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PubMed1987

The late onset form of C1 esterase-inhibitor deficiency presenting as food allergy.

Two cases of late onset recurrent angioedema associated with deficiency of C1 esterase inhibitor are described. Both patients had life-threatening episodes of angioedema that they had related to the ingestion of certain foodstuffs. This was not confirmed by food challenges or by food allergy skin testing, although both patients had embarked on strict exclusion diets before the diagnosis of C1 esterase-inhibitor deficiency. Clinicians should be aware of the entity of late onset angioedema caused by C1 esterase deficiency mimicking food allergy and hence delaying the diagnosis of this potentially lethal condition.

Aged↗
PubMed1988

Activation of the contact system of plasma proteolysis in the adult respiratory distress syndrome.

Adult respiratory distress syndrome (ARDS) is a complex pulmonary clinicopathologic condition associated with pulmonary endothelial injury and blood coagulation activation. In patients with ARDS from all causes, factor VII levels were significantly reduced. Patients with ARDS caused by sepsis had more evidence of intravascular coagulation and fibrinolysis than did patients with trauma-related ARDS by having significantly (p less than or equal to 0.05) increased prothrombin times, activated partial thromboplastin times, and fibrin degradation products, and decreased antithrombin III concentration. We sought to determine whether the proteins of the contact system of plasma proteolysis (factor XII, prekallikrein, high molecular weight kininogen, and C1 inhibitor) were also activated after acute lung injury. Patients with ARDS caused by either trauma or sepsis had significantly (p less than or equal to 0.01) reduced factor XII levels, high molecular weight kininogen functional activity, prekallikrein activity, and prekallikrein antigen levels compared with controls. In both the sepsis-related and trauma-related ARDS groups, C1 inhibitor activity was significantly reduced but C1 inhibitor antigen levels were significantly elevated from control. These findings showed that the proteins of the contact system were more extensively activated in ARDS than were the proteins that contribute to later reactions in intravascular coagulation and fibrinolysis. Activation of the contact system proteins could be the result of endothelial injury occurring as part of ARDS. Intravascular coagulation and fibrinolysis in patients with ARDS also arise from components independent from contact system activation.

Blood Coagulation↗
PubMed1998

A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema.

BACKGROUND: No effective treatment exists in the United States for acute attacks of hereditary angioedema (HAE). STUDY DESIGN AND METHODS: To evaluate the efficacy and safety of C1 inhibitor concentrate in treating HAE, a large primary care and referral center hospital conducted a randomized, placebo-controlled, double-blind trial with intent-to-treat analysis. Of the 36 patients enrolled in the study, 23 received treatment, and 22 completed the trial. C1 inhibitor concentrate or albumin (placebo) infusions were administered in a blind fashion to HAE patients who came to the hospital for treatment no later than 5 hours after an attack began. RESULTS: Relief was almost twice as fast in persons receiving C1 inhibitor concentrate than in the controls: 7.62 hours (mean; SD 7.08) versus 15.35 hours (mean; SD 8.31), respectively. The difference for time-to-relief was highly significant (p = 0.007, Mann-Whitney U test). The median time-to-relief was 6.17 hours (interquartile range 0.33-15.35) in the treatment group and 15.35 hours (interquartile range 14.00-22.83) in the control group. Resolution of symptoms was one-third faster in the C1 inhibitor concentrate group than in the placebo group: 23.98 hours (mean; SD 14.81) and 34.58 hours (mean; SD 13.56), respectively (p = 0.09, Mann-Whitney U test). Recovery of functional C1 inhibitor was 119.65 percent (mean; SD 50.80), and half-life was 37.87 hours (mean; SD 19.75). Recovery of antigenic C1 inhibitor was 147.75 percent (mean; SD 97.68), and half-life was 24.01 hours (mean; SD 9.70). There were no viral infections or serious adverse effects from the drug after 70 attacks in the treatment group and 96 attacks in the control group. CONCLUSIONS: C1 inhibitor concentrate is a safe, effective treatment for acute attacks of HAE.

Acute Disease↗
PubMed2002

A multicentre evaluation of the diagnostic efficiency of serological investigations for C1 inhibitor deficiency.

AIM: To determine the diagnostic efficiency of assays routinely used in the investigation of hereditary angio-oedema. METHODS: Over a four year period, 1144 samples were received for analysis from 907 patients suspected of C1 inhibitor deficiency. Analyses were performed for C4 and C1 inhibitor (functional and immunochemical). Notes were reviewed retrospectively on patients with low serological indicators to determine diagnosis. RESULTS: These are the first data to indicate the sensitivity, specificity, and predictive values of the assays most frequently used to screen for C1 inhibitor deficiency. A combination of low C4 and low C1 inhibitor function has 98% specificity for C1 inhibitor deficiency in this population and a 96% negative predictive value, and is thus a very effective screen. All patients with untreated C1 inhibitor deficiency had a low C4 value. CONCLUSIONS: All patients considered for a diagnosis of C1 inhibitor deficiency should have serum examined to measure both C4 and functional C1 inhibitor. If either is normal at presentation this essentially excludes a diagnosis of C1 inhibitor deficiency. These tests can be performed sequentially. If C4 is normal it is not necessary to proceed to C1 inhibitor analysis. If C1 inhibitor function and C4 are both low then a repeat sample should be obtained to confirm the findings.

Angioedema↗
PubMed1990

Acquired C1 inhibitor deficiency: postmortem diagnosis.

Acquired C1 esterase inhibitor deficiency is a clinical syndrome closely resembling hereditary angioedema in which most patients have an associated malignancy of B cell lineage. Sera from 33 patients with B cell neoplasms were assayed for C1 esterase inhibitor level by rocket immunoelectrophoresis. The clinical summary of a patient who met the biochemical criteria for acquired C1 esterase inhibitor deficiency (low C1 esterase inhibitor, low C4) is presented. We hypothesize that this syndrome represents an autoimmune reaction involving tumor cell rejections and of potential benefit to the patient.

Adult↗
PubMed1985

Cold promoted activation and factor XII, prekallikrein and C1-inhibitor.

During incubation of plasma in the cold an amidolytic activity due to the kallikrein-alpha 2-macroglobulin complex appears in the plasma of about 40% of the women under hormonal contraception. The factor XII and prekallikrein activity are significantly increased 151.9% and 112.4% respectively in the cold promoted activation positive plasmas (CPA pos) whereas the activity of C1-inhibitor is decreased, 76%. The quotient of the product of the C1-inhibitor and alpha 2-macroglobulin values divided by the product of the FXII and prekallikrein values is significantly lower in the CPA pos plasma 0.49 than in CPA neg plasma 0.96 (p less than 0.05). These results alone do not explain the cold promoted activation, since a patient with a C1-inhibitor as low as 9% showed no increase of the amidolytic activity after a 24 hr incubation at 4 degrees C. However, the addition of purified C1-inhibitor to a CPA pos. plasma inhibits the cold activation. Heparin at a concentration of 0.5 IU/ml delays the appearance of the amidolytic activity.

Adolescent↗
PubMed1988

Genomic and cDNA cloning of the human C1 inhibitor. Intron-exon junctions and comparison with other serpins.

Amino acid sequencing of trypsin fragments of C1 inhibitor gave regions of low codon degeneracy that were used for oligonucleotide probes. Human liver cDNA libraries gave clones containing most of the protein sequence, showing that the inhibitory domain belongs to the 'serpin' class of protein inhibitors. Fragments of these cDNA clones were used to probe human genomic cosmid libraries. The genomic sequence was found to be about 17 X 10(3) base pairs, with a coding sequence of approximately 1800 base pairs containing introns at amino acid positions--6, 162, 207, 275, 321, 395, and one in the 5' non-coding region. There is very little similarity of intron position amongst the serpin genes. All but one of the intron positions in the C1 inhibitor structural gene correspond to surface residues if C1 inhibitor is considered to have a structure similar to the cleaved form of alpha 1-antiproteinase. The serine and threonine residues in the N-terminal 100 amino acids of the sequence thought to carry complex carbohydrates are found in a single exon.

Amino Acid Sequence↗
PubMed1998

Baculovirus-mediated expression of truncated modular fragments from the catalytic region of human complement serine protease C1s. Evidence for the involvement of both complement control protein modules in the recognition of the C4 protein substrate.

C1s is the modular serine protease responsible for cleavage of C4 and C2, the protein substrates of the first component of complement. Its catalytic region (gamma-B) comprises two complement control protein (CCP) modules, a short activation peptide (ap), and a serine protease domain (SP). A baculovirus-mediated expression system was used to produce recombinant truncated fragments from this region, deleted either from the first CCP module (CCP2-ap-SP) or from both CCP modules (ap-SP). The aglycosylated fragment CCP2-ap-SPag was also expressed by using tunicamycin. The fragments were produced at yields of 0.6-3 mg/liter of culture, isolated, and characterized chemically and then tested functionally by comparison with intact C1s and its proteolytic gamma-B fragment. All recombinant fragments were expressed in a proenzyme form and cleaved by C1r to generate active enzymes expressing esterolytic activity and reactivity toward C1 inhibitor comparable to those of intact C1s. Likewise, the activated fragments gamma-B, CCP2-ap-SP, and ap-SP retained C1s ability to cleave C2 in the fluid phase. In contrast, whereas fragment gamma-B cleaved C4 as efficiently as C1s, the C4-cleaving activity of CCP2-ap-SP was greatly reduced (about 70-fold) and that of ap-SP was abolished. It is concluded that C4 cleavage involves substrate recognition sites located in both CCP modules of C1s, whereas C2 cleavage is affected mainly by the serine protease domain. Evidence is also provided that the carbohydrate moiety linked to the second CCP module of C1s has no significant effect on catalytic activity.

Animals↗
PubMed2001

Microheterogeneous changes of the C1-esterase inhibitor in plasma cannot predict operability, postoperative complications, or recurrence in cancer surgery.

OBJECTIVE: To find out if microheterogeneous changes--such as in molecular weight, isoelectric point, electrophoretic mobility, lectin binding or complexation of the C1-esterase inhibitor--exist in plasma samples from various subgroups of patients. If so, whether these differences could be used diagnostically in single plasma samples from patients with cancer for prognostic assessment of operability or risk of recurrence, and whether any change indicated an increased risk for development of postoperative complications. DESIGN: Retrospective study. SETTING: University hospital, Sweden. SUBJECTS: 16 patients operated on as emergencies for acute peritonitis, 118 patients electively operated on for benign diseases, 274 patients electively operated on for cancer, and 212 patients admitted with acute abdominal pain. MAIN OUTCOME MEASURES: Curative operation, diagnoses, postoperative complications, recurrence of cancer within 2 years. RESULTS: There were no biochemical differences in the C1-esterase inhibitor between single or sequential plasma samples from four large groups of patients with benign disease, cancer, or inflammatory disease, with operable or inoperable cancer, with postoperative complications or not, or with or without early recurrence of cancer. CONCLUSIONS: Specialised biochemical analyses of C1-esterase inhibitor, the most important plasma protease inhibitor of the complement and kinin systems and of contact activation in plasma, cannot be used for prognostic assessment of operability, risk of postoperative complications, or risk of recurrence in patients with cancer.

Abdomen, Acute↗
PubMed1982

C1 inhibitor deficiency simulating systemic lupus erythematosus.

A 48-year-old Japanese woman with systemic lupus erythematosus-like lesions of the skin and lips was found to have hereditary angio-oedema. Complement studies revealed low CH50, C1q, C4 and C1 inhibitor levels, with normal C3 and C5 levels. Dramatic clinical improvement followed fresh normal human blood transfusion and systemic betamethasone administration, while the deficient complement component levels were unchanged.

Angioedema↗
PubMed1990

Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site.

Hereditary angioneurotic edema is inherited as an autosomal dominant disorder and is characterized by potentially life-threatening episodic angioedema. In type II hereditary angioneurotic edema, a dysfunctional C1 inhibitor molecule is present together with low levels of normal C1 inhibitor. About 70% of these dysfunctional proteins result from reactive center (Arg-444) mutations. We describe the deletion of nucleotides encoding Lys-251 (AAG) in C1 inhibitor Ta, the dysfunctional C1 inhibitor from a family with type II hereditary angioneurotic edema. DNA sequence analysis was derived from clones obtained through polymerase chain reaction amplification of blood monocyte C1 inhibitor mRNA. As expected, clones with both normal and abnormal sequence were isolated. The deletion was verified by protein sequence analysis. These data, together with biochemical analysis of the protein and cell-free translation studies, suggest that this deletion, by altering the normal amino acid sequence from Asn-Lys-Ile-Ser to Asn-Ile-Ser, creates a new glycosylation site. The additional carbohydrate accounts for the larger size on SDS/PAGE and very likely interferes with protein function.

Amino Acid Sequence↗
PubMed1996

Functional characterization of two different Kupffer cell populations of normal rat liver.

BACKGROUND: Kupffer cells of the liver represent the largest population of tissue macrophages. Small and large Kupffer cells were distinguished in normal liver, leading to the suggestion that they have different functions. This study intends to further characterize small and large Kupffer cells of normal rat liver in vivo and in vitro. METHODS: Sections of rat liver were investigated by double-staining immunofluorescence with the monoclonal antibodies ED1 and ED2. Isolated nonparenchymal liver cells were separated according to size to obtain small and large Kupffer cells. In culture, phagocytosis was studied by zymosan ingestion and cell proliferation by incorporation of 3H-thymidine. Synthesis of the proteins C1-inhibitor, apolipoprotein E and interleukin-1 was studied by endogenous labeling of newly synthesized proteins, immunoprecipitation and sodium dodecylsulfate-polyacrylamide gel electrophoresis. RESULTS: ED1+ ED2+ Kupffer cells were located in the liver along the sinusoids. ED1+ ED2+ cells were found mainly located around the central vein and portal vessels. By counterflow elution, small ED1+ ED2- cells were separated from larger ED1+ ED2+ cells and cultured. The larger cells abundantly synthesized C1-inhibitor and apolipoprotein E, while the small cells synthesized only trace amounts of these proteins. Interferon-gamma increased C1-inhibitor synthesis in small (5-fold) and large cells (1.5-fold). 3H-thymidine incorporation was 11-fold higher in small than in large cells. However, lipopolysaccharide-induced pro-interleukin-1 alpha and pro-interleukin-1 beta synthesis and phagocytic activity were similar in both populations. CONCLUSIONS: The data demonstrate two different populations of mononuclear phagocytes in normal rat liver well distinguished by immunocytochemical and functional markers.

Animals↗
PubMed2000

The complement regulators C1 inhibitor and soluble complement receptor 1 attenuate acute lung injury in rabbits.

Because activation of the complement system plays a major role in the pathogenesis of acute lung injury, the availability of new specific complement inhibitors represents a promising therapeutic approach. In the present study we investigated pulmonary edema formation and pulmonary artery pressure (PAP) in acute complement-induced lung injury for possible therapeutic impact of the complement regulators C1 inhibitor and soluble complement receptor 1. Eighteen isolated and ventilated rabbit lungs were perfused with pooled normal human serum (NHS, final concentration 35%) in Krebs-Henseleit buffer in a recirculating system. Lung weight gain and PAP were continuously recorded. Complement activation was blocked by the addition of C1 inhibitor (1.0 U/mL, n = 6) or sCR 1 (2.0 microg/mL, n = 6). Lungs that received NHS without inhibitors served as controls (n = 6). This study was performed according to the Helsinki Declaration and approved by the local government. Application of NHS resulted in an increase of PAP within 20 min from 8+/-2 to 42+/-6 mmHg, which was significantly (P < 0.05) decreased by C1-Inh (25+/-5 mmHg) and sCRI (20 +/-3 mmHg). Moreover, pulmonary edema formation after NHS, as assessed by overall weight gain, was reduced by both C1-Inh and sCR1, compared with controls. These findings were paralleled with significantly decreased thromboxane release rates and reduced tissue deposition of C3c and C5b-9. C1 inhibitor and sCR1 attenuate the complement-induced pulmonary capillary leakage and PAP increase, indicating the protective effect of complement inhibition in isolated perfused rabbit lungs.

Animals↗
PubMed1993

A hinge region mutation in C1-inhibitor (Ala436-->Thr) results in nonsubstrate-like behavior and in polymerization of the molecule.

C1-inhibitor(Mo), a dysfunctional C1-inhibitor molecule produced in two kindred with type II hereditary angioedema, has a mutation at the P10 position (Ala436 to Thr). Like most serpins with hinge region mutations (P14, P12, P10), C1-inhibitor(Mo) loses its inhibitory activity. However, unlike the other hinge region mutations, this mutant is not converted to a substrate. As shown by nondenaturing gel electrophoresis, gel filtration, sucrose density gradient ultracentrifugation, and electron microscopy, C1-inhibitor(Mo) exists in both monomeric and multimeric forms. Polymerization probably results from reactive center loop insertion into the A sheet of an adjacent molecule. Native C1-inhibitor(Mo) was shown to have a thermal stability profile intermediate to those of intact and of cleaved normal C1-inhibitor. Native C1-inhibitor(Mo) did not bind to monoclonal antibody KII, which binds only to reactive center-cleaved normal C1-inhibitor. It did, however, react with monoclonal antibody KOK12, which recognizes complexed or cleaved C1-inhibitor but not intact normal C1-inhibitor. Native C1-inhibitor(Mo), therefore, exists in a conformation similar to the complexed form of normal C1-inhibitor.

Alanine↗
PubMed1976

Physicochemical and functional characterization of the C1r subunit of the first complement component.

C1r was isolated from serum by an improved method and found to be a glycoprotein with a sedimentation coefficient of 7.0S. Under conditions of physiologic ionic strength and pH, C1r consist of two apparently identical noncovalently linked 95,000 dalton polypeptide chains. Antisera to C1r detected a protein of gamma-mobility on electrophoresis of serum in agarose in the presence of calcium, and a Beta-mobility protein when the electrophoretic separation was carried out in EDTA. On sucrose gradient ultracentrifugation of normal human serum in the presence of calcium, C1r antigenicity was found in the 19 S region of the gradient. On the other hand, when the gradient contained EDTA, C1r antigenicity was found in the 7 S region. No reaction of anti-C1r with C1r-deficient sera was observed. C1r had a high affinity for active C1s or proenzyme C1s in the presence of calcium and was able to activate C1s and to form C1 in conjunction with C1q and C1s. Activation of C1s by C1r was inhibited by calcium, C1 inactivator, polyanethol sulfonate, and DFP. Activation of C1s by C1r occurred only after a preliminary incubation of C1r for a brief time at 37 degrees C before addition of C1s. The ability of C1r to form C1 in conjunction with C1q and C1s was, however, progressively lost on incubation at 37 degrees C. Trypsin, although potentiating the activity of crude C1r, did not modify the activity of purified C1r. Its action was on a trypsin-sensitive inhibitor separated from C1r in the final step of the isolation procedure. The binding of 125I-C1r to sensitized sheep erythrocytes required the presence of C1q and calcium but not C1s, whereas the binding of 125I-C1s required C1q, C1r and calcium. Thus, C1r functions as not only the activator of C1s, but also serves as the physical link between C1q and C1s in macromolecular C1.

Animals↗
PubMed1992

Marked increase in plasma interleukin-6 in burn patients.

We measured the levels of interleukin-6 in plasma samples from 18 consecutive burn patients, including three lethal cases, during the early postburn period. In survivors burn injury caused initial increases in interleukin-6 levels that peaked at 6 hours after burn; this was significantly higher than interleukin-6 levels in normal controls (718 +/- 216 vs 70 +/- 4 pg/ml; p < 0.01). The increment in nonsurvivors was even more prominent (11,554 +/- 4,407 pg/ml; p < 0.01). The peak interleukin-6 levels at 6 hours correlated with total burn surface area (r = 0.65, p < 0.025), and tended to be higher in patients with inhalation injury. These data provide evidence that burn injury causes rapid release of interleukin-6 according to the severity of the injury. We also measured acute-phase reactants including fibrinogen, alpha 1-antitrypsin, C1 inhibitor, and alpha 2-plasmin inhibitor. After initial declines, these four proteins increased rapidly in survivors. In addition, the peak interleukin-6 levels correlated well with the increases in fibrinogen (p < 0.025), alpha 1-antitrypsin (p < 0.01), C1 inhibitor (p < 0.01), and alpha 2-plasmin inhibitor (p < 0.0001). In contrast, despite the marked increase in interleukin-6, the levels of acute phase proteins in nonsurvivors remained low. Based on these observations, we suggest that interleukin-6 is released as an alarm signal and has a role for the wound healing in burn patients, and that the levels of interleukin-6 after injury is an indicator of the severity of burn.

Acute-Phase Proteins↗
PubMed1986

The contact activation system: biochemistry and interactions of these surface-mediated defense reactions.

This review is intended to be a critical state-of-the-art overview of the activation and inhibition of the proteins (factor XII, prekallikrein, high molecular weight kininogen, and factor XI) of the contact phase of coagulation. Specifically, this review will reconsider the concept of the reciprocal activation of the proteases of the contact phase of coagulation, factor XII, and prekallikrein, in light of much recent evidence indicating that factor XII, itself, autoactivates when associated with negatively charged surfaces. In addition, the mechanisms for amplification of activation of the proteins of the contact phase of coagulation will be discussed from the pivotal role of high molecular weight kininogen, or one of its altered forms, serving as a cofactor to order the activation of the zymogens it is associated with. The role and relative importance of each of the naturally occurring plasma protease inhibitors (C1-inhibitor, alpha-2-macroglobulin, alpha-1-antitrypsin, antithrombin III, and alpha-1-antiplasmin) will be assessed as they relate to the dampening of contact phase activation. Finally, the contact phase of coagulation activation will be discussed not only as a plasma proteolytic mechanism, but also as it interacts with platelets.

Blood Coagulation↗