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Biomedical subjects

J G Curd

Publications and source records attributed to J G Curd.

At least 37 records · Page 2Linked to original sources
PubMed1986

Activation of complement by pathogenic and nonpathogenic Entamoeba histolytica.

Previous studies had demonstrated that strains of Entamoeba histolytica isolated from patients with colitis or amebic liver abscess were resistant to complement-mediated killing, whereas strains from asymptomatic patients were readily lysed by non-immune serum. Both serum-sensitive and serum-resistant strains of E. histolytica depleted complement rapidly as assessed by CH50, C3, and C7, and C5-9 hemolytic activities. Activation of the alternative pathway was important in lysis of nonpathogenic strains, as demonstrated by lysis by NHS (60.9 +/- 15.6%) and NHS + 5 mM EGTA (59.3 +/- 4.5%) as well as by C4-deficient guinea pig serum (72.8 +/- 7.1%) and C2-deficient human serum (64.4 +/- 11.1%), but not by NHS + 5 mM EDTA. Classical pathway activation also occurs as both pathogenic and nonpathogenic strains deplete greater than 98% of C4 activity, although it is not necessary for lysis. Pathogenic strains are not lysed by either the classical or the alternative pathway. These results suggest that pathogenic strains of E. histolytica activate complement but are able to evade an important host defense, complement-mediated lysis.

Animals↗
PubMed1986

Sjögren's syndrome. Proposed criteria for classification.

The term "Sjögren's syndrome" (SS) is frequently used to describe the occurrence of keratoconjunctivis sicca and xerostomia in association with an autoimmune disorder. However, well-defined criteria for the classification of SS have not been established, and this diagnosis is being applied to a wide spectrum of conditions, ranging from clear "autoimmune" disease in some patients, to sicca complaints without evidence of a systemic immune process in elderly patients. Here, we review the clinical and laboratory features of patients referred for evaluation of sicca symptoms. In particular, we emphasize the need for care in choosing the site for minor salivary gland biopsy, and we describe the histologic features that aid in the evaluation of these biopsy specimens. In an attempt to identify a population of patients whose conditions might have a common etiopathogenesis and, thus, a common treatment program, we propose the following criteria for a diagnosis of SS: 1) objective evidence of keratoconjunctivis sicca, as documented by rose bengal or fluorescein dye staining; 2) objective evidence of diminished salivary gland flow; 3) minor salivary gland biopsy, obtained through normal mucosa, with the specimen containing at least 4 evaluable salivary gland lobules, and having an average of at least 2 foci/4 mm2; 4) evidence of a systemic autoimmune process, as manifested by the presence of autoantibodies, such as rheumatoid factor and/or antinuclear antibody. The diagnosis of "definite SS" would be made when all 4 criteria are met; the diagnosis of "possible SS" would be made when 3 criteria are present. Specific exclusions for this diagnosis are preexisting lymphoma, graft-versus-host disease, sarcoidosis, and acquired immunodeficiency disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1986

Complement-activating abilities of defined antinuclear antibodies.

A complement-fixing immunofluorescence assay on HEp-2 cells was used to assess the ability of various antinuclear antibodies (ANA) to activate complement. Sera which contained only specific antibodies to nuclear RNP, SS-B/La, centromere, Sm antigen, double-stranded DNA, and/or nuclear histone were selected. Relative abilities of various ANA to activate complement were determined from the ratio of titers of C3, C4, or properdin-fixing ANA to the IgG ANA titers. Nuclear RNP-anti-RNP complexes activated and deposited significantly more complement C3 than other ANA (P less than 0.02). Antibodies to SS-B/La, centromere, and Sm activated more complement than anti-DNA or antihistone (P less than 0.02). Antihistone antibodies activated the least complement. These studies demonstrate that different ANA have significantly different orders of complement-activating capabilities when bound to their respective nuclear antigens.

Antibodies, Antinuclear↗
PubMed1986

Decreased synthesis of serum carboxypeptidase N (SCPN) in familial SCPN deficiency.

Serum carboxypeptidase N (SCPN) is the primary inactivator of the C3a, C4a, and C5a anaphylatoxins as well as an inactivator of bradykinin. Thus SCPN deficiency potentially could result in significant pathophysiologic consequences. Previous studies identified a deficient subject afflicted with frequent episodes of angioedema, and other family members also had SCPN deficiency. To delineate this abnormality further, the fractional catabolic rate (FRC) and enzyme synthesis were determined in three members of the afflicted kindred as well as in five normal persons following the infusion of homogeneous 125I-SCPN. The mean FCR and synthesis rates for SCPN in the normal subjects were 1.3%/hr and 20,793 U/kg/hr, respectively. Reduced synthesis was concluded to be primarily responsible for the low SCPN levels in the afflicted kindred. The high FRC of SCPN discourages attempted maintenance therapy with infusions of enriched SCPN preparations.

Carboxypeptidases↗
PubMed1986

Serologic changes during induction of lupus-like disease by procainamide.

Procainamide-induced lupus is a well-recognized syndrome, but the events leading up to clinical symptoms are obscure. In the present study, serologic changes in a 69-year-old man were monitored during his treatment with procainamide and after discontinuation of procainamide because of symptoms of drug-induced lupus. Antihistone antibodies of unique specificity and in vivo complement activation were detected after one year of procainamide therapy during a period prior to development of significant clinical symptoms. Antihistone antibodies and complement activation substantially increased during a full-blown episode of lupus-like symptoms. Progressive return to normal laboratory findings occurred after procainamide was discontinued. The antihistone/complement profile may be useful in the diagnosis of drug-induced lupus and warn of impending clinical deterioration in patients with minimal symptoms.

Aged↗
PubMed1986

The value of rocket immunoelectrophoresis for C4 activation in the evaluation of patients with angioedema or C1-inhibitor deficiency.

The correct diagnosis and characterization of C1-inhibitor deficiency depends on both clinical observations and laboratory evaluation of complement in plasma. Rocket immunoelectrophoresis for C4d is a sensitive assay for C4 activation in plasma. We have evaluated the value of this assay in identifying patients with C1-inhibitor deficiency. C4 activation was assessed in the plasmas of 15 patients with hereditary angioedema, five patients with variant form of hereditary angioedema, and four patients with acquired C1-inhibitor deficiency. Control groups consisted of 27 patients with chronic idiopathic urticaria and/or angioedema and seven normal volunteers. C4 activation was detected in all 52 plasma samples collected from the 24 patients with C1-inhibitor deficiency. The degree of C4 activation increased during attacks of angioedema and decreased (but remained elevated) during treatment with attenuated androgens. The concentrations of C4, C2, and C1 inhibitor were also measured; however, none of these measurements identified all of the patients with C1-inhibitor deficiency. Thus, we conclude that the measurement of C4 activation is one of the best tests available to evaluate a patient for C1-inhibitor deficiency, and a normal result will exclude the diagnosis of C1-inhibitor deficiency.

Androgens↗
PubMed1986

Effects of protamine administration after cardiopulmonary bypass on complement, blood elements, and the hemodynamic state.

Nineteen patients were prospectively selected and studied before and after the administration of protamine sulfate following cardiopulmonary bypass (CPB). After protamine administration, C3a, C4a, and C4d were elevated; the peak levels of C3a and C4a were in samples taken 10 minutes after protamine administration while those of C4d were in those obtained at 5 hours. Only C3a was elevated after CPB and before protamine administration. In vitro, only the combination of protamine sulfate and heparin, and neither alone, resulted in increased C3a and C4a. Administration of protamine was associated with small and transient decreases in total white blood cells, granulocytes, and platelets, and with small and transient reductions in systemic and pulmonary arterial and left and right atrial pressures. Systemic vascular resistance fell (p = 0.07), and pulmonary vascular resistance rose but the change could be due to chance (p = 0.29). These data and those reported by others support the inference that complement activation occurs during CPB by the alternative pathway and again during protamine administration by the classic pathway; and that this accompanies a whole-body inflammatory reaction with blood cell and hemodynamic changes which, when extreme, could result in a severe hemodynamic derangement.

Blood Cell Count↗
PubMed1986

Cloning and sequence determination of a human rheumatoid factor light-chain gene.

The contribution of germ-line variable regions to autoantibody formation in humans is poorly understood. To study the gene structure of a human autoantibody, chronic lymphatic leukemia (CLL) cells from a patient with an IgM anti-IgG (rheumatoid factor, RF) paraprotein were utilized. The rearranged immunoglobulin gene encoding the kappa light chain for the RF was cloned, and the nucleic acid sequence of its variable region was determined. As demonstrated by Southern blot analysis using a kappa joining-region probe, the CLL cells, stable CLL-WIL2-729-HF2 RF-secreting hybridomas, and the cloned light-chain gene all had an identical restriction fragment containing the rearranged light-chain gene. The CLL RF light chains reacted weakly with an antipeptide antibody against a primary structure-dependent idiotype present on the light chains of the majority of IgM RF paraproteins. The nucleotide and predicted amino acid sequences of the CLL light-chain gene place it in the kappa III variable-region subgroup, and a comparison to known RF paraproteins reveals marked homology to the light-chain amino acid sequence of the IgM RF paraprotein Pom. Both Pom and the CLL light chain appear to identify a second kappa III gene or gene group that is able to encode RF paraprotein light chains.

Amino Acid Sequence↗
PubMed1986

Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura.

Many chronic ITP patients have increased amounts of platelet-associated IgG, C3, C4 and C9, suggesting in vivo complement activation. In this study, we assessed the ability of various antiplatelet antibodies (APA) to activate and deposit complement proteins and to cause platelet lysis in vitro. Platelet sensitization with rabbit APA, anti-P1A1 antibody (one patient), anti-HLA antibody (two patients) and ITP autoantibodies (four patients) resulted in the deposition of C4 and C3 onto platelets in an amount proportional to the quantity of antibody-containing sera used to sensitize the platelets. Although C9 deposition onto platelets could not be quantitatively demonstrated on platelets sensitized with ITP serum, platelet lysis (51Cr release) was noted after incubation with each of three ITP sera and complement. When compared, ITP autoantibodies, anti-HLA and anti-P1A1 antibodies activated complement to a similar degree. We conclude that some autoantibodies in chronic ITP activate the classical complement pathway. The demonstration of in vitro platelet lysis by autoantibodies and complement suggests that in vivo platelet lysis may occur in some chronic ITP patients.

Autoantibodies↗
PubMed1986

Association of systemic immune complexes, complement activation, and antibodies to Pseudomonas aeruginosa lipopolysaccharide and exotoxin A with mortality in cystic fibrosis.

The relevance of circulating immune complexes, plasma complement activation, and serum antibodies against discrete antigens of Pseudomonas aeruginosa, to the clinical course in patients with cystic fibrosis (CF) is unknown. We related these factors to outcome in 49 patients with CF colonized by P. aeruginosa, comparing 14 who died of lung disease with 35 survivors of similar age and duration of colonization, as well as 9 uncolonized patients with CF, 24 patients with other bronchorrheic lung disease, and 10 healthy control subjects. The patients with CF colonized by P. aeruginosa who died had a higher incidence of immune complexes than did survivors (71 versus 40%, p less than 0.05). Moreover, C4 activation was highly associated with immune complexes and mortality (p less than 0.001 for each). Those who died also had much higher levels of IgG antibodies to P. aeruginosa lipopolysaccharide (LPS) and exotoxin A than did survivors colonized by P. aeruginosa (p less than 0.005 and p = 0.01, respectively), whereas both groups had similar levels of P. aeruginosa sonicate, elastase, alkaline protease, and endotoxin core antibodies. We conclude that increasing levels of serum IgG antibodies to P. aeruginosa LPS and exotoxin A and the presence of systemic immune complexes and complement activation are associated with poor prognosis in CF, and may provide useful noninvasive markers for studying the possible immunopathogenesis of CF lung disease.

Adolescent↗
PubMed1986

Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients.

The first component of complement (C1) inhibitor plays a critical role in the regulation of the classical complement pathway and the contact system, and the deficiency of C1 inhibitor protein or function is associated with recurrent angioedema. In this study we evaluated the size of the C1 inhibitor antigens present in the plasmas of C1 inhibitor-deficient patients. We found that the C1 inhibitor in the plasmas existed in three forms: high molecular weight forms in complex with proteases, native 110-kD C1 inhibitor, and a modified inactive 94-kD form. The proportion of the total C1 inhibitor in the 94-kD form was 28% in nine hereditary angioedema patients, 92% in five acquired C1 inhibitor-deficiency patients, and 1.2% in five normal controls. In vitro activation of normal plasma with kaolin, but not heat-aggregated gamma-globulin generated 94-kD C1 inhibitor from 110-kD C1 inhibitor. Neither kaolin activation nor heat-aggregated gamma-globulin activation generated 94-kD C1 inhibitor in Hageman factor-deficient plasma. These results suggest that 94-kD C1 inhibitor is generated in vitro by activation of the contact system. The in vivo mechanism of 94-kD C1 inhibitor generation in C1 inhibitor-deficient patients is not known.

Angioedema↗
PubMed1986

Different patterns of C3 and C4 activation in the varied types of juvenile arthritis.

Quantitative assays for C3 and C4 activation were carried out simultaneously on blood from children with varied types of juvenile arthritis. Factor VIII-related antigen was also measured as an indicator of vascular damage. In active systemic juvenile arthritis, the C4d/C4 ratio was frequently elevated and was usually associated with elevated C3d/C3 ratios and elevated concentrations of factor VIII-related antigen. Children with chronic polyarticular arthritis, no matter which forms of onset they had had, also had increased levels of the C4d/C4 ratio, C3d/C3 ratio, and factor VIII-related antigen, but these were less consistent and were not associated with each other. In contrast, in pauciarticular arthritis there was a uniquely isolated increase in the C3d/C3 ratio. This work implies that there are different mechanisms responsible for complement activation in the different types and at different stages of juvenile arthritis.

Adolescent↗
PubMed1986

Meningococcemia and acquired complement deficiency. Association in patients with hepatic failure.

We treated two patients with severe hepatic failure complicated by meningococcemia. Serum complement profiles performed on these patients found low total hemolytic complement assays, normal concentrations of C1q, and low or undetectable concentrations of C3 through C6, C8, C9, and factors B and I. These studies suggest that these patients developed meningococcemia in the setting of acquired complement deficiency from impaired synthesis of multiple complement system proteins.

Acute Disease↗
PubMed1985

The hereditary and acquired deficiencies of complement.

The identification of hereditary and acquired complement deficiencies in humans has led to a better understanding of the biologic importance of the complement system in immunity and autoimmune disease. Although the understanding of the relevance of complement in the pathogenesis of disease is incomplete, several characteristic clinical syndromes associated with complement deficiencies have been recognized and should be known to the practicing clinician. In allergic diseases, one need recognize the C1 inhibitor deficiency syndromes which can present as severe, recurrent angioedema in childhood or in the adult as recurrent angioedema in association with a lymphoid malignancy or autoimmune disease. Complement analyses allow one to readily diagnose C1 inhibitor deficiency in angioedema. Correct diagnosis is critical because safe effective therapy is available. Chronic urticaria is also uncommonly associated with complement deficiencies, particularly acquired C1q deficiency. Again, effective therapy for hypocomplementemic urticarial vasculitis and C1q deficiency is available and differs significantly from the usual management of chronic urticaria. Homozygous and acquired deficiencies of C3 are associated with severe immune deficiency and recurrent infections with gram-positive and gram-negative bacteria. Recurrent meningococcemia and gonococcemia are being identified frequently in patients with a deficient membrane attack mechanism relating to deficiency of C5, C6, C7, or C8. Nearly one third of the patients developing meningococcemia may have an associated complement deficiency indicating the importance of complement determinations in understanding the treatment and prognosis for these patients. Deficiency of almost every complement component has been reported in association with one or more rheumatic diseases, particularly systemic lupus erythematosus. Extensive studies of C2 deficiency and limited studies of C4 deficiency indicate that these components of the classical pathway of complement are important in preventing the development of SLE or are linked to other genes predisposing to SLE. The clinical presentations of SLE in association with C2 or C4 deficiency are relatively uniform. The patients exhibit typical skin manifestations suggestive of SLE and DLE and often exhibit antibodies to SSA (Ro). The association of complement deficiencies with clinical syndromes is important for today's physician. The syndromes and deficiencies described here are the beginning of an expanding knowledge relating to the pathobiology of complement in human disorders.

Angioedema↗
PubMed1985

Platelet-associated complement in chronic ITP.

Chronic ITP is due to antibody-induced destruction of platelets by the reticuloendothelial (RE) system. The role of complement in this process is unclear. We measured platelet-associated complement (PAC) components C3, C3bi, C4 and C9 in 16 patients with chronic ITP, in two of these patients prior to and after splenectomy. Competitive solid-phase radioimmunoassays using monoclonal antibody (anti-C3d, anti-C3bi neoantigen or anti-C9) or affinity-purified heterologous antibody (anti-C4) were used. Mean values (+/- SD) of normal subjects (ng/10(7) plts) were: PAC3d 17.6 +/- 6.8; PAC3bi 11.6 +/- 2.3; PAC4 1.6 +/- 0.5; PAC9 9.9 +/- 2.6. Significantly elevated (greater than 2 SD) PAC3, PAC3bi, PAC4 and PAC9 levels occurred in 12/16, 11/14, 10/14 and 5/9 chronic ITP patients. The PAC3, PAC3bi and PAC9 values correlated inversely with the patients' platelet counts (P less than 0.001); PAC4 levels did not. A positive correlation was also noted between PAC3, PAC3bi and PAC9 while PAC4 values showed no correlation. Two patients with preoperative elevation of all four PAC proteins showed normalization of PAC3, PAC3bi and PAC9 values after a splenectomy-induced remission; PAC4 levels remained elevated for up to 5 months after surgery. We conclude that in vivo C activation occurs in most chronic ITP patients with binding of C3 and C9 to the platelet surface. This in vivo C activation may promote more efficient phagocytosis (C3b) and possibly platelet lysis (C5-9) in some ITP patients.

Adult↗
PubMed1984

Increased von Willebrand factor antigen in the plasma of patients with vasculitis.

The plasma concentrations of von Willebrand factor antigen (vWF:Ag) were determined in 101 patients who had the following diagnoses: vasculitis 8 patients, systemic lupus erythematosus (SLE) 51, rheumatoid arthritis (RA) 28, asthma 7, hereditary angioedema 7. The greatest mean concentration of vWF:Ag, 469% (normal 100% +/- 50), was observed in patients with vasculitis, often without elevation of the erythrocyte sedimentation rate. The mean concentration of vWF:Ag was also increased in both SLE (277%) and RA (194%). Twenty-four patients (15 with SLE, 6 with vasculitis, 3 with RA) had vWF:Ag concentrations greater than 300%. Four of these patients died within 1 year of the date of the study. Of the 15 SLE patients, 9 had vasculitis and 2 had active glomerulonephritis. The 3 RA patients had severe disease associated with extraarticular manifestations. Elevated vWF:Ag may reflect vascular damage, while markedly elevated levels of vWF:Ag appear to indicate a poor prognosis.

Angioedema↗