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Biomedical subjects

J Forristal

Publications and source records attributed to J Forristal.

At least 37 records · Page 2Linked to original sources
PubMed1983

An inherited defect in the C3 convertase, C3b,Bb, associated with glomerulonephritis.

The control of the amplification C3 convertase, C3b,Bb, of the serum complement system has been found to be defective in five members of a family spanning three generations. One of the five has membranoproliferative glomerulonephritis (MPGN) type III and another has mild idiopathic rapidly progressive glomerulonephritis. The defect is manifested by low serum concentrations of C3 and usually factor B with normal levels of the proteins which control the convertase, H and I. C3 nephritic factor (C3NeF) was not demonstrable. Enhanced C3 conversion was produced by the incubation of their serum at 37 degrees C for 30 min. This conversion was further accelerated by incubation after increasing the serum magnesium concentration by increments ranging from 0.25 to 1.9 mM. Incremental additions of H to serum depleted of H indicated that the amplification convertase of affected family members required more H for its inhibition than did that of normal subjects. This requirement was reduced by the addition of purified normal C3 but not by the addition of purified C3 of the propositus. It is postulated that affected family members are heterozygous for a gene producing an abnormal C3 which, as a constituent of the amplification convertase, C3b,Bb, confers resistance to H. Investigation of this apparently nephritogenic defect may provide insight into the pathogenesis of these glomerulonephritides.

Adult↗
PubMed1982

Reduced alternative complement pathway control protein levels in anorexia nervosa: response to parenteral alimentation.

Serum levels of 16 proteins, including 11 component and control proteins of the complement system were determined before and after nutritional repletion in five female patients with severe malnutrition secondary to anorexia nervosa. Before parenteral alimentation significantly decreased serum levels were found for IgG, IgM, transferrin, Clq, C2, C3, factor B, beta lH, C3b inactivator, properdin, and C4 binding protein. A significant increase in posttreatment serum levels compared with pretreatment levels were found for transferrin, C3, factor B, beta lH, and C3b inactivator. Of the proteins measured, the C3b amplification loop control and component proteins, beta lH, C3b inactivator, C3, and factor B rose to the normal range in response to therapy most rapidly. In the absence of an acute phase reaction, these proteins appear to be particularly good indices of malnutrition and its response to therapy.

Adolescent↗
PubMed1981

Hypocomplementemia in Reye syndrome: relationship to disease stage, circulating immune complexes, and C3b amplification loop protein synthesis.

Measurement of C1q, C2, C4, C5, C6, factor B, properdin, beta1H, and C3bINA were made in acute sera from 31 patients with Reye syndrome. Abnormalities were found in 18 patients. The magnitude of the complement component depression correlated with disease severity. Sera from patients with stage IV illness had significantly lower complement levels than did sera from patients with state I (P less than 0.001), II (P less than 0.05), and III (P less than 0.05) disease. Circulating immune complex measurements were performed on all 31 acute sera and were present in six (19%). However, from the results of the present study, it would appear that in the majority of the patients circulating immune complexes are not the cause of the lowered levels of, at least, C3 and factor B. Rather, these low levels could be explained as secondary to reductions in the levels of the C3b amplification loop control proteins beta1H and C3bINA.

Antigen-Antibody Complex↗
PubMed1981

A serum C3-activating factor: its characterization and its presence in glomerular deposits.

A non-IgG C3 activating factor (C3AF) isolated from the serum and plasma of a patient with membranoproliferative glomerulonephritis with subendothelial and subepithelial deposits (type III) was studied to define its molecular structure, functional characteristics, and presence in renal biopsies. Alternative complement pathway (ACP) activation of C3 was comparable to that of zymosan, but significantly less than that of IgG C3 nephritic factor (C3NeF). Functionally active isolate contained beta 1H globulin (beta 1H) and the C3AF protein, which had a gamma-electrophoretic migration. beta 1H present in the isolate exhibited an altered gamma-beta electrophoretic mobility. The function of this complex is heat labile. Time/temperature studies demonstrated that inactivated preparations of this isolate show a return to the normal beta migration of beta 1H followed by the development of an alpha 2 electrophoretic migration of the previously gamma-migrating material of functionally active isolate. Normal human serums contain an alpha 2 protein that shows complete antigenic identity with the gamma protein of C3AF, but this alpha 2 protein lacks C3 activating function. On polyacrylamide gel electrophoresis, the C3AF isolate contains a high m.w. protein of 500,000 to 590,000 that is composed of 2 major subunits. Carbohydrate is not demonstrable, and the protein is antigenically distinct from plasma fibronectin. Immunofluorescence studies of renal biopsies of patients with types I and III MPGN revealed the presence of C3AF antigen in granular deposits in 10 of 16 cases. The presence of this antigen in glomerular deposits was associated with C3 and beta 1H, but was independent of Ig. These studies suggest that the mechanism of ACP activation by C3AF results from interference with beta 1H function. The presence of this material in renal biopsies from some MPGN patients further suggests a pathogenetic role in mediating glomerular pathology.

Chemical Precipitation↗
PubMed1980

Control of serum C3 levels by beta 1H and C3b inactivator.

In serum specimens from 50 normal adults, a high correlation was found between the sum of the levels of the control proteins of the C3b amplification loop, C3b inactivator and beta 1H, and the sum of the component proteins, C3 and factor B (R = 0.83), when the concentrations are expressed as percent of the normal adult level. The slope for this regression was 0.98 and the y intercept practically zero, indicating that under normal conditions, beta 1H + C3b inactivator = C3 + factor B +/- 35% (95% error of the prediction). Biological significance of the combined values was suggested by the fact that their equality was largely preserved in serum specimens from cord blood, from infants, and from patients with idiopathic nephrotic syndrome, malnutrition, chronic illness, and partial C3b inactivator deficiency even though, individually, control and component protein concentrations deviated from normal in many of these conditions and, as single proteins, did not correlate with each other as in normal subjects. On the other hand, C3 + factor B was disproportionately lower than beta 1H + C3b inactivator in subjects heterozygously deficient in C3 and in those with hypocomplementemic glomerulonephritis and was often disproportionately high in those with an acute-phase reaction. The data indicate that for meaningful interpretation of the serum C3 level, the concurrent levels of factor B, C3b inactivator, and beta 1H must be taken into consideration.

Adolescent↗
PubMed1980

Partial properdin deficiency.

The action of properdin in supporting complement consumption has been investigated in the serum from two individuals with partial properdin deficiency. Our studies are in agreement with those in which serum were artificially depleted of properdin in showing that serum deficient in properdin results in less C3 consumption in the presence of activators of both the alternative and classical complement pathways. Properdin deficiency did not lessen C3 consumption by C3NeF or CoF, confirming that properdin is not necessary for the action of these substances. Our findings indicate that partial properdin deficiency is innocuous but that complete absence of properdin may severely limit one's ability amplify complement activation.

Animals↗
PubMed1979

Idiopathic rapidly progressive glomerulonephritis with C3 nephritic factor and hypocomplementemia.

A 7-year-old boy with mild renal failure and signs and symptoms of acute poststreptococcal glomerulonephritis including severe hypocomplementemia had, by renal biopsy, numerous crescents but no deposits in the glomerular capillary loops. Instead, deposits identical in location and composition to those described for children with idiopathic rapidly progressive glomerulonephritis were present. The severe hypocomplementemia was found to be due to high levels of C3 nephritic factor; niether nephritic factor nor hypocomplementemia has been reported in rapidly progressive glomerulonephritis of the idiopathic type. Following prompt therapy with methylprednisolone intravenously, serologic abnormalities disappeared and renal function greatly improved, but a later biopsy showed 50% of the glomeruli obliterated by scarring. The case is of importance not only in indicating that severe hypocomplementemia does not rule out idiopathic rapidly progressive glomerulonephritis but also in adding to the list of diseases in which nephritic factor can be found.

Antigen-Antibody Complex↗
PubMed1979

Glomerular deposition of complement-control proteins in acute and chronic glomerulonephritis.

Acute poststreptococcal glomerulonephritis (AGN) differed from membranoproliferative glomerulonephritis (MPGN) and lupus nephritis (SLE) in that two of the proteins that control the C3b-dependent convertase, beta 1H and the C3bC4b-inactivator cofactor (C3bC4bICo), were frequently absent from the glomerular deposits. In addition, factor B was distributed with C3 in the capillary walls in hypocomplementemic AGN patients. From this, it can be assumed that C3bBb is in the deposits, uninhibited by control proteins as would be predicted for alternative pathway activation. Factor B could not be found in normocomplementemic AGN, was rarely present in MPGN, but was usually present in SLE, most often in the mesangium. In MPGN and SLE, the control proteins were nearly always present in the glomeruli in a distribution like that of C3; IN MPGN they were particularly abundant. Complement profiles indicated an occasional transient reduction in serum C4 level early in AGN. Thus, although there is occasional evidence of early classical activation in AGN, more characteristic is a long period of alternative activation. Serum levels of control proteins did not deviate greatly from normal except for reduced serum beta 1H levels in MPGN type I.

Biopsy, Needle↗
PubMed1979

Serum complement levels in infancy: age related changes.

Levels of eight complement components and two control proteins, were determined on cord serum from normal full term neonates and serum from healthy infants aged 1 and 6 months. For all proteins, the levels were below the adult normal at birth and rose toward the adult range by age 6 months. In a second group of 271 patients, ages 1-36 months, serum Clq and properdin levels were measured. For both proteins, the mean values in early infancy were more than two SD below the adult range and did not reach the adult range until 18-21 months of age. The Clq concentration was more variable than that for any other component studied. In infants from 11 months-3 yr of age, Clq levels correlated with serum IgG levels, but properdin levels did not.

Adult↗
PubMed1978

Remissions induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentrations of C1-inhibitor and the forth and second components of complement.

Serum concentrations of antigenic and functional C1-INH increased in patients in whom remissions from attacks of HANE were induced with danazol. The levels of C4 were directly related to serum concentrations of C1-INH antigens up to a concentration of about half the C1-INH found in normal plasma; at this point, the C4 concentrations were in the normal range and no longer correlated well with C1-INH concentration. Serum C2 levels correlated less well with C1-INH concentration. In normal serum there was a poor correlation between C1-INH, C4, and C2 levels, suggesting that C1-INH is normally present in excess of the amount needed for normal C4 levels. The increments in serum C1-INH were related to the dose of danazol.

Angioedema↗
PubMed1977

Alternative pathway of complement in sickle cell disease.

Thirty-one patients, 10 months to 20 years of age, were studied. A complement abnormality was not identified in sera from patients with sickle cell disease (SCD) by the methods employed in the present study. Concentrations of C3, factor B, total hemolytic activity (CH50), properdin, and C3b inactivator were similar in sera from patients and control subjects (Table 1 and Fig. 2). Although concentrations of C3b inactivator protein were below normal in a few patients, there was no evidence that these levels were low enough to alter the functions mediated by this protein. Initiation of the complement sequence via the alternative pathway by reaction with inulin was equal in patient and control sera when assessed by the activation of factor B, cleavage of C3 and the comsumption of hemolytic complement components (Table 1). Lysis of erythrocytes treated with reduced glutathione was similar in patient and control sera during alternative pathway activation (Fig. 3), indicating comparable formation of lytic complexes via this pathway. An abnormality of the alternative pathway was not detected when the serum from patients with sickle cell disease was reacted with inulin. Thus, this polysaccharide, although commonly empolyed to assess alternative pathway function, is not satisfactory for studying serum from these patients. In addition, activation of the alternative pathway by cobra venom factor was comparable with controls when assessed by the lysis of glutathione-treated erythrocytes.

Adolescent↗
PubMed1977

Correlations between serum factor B and C3b inactivator levels in normal subjects and in patients with infections, nephrosis and hypocomplementaemic glomerulonephritis.

In normal subjects, factor B and C3b inactivator (KAF) levels were linearly related (r = 0-71); factor B levels in subjects with low normal levels of KAF were significantly lower than in those with high normal levels of KAF. This relationship is postulated to be the result of modulation by the level of KAF of the availability of nascent, spontaneously formed, C3b, in turn responsible for a constant low-grade activation of the C3b feedback which determines in part the level of factor B. The correlation did not obtain in patients with infections; levels of KAF and, to a greater extent, factor B were elevated. In patients with glomerulonephritis and hypocomplementaemic because of in vivo classical pathway activation, KAF and factor B levels were also poorly correlated, presumably because many factors were influencing the levels of these proteins transcending the modulating effect of the concentration of KAF. On the other hand, in patients with nephrosis and with MPGN Type II, KAF and factor B levels were low but were directly correlated. In nephrosis the correlation may be the combined result of an equal rate of catabolism of these proteins and of modulation of factor B levels by the level of KAF as in normal subjects. In MPGN Type II, the correlation may reflect the fact, noted in in vitro studies, that with alternative pathway activation, the level of KAF influences the extent of factor B and C3 conversion to a greater extent than when complement is activated by the classical pathway.

Analysis of Variance↗
PubMed1974

A serum factor in chronic hypocomplementemic hephritis distinct from immunoglobulins and activating the alternate pathway of complement.

Nephritic factor (C3NeF) has been isolated from plasma of patients with hypocomplementemic chronic glomerulonephritis (HCG) by ion exchange and molecular sieve chromatography. This material was further treated with solidified anti-Ig antiserum. The purified material failed to react with antiserum to human IgG, IgG3, Fab, Fc, and kappa and lambda chains, but retained full C3NeF activity. The nonidentity of C3NeF with IgG was further demonstrated by Ouchterlony analysis using anti-IgG and anti-C3NeF. Isolated C3NeF was found to be a protein with a sedimentation coefficient of 7S and a mol wt of 150,000 daltons, which on microzone electrophoresis and gel electrophoresis at pH 8.6 behaved as a gamma-globulin. C3NeF is not a C1q precipitin and does not activate the classical complement pathway. Unlike cobra venom factor, it failed to enter into a complex with C3 proactivator (C3PA) when incubated with normal human serum (NHS) and then subjected to sucrose density gradient ultracentrifugation. The action of isolated C3NeF on C3 requires C3PA, C3PA convertase (C3PAse), and properdin (P). Similarly, C3PA conversion by C3NeF requires P, C3PAse, and C3. Total hemolytic activity was lost by incubation of 64 microg of C3NeF/1 ml NHS at 37 degrees C for 30 min. Both C3a and C5a anaphylatoxin could be generated by C3NeF in serum previously depleted of anaphylatoxin inactivator. Anti-C3NeF was found to detect an antigen in all NHS tested. Treatment of NHS with solidified anti-C3NeF caused impairment of the alternate complement pathway. It failed to sustain lysis of glutathione-treated human erythrocytes initiated by inulin. It is conceivable that the normal serum constituent which is removed by anti-C3NeF constitutes the inactive precursor of C3NeF, and a heretofore unrecognized component of the alternate pathway.

Adsorption↗
PubMed1973

Hypocomplementemia of membranoproliferative nephritis. Dependence of the nephritic factor reaction on properdin factor B.

Membranoproliferative nephritis in children is frequently associated with a hypocomplementemia produced at least in part by C3 breakdown mediated by a circulating anticomplementary factor known as C3 nephritic factor (C3NeF). C3 breakdown by this factor in vitro requires the presence of a pseudoglobulin cofactor and magnesium. The present study provides evidence that properdin factor B (C3 proactivator) is activated in the nephritic factor reaction and is the direct mediator of C3 breakdown by C3NeF. Depletion of factor B from mixtures of normal human serum (NHS) and plasma from a patient with membranoproliferative nephritis (MPP), either by heating or by immune equivalence absorption, blocks C3 breakdown by C3NeF. Addition of purified factor B to these mixtures restores the anticomplementary effect. When purified factor B is added to mixtures of MPP and purified C3, breakdown also occurs. Associated with the C3 breakdown is a change in the electrophoretic mobility of factor B from the beta to the gamma position, a shift which has been associated with cleavage activation of the molecule. Further, serum factor B levels are often low in patients with membranoproliferative nephritis and bear a rough inverse correlation with C3NeF levels. It thus appears that factor B is the previously described heat-labile C3NeF cofactor. Whether the C3NeF reaction proceeds via a pathway comparable to that activated by the cobra venom factor or via that activated by zymosan or inulin cannot be determined from the present data.

Absorption↗
PubMed1971

Continuing C3 breakdown after bilateral nephrectomy in patients with membrano-proliferative glomerulonephritis.

Serum levels of complement components and of C3 nephritic factor (C3NeF) were measured serially in two patients with membrano-proliferative glomerulonephritis who were subjected to bilateral nephrectomy and maintained by peritoneal dialysis for 2 wk before renal transplantation. In both patients, low levels of C3 and high levels of preformed alpha 2D, a C3 breakdown product, were present before nephrectomy and remained essentially unchanged during the anephric period. With transplantation, C3 levels rose towards normal and alpha 2D disappeared from the serum. The serum of both patients contained detectable amounts of C3NeF, a factor which has been shown to react with a cofactor found in normal serum to form an enzyme, designated C3 lytic nephritic factor (C3LyNeF), which will cleave C3 to form the breakdown products, beta1A and alpha 2D. The level of C3NeF was high in one patient before nephrectomy, increased somewhat during the anephric period, and fell after transplantation. In the other patient, the C3NeF level was initially lower, remained relatively constant during the anephric period, and was not significantly affected by transplantation. In both patients, levels of C4 and C5 were either normal or elevated over the period of the study and bore no relationship to the C3 level. The following conclusions can be drawn from the data. The high levels of alpha 2D during the anephric period and the disappearance of this protein as C3 levels approach normal at the time of transplantation indicate that the low C3 levels were largely the result of C3 breakdown rather than diminished synthesis. The presence of C3NeF in detectable amounts in both patients suggest that C3LyNeF, formed by the reaction of C3NeF and cofactor, was responsible for the low C3 levels. Finally, the lack of effect of nephrectomy on C3, alpha 2D, and C3NeF levels indicate that the site of C3 breakdown was extrarenal and that C3NeF and cofactor are at least in large part of extrarenal origin.

Adolescent↗
PubMed1970

Characteristics of a non-complement-dependent C3-reactive complex formed form factors in nephritic and normal serum.

When serum from a patient with membrano-proliferative glomerulonephritis and normal serum are mixed at 37 degrees C, C3 is rapidly broken down to two more rapidly migrating components. In the mixture, a heat-labile pseudoglobulin, designated as the C3 nephritic factor or C3NeF, reacts with a pseudogolbulin in the normal serum, designated as cofactor, to form a C3 inactivator. By analogy with the cobra venom factor, the C3 inactivator is most likely a complex of the nephritic factor and cofactor. The complex has been designated as the C3 lytic nephritic factor or C3LyNeF. The reaction which results in the Formation of C3LyNeF requires the presence of Mg(++), is highly temperature sensitive but occurs very rapidly at 37 degrees C. In 20 min at 37 degrees C, C3LyNeF can break down over 80% of the C3 in a mixture of normal and nephritic serum. The two-step reaction which leads to C3 breakdown has an optimum pH ranging from 6.0 to 9.0. Experiments employing serum depleted of C4 and C2, as well as certain characteristics of the C3NeF system provide evidence that C3 breakdown with nephritic serum is not dependent on complement-inactivating immune complexes or on the action of convertase (C4, 2). Data relating rate of C3 breakdown to the concentrations of C3NeF, C3, and C3LyNeF in the reaction mixture are similar to those for the reaction of enzyme with substrate. The biological significance of C3LyNeF in the production of glomerular inflammation has not been established.

Antigen-Antibody Reactions↗