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M Kirschfink

Publications and source records attributed to M Kirschfink.

At least 73 records · Page 4Linked to original sources
PubMed1995

[The effect of the complement system on the acute reversible rejection of kidney transplants].

Although the involvement of complement in hyperacute renal allograft rejection is well established, its possible implication in acute reversible and chronic graft rejection remains uncertain. In recent clinical studies with a total of 83 patients undergoing renal transplantation, plasma levels of complement activation products were elevated 4-7 days before clinical diagnosis of graft rejection. Immunohistochemical analysis of biopsies revealed local complement activation with glomerular deposition of the terminal C5b-9 complex within 1 h after organ reperfusion. Increasing levels of complement activation products, preceding the clinical manifestation of renal graft rejections may be of diagnostic value in recognizing patients at risk.

Acute Disease↗
PubMed1994

Complement activation by recombinant HIV-1 glycoprotein gp120.

The mechanism of CD4+ cell depletion in HIV-infected patients is poorly understood. In this study we investigated whether rgp120 can activate the complement system in the absence of anti-gp120 Abs. We found that the complement proteins C4, C3d, C5b-9, and properdin bind to rgp 120-coated CD4+ T cells of healthy individuals when incubated in autologous serum. Activation of the complement system occurred primarily via the classical pathway and was abolished in sera deficient in C1q and C4 as well as in the presence of EDTA. No cell lysis was observed in a lymphocytotoxicity assay using human serum, possibly because of homologous restriction of complement lysis. In contrast, addition of rabbit sera induced lysis of the rgp 120-precoated cells. Cell lysis by rabbit serum was found to be because of naturally occurring IgM anti-gp 120 Abs. The rgp 120, which was immobilized on the surface of microtiter plates activated complement in the absence of lymphocytes. Complement activation by cell-bound HIV-1 envelope glycoprotein gp120 with subsequent opsonization may be relevant for the elimination of noninfected CD4+ T cells in HIV-infected patients.

Amino Acid Sequence↗
PubMed1994

Activation of complement by cold agglutinins.

OBJECTIVE: To review recent reports on the interaction of cold agglutinins with the complement system and its relevance to cold agglutinin disease. DATA SOURCES: Review articles and original papers have been selected for this contribution. SELECTION CRITERIA: The report focuses on experimental data available from in vitro studies as well as clinical findings regarding the mechanisms of cold agglutinin-induced complement activation. RESULTS: Despite the observation that only few cold agglutinins (almost exclusively IgM molecules with anti-I specificity) induce in vitro hemolysis of human red blood cells with human serum (homologous system), the vast majority of these autoantibodies are able to initiate the classical pathway sequence with the fixation of C1 and to a lesser degree of C4. The ability of IgM cold agglutinins to activate, in principle, complement is demonstrated by their hemolytic efficiency in the presence of animal serum as a source of heterologous complement. In addition to the thermal amplitude of cold agglutinin binding, a possible interference with membrane regulatory proteins may render certain cold agglutinins hemolytically active in a homologous system. CONCLUSION: Despite a hemolytic inefficiency, cold agglutinin-induced fixation of early complement components up to C3 leads to an accelerated clearance of red cells from the circulation by hepatic sequestration. However, it is not yet clear, to what degree these cells are eliminated by the reticuloendothelial system or whether they return to the circulation. Dependent on the amount of membrane-bound C3 fragments these cells may even be protected against further cold agglutinin-induced complement attack.

Agglutinins↗
PubMed1994

Red cell destruction in cold agglutinin disease.

OBJECTIVE: The severity of autoimmune hemolytic anemia (AIHA) caused by cold agglutinins (CAs) is known to differ markedly in chronic CA disease as well as in postinfection cold agglutination. The various cold agglutinin specificities and mechanisms of red cell destruction are described. DATA SOURCES: Original papers and reviews of the German and English literature (Medline research); own results. SELECTION CRITERIA: Original papers and reviews of the recent years on studies of the biochemistry and specificity of CAs and the pathophysiology of AIHA. RESULTS: A crucial point for the severity of AIHA caused by CAs is the CA-binding capacity to red cells in vivo. This is reflected by the serologic behavior of the actual CA in vitro, represented by its thermal amplitude. Because most CAs are IgM molecules, red cell destruction by CAs is limited to mechanisms initiated by complement (C) activation. In recent years, several CA specificities, in addition to anti-I/i, have been identified on a serological and biochemical basis. CAs of the IgG and rarely of the IgA isotypes have been found. CONCLUSION: The CA-induced red cell destruction does not only depend on CA titer or its thermal amplitude. The severity of CA-induced AIHA may also depend on CA isotype and/or specificity. Therefore, the complement activation capacity of CAs with a given isotype but different specificities has to be elucidated in further studies.

Agglutinins↗
PubMed1993

Evaluation of complement activation in premature newborn infants with hyaline membrane disease.

Fifteen premature newborns with hyaline membrane disease causing acute respiratory distress were evaluated for complement activation. A high intrapulmonary right-to-left shunt and marked arterial-alveolar oxygen difference indicated the severity of the respiratory failure. Twenty preterm healthy infants served as controls. Total haemolytic activity, plasma concentrations of complement components and regulatory proteins (C3, C4, C1-inhibitor, factors H and I) as well as activation products (C3a, C3dg, C1rsC1-inhibitor, C3b(Bb)P) gave no evidence of significant complement activation. Functional activity of the ubiquitous regulatory protein C1-inhibitor was significantly reduced without impact on classical pathway activation. These data suggest that, in contrast to the adult form of respiratory distress syndrome, the low-pressure pulmonary oedema characterising hyaline membrane disease is not mediated by activation of the complement system.

Biomarkers↗
PubMed1993

Influence on myoadenylate deaminase function in rat skeletal muscle after homologous and heterologous immunization with the purified enzyme.

The aim of the study was to shed some light on the possibility of anti-MAD autoantibodies in cases of rhabdomyolysis or microtraumatic muscular damage causing the symptoms of the acquired myoadenylate deaminase deficiency. Therefore a homologous and a heterologous immunization of rats was carried out with myoadenylate deaminase (MAD; EC 3.5.4.6.) isolated from rat white gastrocnemius muscle (type IIb) and rabbit skeletal muscle. Antibody response to homologous and heterologous antigens was quantified by ELISA and by the inhibition of MAD activity in vitro. Anti-MAD IgG antibodies obtained by homologous immunization caused an inhibition rate of 80% when using MAD from rat white gastrocnemius muscle. Furthermore, the function of MAD in homologously and heterologously immunized rats was investigated after maximal swimming exercise in comparison to non-immunized animals by determination of muscle ammonia and by HPLC detection of inosine 5'-monophosphate (IMP) in skeletal muscle tissues. Both IMP and ammonia accumulation were significantly reduced in type IIb muscle fibers after homologous immunization of rats compared to non-immunized controls (n = 7), whereas the concentration of muscle lactate showed no differences. According to these results we propose that by homologous immunization with purified MAD, anti-MAD IgG impairs the function of cytoplasmic MAD during vigorous exercise in vivo.

AMP Deaminase↗
PubMed1993

Complete functional C1q deficiency associated with systemic lupus erythematosus (SLE).

A complete functional deficiency of C1q is described in a patient suffering from SLE. From reduced plasma C1 activity of the parents a hereditary trait was assumed. The defective C1q molecule was haemolytically inactive, did not bind to immune complexes, and was not recognized by the monocyte C1q receptor. C1 activity in the patient's serum could be restored by the addition of purified C1q. Analysis by gel-filtration and ultracentrifugation experiments revealed an immunoreactive molecule of about 150 kD mol. wt, corresponding to one structural subunit of the C1q macromolecule, containing two A chain-B chain dimers and a C-C chain dimer. Applying Southern blot analysis with cDNA clones encoding for the three individual chains of the C1q molecule, no restriction fragment length polymorphism was detected, ruling out possible major alterations of the genetic information.

Adult↗
PubMed1993

Complement activation and C3 allotype distribution in patients with bronchial asthma.

61 patients suffering from intrinsic (idiotypic) or extrinsic (allergic) asthma were investigated for signs of complement activation and for C3 phenotype distribution. Activation of both the classical and alternative pathway of the complement system and generation of the membrane attack complex could be assessed by ELISAs for the activation-specific protein-protein complexes C1rsC1 inhibitor, C3b(Bb)P and SC5b-9, respectively. A possible deficiency of the complement regulatory proteins C1 inhibitor, factor H and factor I was excluded. In contrast to earlier studies, C3 allele frequencies did not differ from those found in the healthy population. Our results support the role of complement activation during bronchial asthma and, thereby, provide further evidence for the inflammatory nature of the disease.

Alleles↗
PubMed1993

Extracorporeal circulation: in vivo and in vitro analysis of complement activation by heparin-bonded surfaces.

Complement activation was analyzed during extracorporeal CO2 removal to compare heparin-coated with standard surfaces where systemic heparinization was required. In vivo studies were performed in adult sheep for up to 5 days under standardized conditions using a capillary membrane oxygenator. Applying assays for hemolytic complement function (CH50, APH50) and C3-derived split products, we found that complement activation was markedly reduced in sheep connected to an extracorporeal circuit where heparin was covalently bound by end-point attachment. In addition, incubation of human serum in a miniaturized circulation system revealed less complement activation by heparin-bonded surfaces, as evaluated by enzyme-linked immunosorbent assays for C3a and the activation-specific protein-protein complexes, C1rsC1 inhibitor (classical pathway) and C3b(Bb)P (alternative pathway). Our results provide further evidence that biocompatibility can be improved by end-point attachment of heparin to the surfaces of the extracorporeal circuit.

Animals↗
PubMed1992

Complement fragment C3a in plasma of asphyxiated neonates.

Recent clinical studies with adult polytrauma patients indicate that elevated plasma levels of anaphylatoxin C3a correlate with the subsequent development of the adult respiratory distress syndrome (ARDS). However, there are no parameters which allow a reliable diagnosis of ARDS in neonates. As the most predisposing condition for ARDS seems to be shock, plasma C3a was determined in 30 ventilated premature infants and neonates with respiratory distress syndrome (birth weights 660-3350 g) within the first 24 h post partum or 6-24 h after acute asphyxia or shock during the neonatal period. The range of C3a, measured by ELISA, was between 57 and 1000 ng/ml. In the asphyxia group (n = 15) peak levels of C3a in plasma (mean 388 ng/ml) were significantly higher (P less than 0.001) than in the control group (mean 153 ng/ml). In some neonates with suspected ARDS, additional samples were taken. A rise in C3a between days 2 and 8 was associated with a fatal outcome of the disease. As in adults, C3a might be a useful indicator for ARDS in neonates.

Asphyxia Neonatorum↗
PubMed1992

Generation of anaphylatoxin C3a in plasma and bronchoalveolar lavage fluid in trauma patients at risk for the adult respiratory distress syndrome.

OBJECTIVE: To determine the generation of anaphylatoxin C3a in plasma and bronchoalveolar lavage fluid in trauma patients at risk for the adult respiratory distress syndrome (ARDS). DESIGN: Prospective study. SETTING: ICU in a university hospital. PATIENTS: Severely traumatized patients at risk for the ARDS (n = 25). INTERVENTION: EDTA plasma samples and bronchoalveolar lavage fluid were obtained. MEASUREMENTS AND MAIN RESULTS: Complement proteins C3, C4, C5, and the inhibitors C1-inhibitor, Factor H, and Factor I were quantitated in EDTA-plasma samples obtained every 6 hrs during the first 48 hrs after ICU admission and every morning from days 4 to 14 after injury. In bronchoalveolar lavage fluid, the complement activation production of C3a-desArg was quantitated and the volume of epithelial lining fluid was calculated. All patients showed a decrease of the complement proteins C3, C4, C5 and of the inhibitors C1-inhibitor, Factor H, and Factor I during the first 24 hrs, indicating complement consumption. Patients developing ARDS (n = 11) showed significantly higher C3 concentrations and a higher C3a/C3 ratio in the first few hours after multitrauma. Follow-up bronchoalveolar lavages demonstrated highly increased amounts of C3a in epithelial lining fluid during the first 24 hrs, mainly in ARDS patients and, to a lesser degree, in non-ARDS patients. To determine the origin of C3a in bronchoalveolar lavages, the ratio of C3a in epithelial lining fluid and plasma was calculated. CONCLUSION: The C3a of epithelial lining fluid to plasma ratio was extremely high in patients developing ARDS, but even the non-ARDS group had a ratio greater than 1, indicating that a substantial local complement activation occurs in the lung.

Adult↗
PubMed1992

Inherited neuroaxonal dystrophy in C6 deficient rabbits.

We report the occurrence of a progressive neurological syndrome clinically characterized by subacute motor neuropathy in offspring of C6 deficient rabbits. On the basis of the pedigree analysis, the disease appears to be genetically transmitted, most probably with an autosomal recessive mode of inheritance. Pathological studies of affected animals revealed: transmitted, most probably with an autosomal recessive mode of inheritance. Pathological studies of affected animals revealed: 1) severe axonal degeneration in the sciatic nerve system involving mainly motor fibers; 2) occasional peripheral axonal enlargement closely associated with axonal degeneration; 3) presence of structured abnormal material in normal-size myelinated fibers of central nervous system (CNS) and peripheral nervous system (PNS); and 4) widespread occurrence of dystrophic axons and axonal spheroids in the gray matter of CNS. By ultrastructural examination, dystrophic axons are filled with tubulovesicular material, stalks of parallel membranes and dense bodies similar to what is described in human neuroaxonal dystrophies (NAD). The disease manifested by C6 deficient rabbits may represent an animal model of primary human NAD.

Animals↗
PubMed1992

Complement activation by cold agglutinins.

Purified monoclonal human IgM cold agglutinins (CA) of different specificities (anti-I, anti-i, anti-Pr) were investigated for their complement-activating capacity in a homologous system. Incubation of human RBC with excess of IgM CA in the cold, and subsequently with human serum at 37 degrees C, resulted in striking differences in hemolysis. Hemolysis did not correlate to the amount of antibodies bound to RBC at 4 or 20 degrees C. Despite the hemolytic inefficiency of anti-i and anti-Pr CA tested, C1 fixation and subsequent activation of the classical pathway of complement could be assessed in all cases. Absolute numbers of C3 molecules bound to RBC, exceeding the critical level to initiate the terminal sequence of the complement cascade, could not fully explain the differences in the hemolytic activity of the CA. Since C8 binding protein (C8bp) carries I determinants it is hypothesized that anti-I-induced complement-mediated hemolysis might also be favored by the binding of the autoantibody to and probably steric hindrance of this major regulatory protein of the terminal complement sequence. The prominent role of homologous restriction of complement-mediated lysis as a protective mechanism can also be deduced from the fact that rabbit as well as rat serum as a source of heterologous complement lysed cold agglutinin-sensitized red blood cells more efficiently than human serum.

Agglutinins↗
PubMed1992

Characterization of I/F1 glycoprotein as a receptor for Mycoplasma pneumoniae.

Serologic evidence of anti-I and anti-Fl cold agglutinins occurring in mycoplasma infections led to the isolation of I/Fl glycoprotein from human erythrocyte membranes. Mycoplasma pneumoniae bound to purified I/Fl glycoprotein in a dose-dependent fashion depending on sialylated carbohydrate determinants. This was shown by the decreased binding of mycoplasmas to either sialidase-treated I/Fl glycoprotein (dot blot analysis) or sialidase-treated erythrocytes (hemagglutination test). Structural properties of the receptor for optimal binding could be explored by hemagglutination inhibition assays. Glycophorins were excluded as receptors. These results indicate that Fl (and I) antigens are receptors for M. pneumoniae.

Agglutinins↗
PubMed1991

Complement activation by house dust: reduced reactivity of serum complement in patients with bronchial asthma.

Among ten different allergens, house-dust extract proved to be the most potent complement activator. It was therefore chosen to investigate the susceptibility of complement in the serum and bronchoalveolar lavage fluid of patients with extrinsic asthma and control persons. Complement activation in serum was assessed by the appearance of C3d as well as the activation-specific protein-protein complexes C1rs-C1inhibitor (classical pathway) and C3b(Bb)P (alternative pathway). Complement was activated via both the classical and the alternative pathway in a dose- and time-dependent manner. In contrast to earlier observations, however, complement was less affected in the serum of asthmatics than in the serum of normal individuals. Differences were restricted to alternative-pathway activation, probably due to preactivation and/or a significantly higher serum concentration of the regulatory protein factor H in asthmatic patients. In vitro generation of C3a in bronchoalveolar lavage fluid could not be achieved, although the presence of alternative pathway proteins C3, B and D was demonstrated.

Allergens↗
PubMed1991

Differences in the complement activation induced by preformed and nascent immune complexes.

While preformed BSA-anti-BSA immune complexes (PIC) bind efficiently to human RBC after their interaction with human complement, nascent BSA-anti-BSA immune complexes (NIC) formed in the presence of complement do not bind to autologous RBC. The same results were obtained with tetanus toxoid-anti-tetanus toxoid PIC and NIC. In order to elucidate the causes of this marked difference between the RBC-binding properties of PIC and NIC, the profile of complement activation induced by them was compared using haemolytic assays and sensitive ELISA tests. BSA-anti-BSA NIC activated C1 more efficiently than PIC. This was reflected in a higher C4 content of the isolated NIC and higher C1 INH-C1s and lower C1q-fibronectin complex level in the NIC-treated serum as compared to the PIC-treated ones. Although isolated NIC contained more C3 than isolated PIC did, there was no significant difference in the AP activation. These findings suggest that the failure of NIC to bind to RBC is not due to a lack of C4-binding, or C3-binding and/or activation, but rather to the special structure of this type of complex.

Antigen-Antibody Complex↗