[Membrane-attacking complexes and membrane complement inhibitors on the leukocyte surface during combined exposure with meningococcus lipopolysaccharide and complement].
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CD55 Antigens↗
Biomedical subjects
I V Vershinina
Publications and source records attributed to I V Vershinina.
[The interconnection between the severity of meningococcal infection and the endotoxicity levels and patient's blood complement].
Seventy-eight patients with severe systemic meningococcal disease admitted to the Intensive Care Unit of the Second Moscow Hospital for Infectious Diseases were divided into four groups by complications of their disease: patients with refractory septic shock (RSS)--group 1; patients with early septic shock (ESS)--group 2; patients without shock but with severe mental disorders--group 3; patients without any of these complications--group 4. The LPS concentration in plasma was assessed by chromogenic method. Initial LPS levels in plasma of group 3 or group 4 patients (170 ng/l, median value and 360 ng/l, respectively) were greater than those of healthy donors (LPS < 15 ng/l). LPS concentration was significantly greater in group 2 (920 ng/l) or group 1 (12,400 ng/l). LPS levels declined exponentially in all the patients. The half-life was calculated to be 1.4 (+) -0.3 h. In group 2 and 1, respectively, the classical pathway complement activity in patients' serum was 50 and 10% of normal control values. To estimate significant prognostic factors for fatality in our patients, specificity and factor fatality difference of various clinical and laboratory factors were calculated. The cut-off LPS value for development of ESS was 600 ng/l and that for development of RSS and death was 8000 ng/l. For the prediction of fatality using the former cut-off value of LPS, sensitivity was 84% and specificity 100%. Using plasma complement activity (cut-off--15% of normal value) for prediction, sensitivity was 75% and specificity was 100%. Other factors (platelet and WBC count, blood pH, BP, etc.) had lower predictive power. Thus to date plasma endotoxin level and complement activity are the best prognostic factors in meningococcal disease.
Adolescent↗
[Clinical features of meningococcal infection in subjects with deficient terminal components of complement].
AIM: To evaluate clinical characteristics of meningococcal disease (MD) in individuals with terminal complement component deficiency (TCCD) who are thousands times more susceptible to MD than complement-sufficient persons. MATERIALS AND METHODS: 61 cases of MD in TCCD patients and 200 randomly selected cases of MD in complement-sufficient patients were analyzed. RESULTS: Meningitis without meningococcemia accounted for 17% of the MD episodes in the control group of complement-sufficient patients but none in individuals with TCCD who had meningococcemia (10%) or meningococcemia with meningitis (90%). Moderate disease predominated in patients with TCCD (70%) and no episodes of fatal disease were noted, whereas severe disease was more common in the control group which had an 8% case fatality rate and frequent complications such as endotoxic shock (15% of episodes) and brain edema (26%). The severity of the disease in TCCD patients did not differ between the first and subsequent episodes, between males and females, between episodes caused by serogroup A and B meningococci, etc. CONCLUSION: In comparison to complement-sufficient persons, the course of the disease in patients with TCCD is statistically less severe.
Adolescent↗
Meningococcal disease and polymorphism of FcgammaRIIa (CD32) in late complement component-deficient individuals.
Late complement component-deficient (LCCD) individuals lack plasma bactericidal activity and are highly susceptible to meningococcal disease. Phagocytosis plays a significant role in immune defence against meningococci and involves FcgammaRIIa (CD32) on leucocytes. Two allotypic forms are currently recognized: FcgammaRIIa-R131 and RIIa-H131. Neutrophils with the IIa-H/H131 allotype are more effective in phagocytosis than IIa-R/R131. We studied the distributions of IIa-R131 and IIa-H131 allotypes among 29 Russian LCCD patients who had suffered from recurrent episodes of meningococcal disease. The distribution of IIa-R/R131 to heterozygous IIa-R/H131 to homozygous IIa-H/H131 genotypes was 0.14:0.29:0.57 for LCCD patients who developed the first episode of disease before 10 years of age. The distribution was 0.21:0.64:0.14 for patients who experienced meningococcal disease above the age of 10 years (chi2 = 6, P < 0.05, odds ratio for IIa H/H131 versus R/R131 = 8). Meningococcal disease had a 'grave' course in 14 of 31 disease episodes in patients with IIa-R/R131 and IIa-R/H131 allotypes, in contrast to 1 of 18 episodes in patients with IIa-H/H131 allotype (chi2 = 7, P < 0.01, odds ratio = 14). We conclude that IIa-H/H131 individuals appear to have a higher acquired antibody-mediated phagocytosis-dependent resistance to meningococcal disease above the age of 10 years. Additionally, effective CD32-mediated phagocytosis may restrict the severity of meningococcal disease in LCCD patients with IIa-H/H131 phenotype.
Adolescent↗
Association of human Fc gamma RIIa (CD32) polymorphism with susceptibility to and severity of meningococcal disease.
Phagocytosis of bacteria constitutes an important defense mechanism against invasive bacterial diseases. Efficacy of phagocytosis by polymorphonuclear neutrophils is known to vary between allotypes of Fc gamma RIIa (a class of Fc receptors for immunoglobulins that is constitutively expressed on neutrophils). We compared the distribution of Fc gamma RIIa-R131 and Fc gamma RIIa-H131 allotypes in 98 Slavic complement-sufficient patients with meningococcal disease with that of the allotypes in 107 healthy controls. A strong association was found between the IIa-R/R131 allotype and the development of meningococcal disease after the age of 5 years, compared with IIa-R/H131 and IIa-H/H131 allotypes (P < .03; odds ratio [OR], 2.9). A severe course of meningococcal disease was observed in 21 (68%) of 31 episodes in patients with IIa-R/R131 genotype and in 22 (54%) of 41 episodes in patients with IIa-R/H131 genotype, in contrast to eight (31%) of 26 episodes in patients with IIa-H/H131 genotype (P < .02; OR, 4.7). Our data show that individuals older than 5 years of age who have the IIa-H/H131 allotype are less susceptible to severe meningococcal disease than are individuals with the IIa-R/R131 or IIa-R/H131 genotype.
Adolescent↗
Heterozygous C8beta complement deficiency does not predispose to meningococcal disease.
We have identified 42 Russian patients with homozygous C8beta complement component deficiency, all of whom had experienced at least one episode of systemic meningococcal disease. About 90% of these individuals have a C --> T exchange in exon 9, leading to a premature stop codon. If, like the homozygous-deficient state, heterozygous C8beta deficiency constitutes a risk factor for meningococcal disease, it would be expected to be detected with increased frequency among individuals suffering from this disease. Using allele-specific polymerase chain reaction (PCR), we studied 153 consecutive patients with meningococcal disease admitted to the Moscow Hospital for Infectious Diseases to determine the frequency of C8 null allele. No individuals with heterozygous C --> T exchange were identified among these 153 patients, despite the fact that seven persons were detected who had homozygous C8beta deficiency, caused by the same C --> T exchange in exon 9, and one patient who had C7 component deficiency. Thus, heterozygous deficiency, although more frequent than homozygous deficiency in the general population, does not result in a substantial increase in susceptibility to meningococcal disease.
Complement C8↗
Molecular bases of combined subtotal deficiencies of C6 and C7: their effects in combination with other C6 and C7 deficiencies.
Combined subtotal deficiency of C6 and C7, in which both proteins are expressed at very low levels, has been observed in homozygous form in two families. A defect at the 5' splice donor site of intron 15 of the C6 gene explains the low molecular weight of the C6 protein and is probably responsible for its low expressed concentration. The C7 defect is more enigmatic: the protein is of normal molecular weight, low circulating concentration, and altered isoelectric point. An Arg > Ser codon substitution in exon 11 is the only molecular alteration within the mature C7 protein. These defects are associated with a characteristic set of polymorphic DNA markers in the C6/C7 region, forming a distinct haplotype. The haplotype has been found in combination with a number of other haplotypes containing defective genes that lead either to C6 or C7 deficiency, but with different consequences. Where it is combined with a C6-deficient gene, the serum C7 levels can be surprisingly high, possibly because there is no C6 generating C56 to consume the C7. In contrast, where the C7 genes are both defective (but still partially functional), there may be a profound deficit of circulating C7 because there is ample C6 to produce C56 and consume the already small amount of C7. Each molecular defect has also been found in isolation and has the expected effect.
Amino Acid Sequence↗
How partial C7 deficiency with chronic and recurrent bacterial infections can mimic total C7 deficiency: temporary restoration of host C7 levels following plasma transfusion.
An apparently completely complement C7-deficient patient with refractory otitis media and two episodes of meningococcal disease was given therapeutic plasma transfusions in 1992 and 1994. Following these transfusions unexpected changes were found in C7 levels. Immediately after transfusion the serum C7 levels failed to rise to the expected levels but then rose to 5-10% of the normal mean during the next 5 days and remained at that level for more than 2 weeks before eventually returning to zero. The patient's DNA genotyped C7 M, and therefore C7 N donor plasma was selected for the second transfusion to allow identification of the source of the C7 circulating post-transfusion. This C7 phenotyped C7 M, demonstrating it to be of recipient origin. Therefore, the apparently completely C7-deficient patient was able to secrete some C7. By a combination of DNA typing and isoelectric focusing of the C7 appearing after transfusion, it was demonstrated that the patient was heterozygous for combined subtotal C6/C7 deficiency (inherited from his father) and a different, so far uncharacterized, subtotal C7 deficiency (inherited from his mother). The low amount of C7 secreted appeared to be constantly consumed, probably by generation of C5b6 as a result of his chronic infection. He had been shown to have circulating C5b6 most of the time, and thus only when sufficient exogenous C7 was given to consume the free C5b6 did his own C7 appear in circulation.
Bacterial Infections↗
Vaccination of patients deficient in a late complement component with tetravalent meningococcal capsular polysaccharide vaccine.
Eighteen patients with late complement component deficiency (LCCD) were immunized with meningococcal capsular polysaccharide vaccine. The LCCD patients had experienced one-to-five meningococcal infections before vaccination, but their immunological and clinical status was normal at the time of immunization. Serum samples from vaccinated complement-sufficient relatives of the LCCD patients and healthy Russian male adults were used as controls. Total and immunoglobulin-specific concentrations of antibodies to group A, C, W135, and Y capsular polysaccharides were determined by enzyme immunoassay in serum samples taken before and 1-108 weeks after immunization. The individual preimmunization and post-immunization antibody concentrations varied greatly. The median antibody concentrations of the LCCD patients increased significantly after vaccination, and were not significantly different from those of the control groups. The antibody concentrations remained elevated for at least 1 year after vaccination. The post-immunization antibody concentrations correlated with the number of meningococcal infections within 10 years before vaccination. In spite of the vaccination two LCCD patients experienced a meningococcal disease 9 and 12 months, respectively, after vaccination.
Adolescent↗
Paradoxical reconstitution of complement activity following plasma transfusion of an individual with deficiency of the seventh component of complement.
A subject deficient in the seventh component of complement (C7) was plasmapheresed with 660 ml C7-sufficient plasma. The expected reconstitution of C7 activity, followed by exponential decay, was not observed. During day 1, serum haemolytic C7 and total haemolytic complement were undetectable and C7 levels were very low by C7 ELISA. However, low levels of circulating fluid phase terminal complement complex (TCC) were detected. On day 2 about microgram C7/ml serum was detected and this rose to 6 micrograms/ml by day 17. Functional complement activity was also present. At day 28 the serum C7 and total haemolytic complement had dropped to pretransfusion levels. A low level of C5b6 was present in pretransfusion serum and this increased markedly immediately following transfusion when the patient's serum also acquired C7 consuming activity. Throughout the study low levels of anti-C7 antibodies were present but there was no evidence that antibody was directly responsible for the C7 consumption. Nevertheless antibody-antigen interactions could have generated circulating C5b6. C5b6 has been shown previously to have the capacity to inhibit C7 activity in vitro. Investigations of the C7 circulating on days 2-17 demonstrated normal molecular weight, functionally active C7. The donor sera and the recirculating C7 allotyped C7-1 by isoelectric focusing; however, the recirculating C7 showed additional weak bands with C7 functional activity, suggesting a possible genetic or acquired abnormality. Although the disappearance of C7 immediately post-transfusion may be explained by the presence of C5b6, there is no satisfactory explanation for the rising C7 levels on days 2-17 and we cannot exclude temporary C7 secretion by the patient.
Adult↗
Meningococcal disease in patients with late complement component deficiency: studies in the U.S.S.R.
The purpose of this study was to examine the occurrence of late complement component deficiency (LCCD) states in the USSR. Thirty deficient individuals were detected: 27 with C8 beta and 3 with C7 deficiency. Among individuals with a first episode of meningococcal infection, about 1% had LCCD, whereas among patients with recurrent bacterial meningitis the prevalence of LCCD rose to approximately 50%. This corresponds to a prevalence for LCCD of approximately 12 per 100,000 in the general population. The individuals with LCCD identified in this study experienced about 77 episodes of meningococcal disease and acute bacterial meningitis. Mathematical analysis of the morbidity from meningococcal disease in individuals with LCCD demonstrated that the probability of disease did not change with the age of the patient and was not affected by prior episodes of infection. This finding suggest that in contrast to the situation in the general population, prior infection fails to protect the deficient individual from recurrent disease. In comparison to complement-sufficient persons, the course of disease in individuals with LCCD is less severe, as shown by a reduction in the number of episodes of endotoxic shock and mortality as well as their more rapid recovery. These findings suggest that exuberant complement activation and concomitant formation of membrane attack complexes during meningococcal infection in complement-sufficient patients plays an important role in the activation and injury of peripheral blood cells and endothelial cells during endotoxic shock.
Adolescent↗
[The bactericidal action of human neutrophils on meningococci in vitro].
32 Russian patients with late complement component deficiency (LCCD) were immunize with tetravalent meningococcal polysaccharide vaccine (A + C + W135 + Y). Their immune response and infectious morbidity rate were followed for 6 years and the partial protective efficacy of vaccination was demonstrated. As the antibody-mediated complement-induced bactericidal activity of plasma was completely absent in persons with LCCD, the bactericidal action of human neutrophils on meningococci of groups A, W135 and B was studied under the conditions of incubation with serum samples collected from persons with LCCD before and after vaccination. In LCCD serum alone the exponential growth of meningococci was observed, while the addition of human neutrophils resulted in the essential inhibition of the growth of meningococci (up to their complete elimination). The proportion of serum samples stimulating the elimination of group A and W 135 meningococci by neutrophils was almost 40% of the serum samples collected before vaccination and significantly increased among the serum samples collected after vaccination (up to 84%) or revaccination (up to 90%). At the same time the capacity of an individual serum sample to promote the bactericidal effect of neutrophils against meningococci correlated with its content of specific anti-polysaccharide IgG and IgM antibodies, as well as antibodies to the inner core of lipopolysaccharide. The interaction of neutrophils with meningococci was significantly inhibited after incubation in heat-inactivated serum, suggesting that this interaction was partly mediated along the following path: the binding of IgM and IgG antibodies with bacteria--the activation of complement and the deposition of C3 complement on bacteria--the binding of meningococci with CR3 receptors of neutrophils.
Bacterial Vaccines↗