreased C3 and C4 complement fraction serum levels have been found. Our data confirm the existence of some immunological abnormalities in a great number of subjects affected with the disease. Besides, these data evidence for most of the subjects the presence of autoantibodies non-organ-specific direct against myocellular antigens. These autoantibodies could be considered the expression of suffering of muscular fibres.

Adolescent↗

Participation of the complement system in ischemia/reperfusion injury.

Reperfusion of ischemic skeletal muscle is associated with an early infiltration of WBC, a process mediated by locally generated chemotactic factors. We present evidence that selective activation of the alternative complement cascade occurs in response to skeletal muscle ischemia/reperfusion injury. Complement activation may result in the generation of peptides which are chemotactic for neutrophils, and the formation of molecular complexes which injure cell membranes.

Animals↗

Relevance of complotyping and subtyping of MHC class I gene products in haplotype definition for allogeneic bone marrow transplantation.

In preparation for a bone marrow transplantation 217 patients and their families were complotyped for Bf, C4A and C4B in addition to the routinely performed HLA-A,B,C,DR and HLA-D typing. In 147 families uncertainties in haplotype definition occurred which could be solved in 37 cases (25%) by complotyping. Additionally, patients and their relatives were subtyped for class I gene products by one-dimensional isoelectric focusing, a method by which serologically identical HLA-A, B, or C antigens could be split in five out of 22 cases tested. The results obtained clearly show the relevance of both methodologies for finding the best match of donor/recipient pairs to help to prevent MHC-induced graft-versus-host disease after bone marrow transplantation.

Bone Marrow Transplantation↗