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PubMed1978

Metabolism of factor B of serum complement in rheumatoid arthritis.

An increased rate of catabolism of radio-iodinated Factor B has been shown in five out of ten patients with rheumatoid arthritis. Serum levels of Factor B were normal, the increased catabolism being matched by increased synthesis. The patients showing high catabolic rates had more manifestations of extra articular disease than did those with normal catabolic rates and they had higher rheumatoid factor titres. In seven patients, the catabolic rate for Factor B correlated significantly with the rate of IgG catabolism. In this series, the Raji-cell assay for immune complex-like material was in the normal or near normal range in all but one patient.

Adult↗
PubMed1978

Change of electrophoretic mobility of purified alternative pathway factor D.

The electrophoretic mobility of factor D (D) of the alternative pathway of human complement activation was examined by the method of lysoelectrophoresis. Purified D was found to have beta-mobility, while D in fresh serum showed alpha-mobility. Addition of D-depleted serum to D induced a change of electrophoretic mobility from beta to alpha. Addition of guinea pig serum to D did not produce this change. The change of electrophoretic mobility of D was not due to complex formation between D and other known alternative factors, P, C3NeF, B and C3. The Factor(s), which mediated the change in the electrophoretic mobility of D, had pseudoglobulin properties and was distributed around the third peak on Sephadex G-200 gel filtration of human serum with a mol. wt. of 50,000-80,000. This phenomenon might be restricted to a semi-solid state reaction, because complexes containing D were not observed upon analyses by sucrose density gradient ultracentrifugation and isoelectrofocusing.

Animals↗
PubMed1992

Eosinophil granule cationic proteins regulate complement. I. Activity on the alternative pathway.

Eosinophil granules contain several cationic proteins that mediate tissue damage in allergic disease. The present study examined the capacity and mechanisms by which these cationic proteins regulate activity of the alternative pathway of C. Eosinophil peroxidase and eosinophil cationic protein inhibited formation of cell-bound alternative pathway C3 convertase, causing 50% inhibition of lysis at about 0.19 and 0.75 microgram/10(7) cellular intermediates, respectively. Major basic protein inhibited alternative pathway C3 activity by only 19% at 1.5 micrograms/10(7) cellular intermediates. Eosinophil-derived neurotoxin had no activity on the alternative pathway. The eosinophil granule proteins were examined for the mechanism by which they inhibited alternative pathway activity. Eosinophil peroxidase and major basic protein inhibited fluid phase factor B consumption in a reaction mixture that also contained factors D and C3b, eosinophil-derived neurotoxin had no activity on factor B consumption, and eosinophil cationic protein consumed factor B in the absence of C3b and factor D. Both eosinophil cationic protein and eosinophil peroxidase enhanced the decay of preformed alternative pathway convertase. Lysis of EAC4b,3b cellular intermediates formed to contain a low surface amount of C3b was more inhibited than was lysis of cells formed with a standard amount of C3b on the surface. This suggests that these eosinophil proteins acted predominantly on C3b to regulate alternative pathway activity. We also found that none of the eosinophil granule cationic proteins had any effect on later events after the formation of the C3 convertase. We conclude that although eosinophil-derived neurotoxin (isoelectric pH value (pI) = 8.9) does not regulate alternative pathway activity, the more highly charged eosinophil granule cationic proteins--major basic protein (pI = 10.9), eosinophil cationic protein (pI = 10.8), and eosinophil peroxidase (pI = 10.8)--do share the capacity to regulate C activity and may exert this activity in vivo.

Blood Proteins↗
PubMed1979

Relationships between the haemolytic activities of the human complement system and complement components.

The relationships between the haemolytic activities of complement and its components were studied. The activities studied included CH50 (classical pathway), AP50 (alternative pathway), CV50 (early part of alternative pathway) and C(3--9)H50 ((the late part of both pathways). The components included C3, C4, C5, C9, B and D. There was a good correlation between CH50 and AP50. AP50 had a good correlation with B and CV50. There was no correlation between AP50 and C(3--9)H50, and none between C(3--9)H50 and C5 or C9. AP50 may primarily represent changes in the early part of the alternative pathway. C(3--9)H50 is not influenced by respective changes in the amounts of C5 or C9. Since cell lesion is now considered to be caused by a unit of C5b to C9, a change in each component of C5 to C9 may not influence haemolytic activity.

Adult↗
PubMed1991

Plasma levels of proteins of the alternative complement pathway in inbred mice that differ in resistance to Trypanosoma congolense infections.

Inbred BALB/c, A/J, and C57B1/6J mice were infected with Trypanosoma congolense (Trans Mara strain), clone TC13, and monitored for parasitemia, survival times, and plasma levels of complement components C3, C5, factor B, and factor H. Parasitemia was highest in BALB/c, intermediate in A/J, and lowest in C57Bl/6J mice. The mean survival times were 11.5 +/- 0.9, 23.8 +/- 2.3, and 119 +/- 26 days for BALB/c, A/J, and C57Bl/6J mice, respectively. Preinfection levels of factor H were significantly correlated with survival times (r = 0.7722, P less than 0.001). Marked differences were observed between the plasma levels of C3, factor B, and factor H in the 3 mouse strains following infection. Complement C5 levels showed the fewest changes. In the initial postinfection period, BALB/c mice had highest increases in the levels of the 4 complement proteins but also had the greatest declines toward the end of the infection. Factor H levels showed a biphasic increase in BALB/c and C57Bl/6J, but not in A/J mice, with peaks at days 3 and 9. Complement C3 levels declined in all mice toward the terminal stage of the disease. In the late stages of infection, factor B levels markedly decreased in BALB/c but significantly increased in C57Bl/6J mice. Factor B levels measured at the terminal stages in BALB/c, A/J, and C57Bl/6J were correlated positively with their respective survival times (r = 0.714, P less than 0.01). The results suggest that genetic differences in the alternative complement pathway might affect the resistance to T. congolense infections.

Animals↗
PubMed1992

Activation of the alternative complement pathway accompanies disease flares in systemic lupus erythematosus during pregnancy.

OBJECTIVE: To assess the activity of systemic lupus erythematosus (SLE) during pregnancy and to distinguish it from preeclampsia. METHODS: We prospectively measured the complement activation products Ba, Bb, SC5b-9, and C4d, as well as the conventional complement determinants C3, C4, and CH50, during pregnancy in 14 patients with SLE and 10 women with preeclampsia. RESULTS: Four of the 14 SLE patients were considered to have disease flares, 3 occurring in the second trimester and 1 postpartum. In these patients, significant abnormalities of Ba, Bb, SC5b-9, and CH50 were noted. In contrast, measures of C4d did not distinguish between pregnant patients who had flares and those whose SLE remained stable. Although decreased values of C3 were rarely seen in the patients with stable disease, normal values of C3 during lupus pregnancy were not reliably associated with stable disease. Three of 10 non-SLE patients with preeclampsia had elevated levels of Ba; however, in each case, the CH50 level was close to or within the normal range. This was in sharp contrast to the findings observed in the 4 patients with active SLE, in whom high levels of plasma Ba were always associated with low CH50 values. Moreover, the ratio of CH50 to Ba was significantly lower in the patients with lupus flares than in the non-SLE patients with preeclampsia. CONCLUSION: While a decline in the CH50 level alone could otherwise be attributed to decreased synthesis of complement components, these data demonstrate that ongoing activation of the alternative complement pathway can accompany disease flares in pregnant women with SLE.

Complement Activation↗
PubMed1992

Production and interferon-gamma-mediated regulation of complement component C2 and factors B and D by the astroglioma cell line U105-MG.

In this paper, we demonstrate the synthesis of the complement component C2 and factors B and D by the human astroglioma cell line U105-MG. All three components were structurally and antigenically similar to their serum counterparts, as determined by biosynthetic labelling studies or Western blot analysis. Northern blot analysis demonstrated that the mRNAs of all three components had the same apparent sizes as the equivalent mRNAs from hepatocyte and monocyte cell lines. Interestingly, U105-MG cells produce two C2 transcripts with sizes of approximately 2.8 and 2.3 kb. Interferon-gamma (IFN-gamma) enhanced the expression of C2 and factor B mRNA and protein in a dose- and time-dependent fashion, while factor D expression was refractory to IFN-gamma. IFN-gamma appeared to predominantly enhance the expression of the large (2.8 kb) C2 transcript. Kinetic studies demonstrated peak C2 and factor B expression in 48 h in response to IFN-gamma, similar to the acute-phase response of factor B in serum. These data are the first to demonstrate the synthesis of C2 and factor D by astroglioma cells. Combined with previous reports documenting the synthesis of C3 by astrocytes, our data suggest that endogenous synthesis of complement proteins, and particularly of alternative pathway activation components (C3, factors B and D), may play an important role in host defence in the central nervous system.

Astrocytoma↗
PubMed1979

Limited proteolysis of complement components C2 and factor B. Structural analogy and limited sequence homology.

A method is described for the simultaneous purification of milligram quantities of complement components C2 and Factor B. Both products are homogeneous by the criteria of polyacrylamide-gel electrophoresis and N-terminal sequence analysis. Component C2 is cleaved by serine proteinase C1s at an X-Lys bond to give fragment C2a (approx. mol.wt. 74000) and fragment C2b (approx. mol.wt. 34000). The two fragments can be separated by gel filtration without the need for reducing or denaturing agents. Fragment C2b represents the N-terminal end of the molecule. Similar results were seen on cleavage of Factor B by Factor D in the presence of component C3. Again two non-covalently linked fragments are formed. The smaller, fragment Ba (approx. mol.wt. 36,000),) has threonine as the N-terminal residue, as does Factor B; the larger, fragment Bb (approx. mol. wt. 58000), has lysine as the N-terminal residue. A similar cleavage pattern is obtained on limited proteolysis of Factor B by trypsin, suggesting an Arg-Lys-or Lys-Lys bond at the point of cleavage. Although component C2 and Factor B show no apparent N-terminal sequence homology, a limited degree of sequence homology is seen around the sites of proteolytic cleavage.

Amino Acid Sequence↗
PubMed1992

Assessment of disease activity and impending flare in patients with systemic lupus erythematosus. Comparison of the use of complement split products and conventional measurements of complement.

OBJECTIVE: To determine whether increased levels of the complement split products generated in the activation of the alternative or classical pathway accompany more severe disease activity in patients with systemic lupus erythematosus (SLE) and whether these measurements are useful in predicting flares of disease. METHODS: Levels of Ba, Bb, SC5b-9, and C4d were measured in 380 plasma samples obtained from 86 SLE patients who were prospectively followed up for 15 months. RESULTS: In the 20 patients who had inactive disease at the initiation of the study, the mean values of all of the complement split products at entry were within the normal range. In the 47 patients with stable or moderate disease activity, levels of Ba were significantly increased, while the mean values for Bb, SC5b-9, and C4d did not differ significantly from those in patients with inactive disease. The mean entry value of each analyte was highest in the group of 19 patients who had the most severe disease activity at initial evaluation. Traditional measurements of complement, i.e., C3, C4, and CH50, followed similar trends, but did not discriminate between the 3 groups of patients as well as did measurements of the split products. Analysis of the disease course in the patients with inactive or stable/moderate disease revealed that an elevated level of C4d had the most sensitivity with regard to subsequent flare, while an elevated Bb level had the highest specificity and the greatest predictive value. CONCLUSION: These data suggest that elevated levels of complement split products, particularly products of alternative and terminal pathway activation, more accurately reflect disease activity than do conventional measurements of complement in SLE and may be useful in the prediction of impending disease flares.

Complement C3 Convertase, Alternative Pathway↗
PubMed1991

In vitro formation of complement activation products by lipopolysaccharide chemotypes of Salmonella minnesota.

We have applied immunoassays for complement activation products C4d, fragment Bb and the protein S-C5b-9 neoantigen (S-MAC) to assess activation of classical, alternative and terminal pathways, respectively, by lipopolysaccharides (LPS) from the smooth strain (SS) of Salmonella minnesota and the shallow rough (core) mutants R60, R345, R5 and R7. Incubations of sera (n = 6) with LPS generated small and insignificant quantities of Bb and S-MAC in the case of Rb, Rc and Rd chemotypes and slightly greater quantities with Ra. SS-LPS brought about significant (p = 0.01) increases in the formation of both Bb and S-MAC. No significant changes were observed in the concentration of C4d. Polymyxin B enhanced Bb and S-MAC production by SS-LPS, optimally at the lowest concentration of polymyxin B studied, 10 ng/ml. These data confirm and extend observations about complement activation by LPS and suggest that immunoassay may be useful in studying mechanisms of complement activation.

Adult↗
PubMed1979

Relative importance of C3b inactivator and beta 1H globulin in the modulation of the properdin amplification loop in systemic lupus erythematosus.

Serum concentrations of C4, C3, factor B (B), properdin (P), C3b inactivator (C3bINA) and beta 1H globulin have been measured by radial immunodiffusion in sixty-two samples from thirteen patients with systemic lupus erythematosus (SLE). Significant reductions in the mean serum concentrations of C4 (classical pathway) B and P (alternative pathway) and C3 were found. In addition, the mean level of the control protein beta 1H, but not C3bINA, was reduced. Sera from thirteen patients taking during disease exacerbation (low C3) showed significantly lower levels of both C3bINA and beta 1H than sera taken from the same thirteen patients during disease remission (high C3). Serum concentrations of C3bINA correlated with B (P less than 0.005) but not C4, C3 or P, whereas levels of beta 1H correlated with C4 (P less than 0.01), B (P less than 0.005) and properdin (P less than 0.01). Serial measurements of the serum concentrations of C3bINA and beta 1H showed that levels of these protein fell during exacerbation, and such falls were more closely associated with diseases in the serum levels of the alternative pathways proteins than C4. It is concluded from these observations that serum concentrations of the control proteins C3bINA and beta 1H, especially the latter, control the extent of turnover of the alternative pathway in SLE. Metabolic studies are required to determine the causes of the decreased serum concentrations of these control proteins.

Complement Activation↗
PubMed1979

Membrane-bound antibodies to bloodstream Trypanosoma cruzi in mice: strain differences in susceptibility to complement-mediated lysis.

The Y, CL and other strains of Trypanosoma cruzi display different morphological and immunological characteristics. Such observations are here extended to the interaction of bloodstream forms of different strains of T. cruzi with components of the complement system. We demonstrate that the bloodstream forms of the Y and B strains, but not those of the CL strain, are lysed by normal human serum. Lysis is mediated by combined activities of the alternative and classical complement pathways. These activities are triggered by antibodies on the surface of the parasites as shown by: (a) binding of fluorescein or radiolabelled anti-mouse immunoglobulin to the parasite's membrane and (b) the finding that bloodstream forms from lethally irradiated mice can be sensitized and rendered susceptible to complement-mediated lysis by incubation with sera from acutely infected animals. Bloodstream forms of the CL strain also bear surface immunoglobulin and sensitizing antibodies are present in the sera of mice infected with this strain. However, CL trypomastigotes from acutely infected mice fail to be lysed by human or mouse complement unless the parasites are pre-incubated with sera from chronically infected animals. The basis of the different interactions between CL and Y trypomastigotes with antibodies and the complement system, and their biological significance are discussed.

Animals↗
PubMed1979

Complement activation in asymptomatic patients with sickle cell anaemia.

Previous reports have suggested that a defect in serum complement may contribute to the increased susceptibility to infection shown by patients with sickle cell anaemia (SCA). In order to define the nature of any complement abnormality in SCA, we investigated the complement system in eighty-seven patients during asymptomatic periods, and analysed factor B turnover in a small sample. In these patients geometric mean serum concentrations of functionally active factor B and factor D, and of C3 and C4 protein (expressed as a percentage of normal reference serum) wer lower than in controls (78% vs 107%, P less than 0.001, 86% vs 103%, P less than 0.001, 91% vs 100%, P less than 0.01, 89% vs 105%, P less than 0.05 respectively). The ratio of the serum concentration of functionally active factor B to factor B protein was lower in patients than in controls (means 75% s.d. 16% vs mean 93%, s.d. 22% P less than 0.001), indicating a functional deficiency of factor B protein. In addition, the fractional catabolic rate of radiolabelled factor B was markedly increased in four out of seven asymptomatic patients studied, and was inversely related to the functional factor B concentration in serum (r = -0.59, P less than 0.05); factor B synthesis was uniformly increased. Complement activation was not related to the presence of circulating C1q binding material. We conclude that complement activation, rather than defective synthesis as previously suggested, contributes to the abnormalities in complement componenet concentration and function in asymptomatic subjects with sickle cell anaemia.

Adolescent↗