C1-inhibitor deficiency and angioedema

Molecular Immunology 38 (2001) 161– 173 www.elsevier.com/locate/molimm

Review

C1-inhibitor deficiency and angioedema Anna Carugati, Emanuela Pappalardo, Lorenz C. Zingale, Marco Cicardi * Department of Internal Medicine, Uni6ersity of Milan, IRCCS Ospedale Maggiore, Via Pace 9, 20122 Milan, Italy

Abstract C1-inhibitor deficiency can be inherited or acquired; both conditions lead to recurrent angioedema that can be life threatening when the larynx is involved (hereditary angioedema, HAE; acquired angioedema, AAE). The genetic defect is due to the heterozygous deficiency of C1-Inh that is transmitted as an autosomal dominant trait. Mutations causing HAE have been found distributed over all exons and splice sites of C1-Inh structural gene: only a few of them have been found more than once. Depending on DNA defect, C1-Inh is not transcribed, or not translated or not secreted. Finally, in 15% of HAE patients, an antigenically normal, but non-functional C1-Inh is present in serum (HAE type II). C1-Inh deficiency can be acquired, due to an accelerated consumption. Such an accelerated consumption can depend on circulating autoantibodies that bind C1-Inh causing its inactivation and catabolism; or to associated diseases, usually lymphoproliferative diseases, that consume C1-Inh with different mechanisms. Effective therapies can prevent or revert angioedema symptoms in C1-Inh deficiency, the main problem of this condition remaining misdiagnosis. The common knowledge that angioedema is an allergic symptom frequently prevents a correct diagnostic approach: C1-Inh deficiency goes unrecognized and the disease can still be lethal. Correct prophylactic treatment is based on attenuated androgens in HAE and on antifibrinolytic agents in AAE. Life threatening laryngeal attacks and severe abdominal attacks are effectively reverted, in both conditions, with C1-Inh plasma concentrate. A special remark to this treatment should be made for autoantibody-mediated AAE where very high doses can be needed depending on the rate of C1-Inh consumption. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: C1 inhibitor; Hereditary angioedema; Acquired angioedema

1. Genetic of C1-inhibitor deficiency The evidence for a C1 esterase inhibiting activity in plasma was first provided by Levy and Lepow (1959). Shortly thereafter the same group (Pensky et al., 1961) obtained a partial purification of the plasma protein responsible for such an activity that was called C1-inhibitor (C1-Inh). Donaldson and Evans (1963) demonstrated that C1-Inh was genetically defective in patients with hereditary angioedema (HAE) thus identifying the biochemical abnormality of this condition whose first complete clinical description had been given by Osler in 1888. The spectrum of inhibitory activities of C1-Inh is not limited to C1: it is a major physiological inhibitor of kallikrein, Hageman Factor (coagulation factor XII, * Corresponding author. Tel.: + 39-02-5460-826; fax: +39-0255180-354. E-mail address: [email protected] (M. Cicardi).

FXII) and coagulation factor XI (FXI). Moreover, it forms stable complexes with plasmin although the in vivo relevance of such interaction has not yet been defined. For a review of biochemical and functional characteristics of C1-Inh (Davis, 1988). As mentioned, the existence of a familial form of angioedema was known since the last century and Crowder and Crowder (1917) demonstrated that the character was inherited as an autosomal dominant trait. Rosen et al. (1965) described an HAE phenotypic variant in which C1-Inh was detectable in plasma at normal to elevated antigenic levels, but with defective activity, due to the presence of a dysfunctional C1-Inh protein (HAE type II). Attempts to demonstrate a linkage between HAE and loci as Rh on chromosome 1, MNSs on chromosome 4, ABO on chromosome 9 and HLA on chromosome 6 did not give positive results (Ohela et al., 1977; Robson et al., 1979; Stewart et al., 1979; Eggert et al., 1982).

0161-5890/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 1 6 1 - 5 8 9 0 ( 0 1 ) 0 0 0 4 0 - 2

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

162

1.1. C1 -inhibitor gene

1.2. C1 -inhibitor mutation in hereditary angioedema

Sequencing of C1-Inh cDNA, obtained by three independent groups in 1986 (Bock et al., 1986; Davis et al., 1986; Tosi et al., 1986), stands as the milestone for the understanding of the structural aspects of C1-Inh functions and of the molecular basis of its genetic defect. C1-Inh was identified, by sequence analogies, as a member of the protein superfamily of serine protease inhibitors (Serpin) and its gene was assigned to chromosome 11q11.2-q13 (Table 1). Isolation of genomic clones allowed first the definition of exon– intron junctions (Carter et al., 1988) and later the complete nucleotide sequence of the gene of human C1-Inh that included also 1182 bp of sequences upstream from exon 1 and 346 bp downstream from the polyadenilation site (Carter et al., 1991). The gene is 17159 bp long from the transcription start site and gives rise to an mRNA product of 1827 bp excluding the poly(A) tail. It is composed of 8 exons and 7 introns, the first one containing 38 bp of a non-coding sequence and the second one having a signal peptide of 22 bp before the first methionine. Translation of this sequence results in a protein of 478 aminoacids, whose molecular weight based only on aminoacids composition, is about half of 105 kDa that have been estimated for the plasma protein (Harrison, 1983). C1-Inh is in fact highly glycosilated (26–33% of the total mass) with six sites of N-linked glycosilation and seven of O-linked. These sites are located within a stretch of 100 aminoacids at the amino-terminal end of the molecule (Bock et al., 1986) they do not appear to be relevant for the protein function, but removal of the sugars increases the catabolic rate. The N-terminal end represents the nonserpin-like domain that is highly divergent among different species suggesting that they accept extensive variations both in primary sequence and in glycosilation pattern (Russell et al., 1997; Lener et al., 1998).

Between 1986 and 1991 several different mutations in C1-Inh gene have been proved, by segregation studies, to be responsible for HAE (Cicardi et al., 1987a; Stoppa-Lyonnet et al., 1987; Ariga et al., 1989, 1990; Skriver et al., 1989, 1991; Aulak and Harrison, 1990; Levy et al., 1990; Parad et al., 1990; Stoppa-Lyonnet et al., 1990; Frangi et al., 1991; Siddique et al., 1991). Mutation screening was first based on the identification of restriction fragment length polymorphism (RFLP). By these studies, it became apparent that a large array of different mutations was responsible for HAE. We now know that large deletion/insertion are responsible for : 20% of the mutations detected in HAE patients, the remaining 80% being due to small/point mutations (Tosi, 1998).

Table 1 Main characteristics of C1 inhibitor Chromosome mapping Gene length mRNA length (without poly(A) tail) Number of exons and introns Protein length Plasma protein molecular weight Protein glycosilation Reactive site

11 subregion q11.2-q13 17159 bp 1827 bp 8 exons, 7 introns 478 aminoacids 105 kDa From 26 to 33% of total protein mass Arginine 444

1.2.1. Large mutations Large mutations appeared to be related to clusters of Alu repeats in various orientations, particularly in introns 4 and 6 (Ariga et al., 1990; Stoppa-Lyonnet et al., 1990, 1991). They represent a major source of genetic instability in C1-inhibitor gene. In 1990, Ariga et al. (1990) found that two deletions, 2 and 8.5 Kb, respectively, into two different families were due to unequal crossing-over between Alu repeat. One year later, Stoppa-Lyonnet et al. (1991) found eight partial C1-Inh gene deletions and a partial duplication caused by recombination breakpoints spread over the entire length of Alu1. They hypothesized that this could be due to a region of potential Z-DNA structure located upstream Alu1 sequence. Similar results were obtained in other studies in which the deletion boundaries were located and sequenced within Alu repeats (Ariga et al., 1989; McPhaden et al., 1991): in a study the modification was placed in exon 6/intron 6 boundary (Siddique et al., 1991). 1.2.2. Small mutations Small mutations causing HAE are also genetically heterogeneous. They can be divided into missense mutations (more than 36% of mutations in type I and almost 100% in type II), frameshifts mutations (14%), stop codon mutations (10%), splice-site mutations (7– 10%), promoter variants (4%), deletions of a few aminoacids (less than 3%) (Tosi, 1998). When mutations occur within C1-Inh reactive site almost invariably result in HAE type II. The reactive site is located in exon 8 at arginine 444: it is identified as P1 site by analogy with a1-antitrypsin. Aminoacids upstream and downstream from this residue are, respectively, identified as P2, P3 etc. and P%2, P%3 etc following their alignment with the sequence of a1-antitrypsin. Parad et al. (1990) estimated that mutations at Arg 444 could account for up to 70% of HAE type II

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

(Skriver et al., 1989; Aulak and Harrison, 1990; Aulak et al., 1990; Frangi et al., 1992; Davis et al., 1993; Ocejo-Vinyals et al., 1995; Bissler et al., 1997; Pappalardo et al., 2000; Zuraw and Herschbach, 2000). The most frequent such mutation is due to spontaneous de-amination of cytosine in CpG dinucleotides. This can lead to the substitution of arginine 444 with either cysteine or histidine depending upon the fact that the deamination realizes within the codon or the anticodon. Other mutations in the reactive site responsible for dysfunctional C1-Inhs are Arg to Ser or to Leu. It is interesting to note that the Arg to Leu results a phenotype that appears intermediate (C1-Inh antigenic plasma levels between 30 and 50% of normal) between type I and type II (Pappalardo et al., 2000). In 3 unrelated HAE families two pathologic mutations were detected on the same C1-Inh allele. A fourth one (Verpy et al., 1995), in position 566, was a nonpathologic polymorphism (Pappalardo et al., 2000). The first family with two mutations on one allele had HAE type II: the mutations were both in exon 8 at P1 (16789G“ A) and P10 (16765C“ T), respectively (Siddique et al., 1992). The two others families were described by Verpy in 1995 (Verpy et al., 1995). In one family there were two point mutations: their expression demonstrated that Gln 452 Glu had little or no effect on protein structure and function, while Leu 459 Pro totally impaired protein secretion. The last family presented one mutation involving the pyrimidine-rich region (C“ G at position −40) and the second one was a 3 bp deletion in exon 5. The precise consequences of the mutation have not been fully clarified. C1 inhibitor contains two-hinge regions upstream (proximal hinge) and downstream (distal hinge) the reactive site: mutations within these regions lead to HAE type II. So far, mutations have been described at P10 (Levy et al., 1990; Davis et al., 1992; Aulak et al., 1993), P12 (Skriver et al., 1991) and P14 (Davis et al., 1992). Mutation at P12 and P14 probably prevent correct movement of the reactive site during the interaction with the target proteases and in case of the P12 mutant converts the inhibitor into a substrate. The P10 mutant results in polymerization of the protein. Only one mutation causing HAE type II has been located far from the reactive center region (Parad et al., 1990). It is a deletion of Lys 251 that creates a potential new glycosilation site. The carbohydrate group Asn 250 could interfere with the reactive center region or simply lead to an essentially irreversible alteration in this region. Zahedi et al. (1995) described a substitution in C1Inh P2 residue (Ala 443 Val) in a group of 11 members of one family spanning three generations with an autosomal dominant pattern of inheritance for lupus erythematosus, low C4 levels, and angioedema. This mutant C1-Inh had decreased capacity to inhibit C1r and C1s,

163

but maintained the kallikrein inhibitory activity and was able to inhibit trypsin (Zahedi et al., 1997b). The identification of such mutant provided important information to the understanding of the relative importance of the different inhibitory activities of C1-Inh to the pathogenesis of angioedema attacks. Systematic detection of small mutations in HAE patients has been approached using either SSCP (Bissler et al., 1997; Zuraw and Herschbach, 2000) and FAMA (Pappalardo et al., 2000; Verpy et al., 1994, 1996) techniques, followed by sequencing. The identification of large insertion/deletion still relays Southernblot detection of RFLP. However, a new system for rapid detection of exon deletions and duplications by florescent multiplex PCR was recently proved to be helpful for detection of large mutations within C1-Inh gene (Duponchel et al., 2001). Looking back to the mutations so far described in HAE patients, we can see that they span over the entire gene with higher concentration in exon 8, 5 and 6 and low concentration in the aminoterminal end (Tosi, 1998). Due to the relatively high number of sporadic cases of HAE, nearly 30% of all unrelated cases, we recently defined de novo mutations in 19 such patients (Pappalardo et al., 2000). The type of these mutations and their distribution in C1-Inh gene does not differ from what is reported for the inherited cases.

1.3. Expression of C1 inhibitor in hereditary angioedema Because of the evidence that C1-Inh plasma levels in HAE patients are largely below the 50% of normal that one would expect in a heterozygous defect, several studies were designed to define at a cellular levels, the effect of C1-Inh mutations on the synthetic rate of C1-Inh mRNA and C1-Inh protein. Nevertheless, these studies provided conflicting results (Cicardi et al., 1987b; Lappin et al., 1989; Kramer et al., 1991). Semiquantitative techniques, different cell systems, small number of specimens available and the high variability of the molecular defect account for the inconsistency of the results. Therefore the question whether HAE patients have C1-Inh plasma levels largely below the 50% because of defective synthesis or because of increase consumption remains unanswered. Two mutations have been found in the promoter region of C1-Inh gene. One (Verpy et al., 1996) is a C to T transition at position − 103 within one of the two putative CAAT boxes. It was found in a family with recessive transmission of angioedema. This mode of inheritance is exceptional for this autosomal dominant disease, but its occurrence could be related to an important consanguinity. It has been hypothesized that promoter variants determine a moderate reduction of gene expression, resulting in angioedema only when both

164

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

alleles are affected (Tosi, 1998). In fact, heterozygous individuals have C1-Inh levels within the normal range, although at lower limit, and they are asymptomatic, while homozygous patients have low C1-Inh level and severe angioedema. The other promoter variant is a C “ G transversion at position − 40 in a pyrimidinerich region of potential H-DNA structure. It contains a sequence element similar to a sequence found upstream the human c-myc gene, which binds positive transcriptional regulator (Davis et al., 1989). It arises in cis with a 3 bp deletion in exon 5 that give rise to a deletion of Asn 250, and cosegregate in the family. Attempts to modify C1-Inh gene expression have been performed in order to correct the genetic defect. Several cytokines and grow factors (Hamilton et al., 1987; Katz and Strunk, 1989; Falus et al., 1990a,b; Heda et al., 1990; Zuraw and Lotz, 1990; Kramer et al., 1991; Lappin et al., 1992) were proved to increase C1-Inh expression in different cell systems. Accordingly, INFg response elements were mapped in 5%-flanking region and the first intron of C1-Inh gene (Zahedi et al., 1994, 1997a). Nevertheless, none of these stimuli has so far been proved to be of any relevance as therapeutic agent for HAE patients.

2. Hereditary angioedema One hundred years before the discovery that C1-Inh deficiency was the biochemical defect causing HAE, the disease was already clearly recognized in its clinical aspects (Osler, 1888). At that time, and up until recently, the term angioneurotic edema was preferred to angioedema to highlight the influence that psychological stress had in the appearance of symptoms. The relevance given to the neurological factors, is best demonstrated by an article of 1957 (Douglas and Blitzer, 1957), in which HAE was viewed as a familial disorder of the autonomic nervous system. The cardinal symptom of the disease is angioedema: a recurrent, self limiting, non inflammatory edema of the subcutaneous or submucosal tissues that completely resolves in 1–5 days (Frank et al., 1976; Agostoni and Cicardi, 1992). Three sites can be affected: the skin, the gastrointestinal mucosa and the mucosa of the upper airways. Angioedema of the skin causes monstrous deformities that can impair the social life, but do not create any local or systemic damage. Involvement of the gastrointestinal mucosa can lead to untreatable pain, vomiting and diarrhea. It can easily be misdiagnosed as a surgical emergency and HAE patients frequently undergo unnecessary operations. During intestinal symptoms limited amounts of free peritoneal fluid can be present that further complicate their differentiation from a true peritonitis (Shah et al., 1995; Talavera et al., 1995; Laurent and Guinnepain, 1996;

Branco-Ferreira et al., 1998; Sofia et al., 1999; Dinkel et al., 2001). Intestinal attacks usually resolve without reliquates the only risk being, in infancy or elderliness, dehydration. Oral mucosa, pharynx and larynx are frequently involved: the first two locations do not represent an emergency per se, but angioedema from this sites can easily diffuse to the larynx where it can lead to asphyxia if not promptly and properly treated (Bork and Barnstedt, 2001). Unfortunately, this disease can still be life threatening when it goes unrecognized. Three fatalities have been reported to us during the last year. Misdiagnosis is a relevant problem for HAE (Morris et al., 1987). The common knowledge that angioedema is an allergic condition is responsible for most diagnostic errors: chronically recurrent angioedema and, even more, familiar angioedema are never allergic. The physician should always consider C1-Inh deficiency when dealing with a patient in whom angioedema chronically recurs and particularly if there is no significant urticaria. Diagnosis can be confirmed in 100% of patients by measuring C1-Inh function (Atkinson, 1979; Nielsen et al., 1994). If this is not possible the simple antigenic measurement will still achieve 85% of the diagnosis since HAE type II accounts for 15% of all the cases of HAE. In addition, C4 levels below 50% of normal, although not specific, help in reaching the diagnosis: normal levels of C4 virtually exclude HAE. A new inherited form of angioedema has been recently described that affects just the female members of the family and in one of the families seems to be strongly related to estrogen levels. No biochemical defect has been identified so far and no abnormalities were found in C1-Inh: this angioedema has been identified as HAE type III (Bork et al., 2000; Binkley and Davis, 2000).

2.1. Treatment of hereditary angioedema 2.1.1. Long-term prophylaxis The difficulty of long-term prophylaxis of HAE is not to find an effective medication, but to calculate the final benefit of a continuous pharmacological treatment versus symptoms that unpredictably vary in frequency and severity. People can die from HAE, but people can have hereditary C1-Inh deficiency without a single angioedema all their life long. Thus, before starting longterm prophylaxis one should carefully calculate the impact of the disease on quality of life. We do not usually consider eligible to long-term prophylaxis patients who have one attack per month or less. From this frequency up consideration should be taken based on the specific characteristic of the patient and of the drugs available for this kind of treatment. In term of efficacy, long-term prophylaxis is best achieved with attenuated androgens. In 1960, Spaulding

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

165

Table 2 Therapy of hereditary angioedema Acute attack

Prophylaxis

Severe

Mild

Long-term

Short-term

C1-inhibitor concentrate Tranexamic acid

1000–2000 U ev

–

–

1000–2000 U ev

–

0.5–1 g t.i.d.

–

Danazol

–

1 g p.o. every 3–4 h for 12–18 h –

Stanozolol

–

–

400–600 mg/day for 1 month, then tapering down to minimal effective dose (50–200 mg/day) 4–6 mg/day for 1 month, then tapering down to minimal effective dose (0.5–2 mg/day)

600 mg/day 5 days before oral manipulation (or important event) till 3 days after 6 mg/day 5 days before oral manipulation (or important event) till 3 days after

first showed that methyltestosterone was effective in preventing attacks in one family affected by hereditary angioedema (Spaulding, 1960). Sixteen years later Gelfand et al. (1976) demonstrated, in a double blind study, that Danazol, an attenuated androgen with reduced hormonal activity, was effective in correcting the biochemical defect and the clinical symptoms of HAE. Several studies have since confirmed the efficacy of other attenuated androgens, all of them 17a alkylated (Sheffer et al., 1977; Pitts et al., 1978; Agostoni et al., 1980b). Alkylation at position 17a is critical for the metabolism of androgens through the liver, but at the same time is responsible for their hepatotoxicity. In order to minimize side effects, doses have been progressively reduced and soon it became clear that therapeutic efficacy was independent from any increase in C1-Inh plasma levels (Warin et al., 1980). Thus, the exact mechanism of action of these drugs in HAE remains to be explained. Danazol and Stanozolol are the two attenuated androgens more commonly used for HAE. Their minimal effective doses, determined on purely empiric clinical criteria, are reported in Table 2. The most common complaints from patients on attenuatedandrogens are due to their residual hormonal activity and include body weight gain, minimal signs of virilization and menstrual irregularities (Hosea and Frank, 1980; Sheffer et al., 1987; Zurlo and Frank, 1990; Cicardi et al., 1991). Apart from hormonal effects, HAE patients on attenuated androgens tend to be polyglobulic (Ford et al., 1994) and to have slight elevation in cholesterol and in blood pressure (Bretza et al., 1980; Cicardi et al., 1997). It has also been well documented that Danazol can cause hemorrhagic cystitis resulting in microhematuria (Andriole et al., 1986). Nevertheless the main concern of long-term treatment with attenuated androgens is their capacity to induce benign and malignant liver neoplasia (Johnson et al., 1972; Farrell et al., 1975; Ishak and Zimmerman, 1987). To our knowledge the literature reports of two HAE

patients who developed an hepatocarcinoma and three who developed an hepatic adenoma while on androgens (Crampon et al., 1998; Bork et al., 1999; Veit et al., 1999). In order to prevent serious side effects, all treated patients have to undergo periodic (once or twice a year) blood testing and hepatic ultrasounds. Among the over 100 patients of our case list who are on attenuated androgens, some of them since 1977, no sign of liver neoplasia has been detected so far. The use of attenuated androgens is substantially contraindicated in children and in pregnant women. Children with very severe disease have been seldom treated, but we have not personal experience and very scattered reports are available from the literature (Barakat and Castaldo, 1993). We used Danazol for the last trimester of pregnancy in a women with weekly laryngeal attacks (Cicardi et al., 1991). The female newborn presented signs of virilization at birth that quickly disappeared without consequences. She is now a perfectly healthy 14-year-old girl. The other drugs proposed for prophylaxis of HAE are the antifibrinolytic agents (o-aminocaproic acid and tranexamic acid). Efficacy of these drugs probably depends on their capacity to inhibit active plasmin, an enzyme that plays a critical role in the generation of the vasoactive peptide responsible for angioedema (Donaldson et al., 1977; Nilsson and Back, 1985; Cugno et al., 1993). Frank et al. (1972), in a double-blind study, showed that o-aminocaproic acid reduced attacks of hereditary angioedema. The principal side effects (muscle pain, weakness accompanied by elevations in the serum enzymes creatine phosphokinase and aldolase) occurred when the dose of the drug exceeded 20 g per day, but disappeared when the drug was discontinued or the dosage was lowered. During the same year other investigators (Blohme, 1972; Sheffer et al., 1972) showed that also of tranexamic acid, an analogue of o-aminocaproic acid, had similar efficacy and reduced side effects (slight transient diarrhea, nausea, slight

166

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

headache). During the following years the use of antifibrinolytic agents for HAE prophylaxis has declined due to higher efficacy of attenuated androgens.

2.1.2. Short-term prophylaxis This treatment is indicated when patients undergo manipulation of the oral cavity (as for dental care, endoscopic investigations, endotracheal intubation) that can trigger a laryngeal attack. But this approach can be extended to situations where the patients just needs not to be swelling i.e. important events, traveling, vacation etc. Attenuated androgens are highly effective without any serious side effect for this type of treatment (Table 2). Due to the short period of treatment, this kind of approach has no contra-indications even in children (Agostoni and Cicardi, 1992). Substitutive therapy with partially purified preparation of C1-Inh can be used for short-term prophylaxis when there is no time to induce protection with attenuated androgens. 2.1.3. Treatment of acute attacks In 1980 two independent investigators reported the first results of the infusion of partially purified C1-Inh preparations in patients with HAE during acute attacks (Agostoni et al., 1980a; Gadek et al., 1980). In both studies C1 inhibitor was effective and well tolerated: mucous edema began to subside within 15– 60 min, subcutaneous edema required a longer time to decrease (1 – 3 h). No side effects were observed in any of the patients. C1-inhibitor plasma concentrate is now considered the treatment of choice for life-threatening attacks in patients with HAE (Waytes et al., 1996; Kunschak et al., 1998). The transmission of hepatitis C virus (HCV) infections was the critical complication of the use of protein concentrate up until the introduction of virucidal methods. In 1995 we surveyed our case-list (Cicardi et al., 1995) and reported HCV infection in 86% of the patients who received C1-Inh before virucidal methods were introduced. Nevertheless, we do not know of any case of transmission of HIV infection via C1-Inh concentrate. Since the introduction of viral inactivation steps HCV infection has been possibly related to C1Inh concentrate in only two patients out of several hundreds infusions. Fresh frozen plasma was successfully used by Pickering et al. (1969), but it is now obsolete in countries where C1-Inh concentrate is available. Plasma, besides a higher risk of blood borne infection, has the disadvantage of containing not only the deficient protein, but also the substrates responsible of edema formation. Marasini et al. (1978) used infusion of the kallikrein inhibitor aprotinin for episodes of laryngeal edema in hereditary angioedema patients. Dysphonia, dysphagia and tirage, when present, disappeared in 1– 2 h after the

beginning of the infusion. Aprotinin has not been used later because there were reports of deaths due to allergic reactions to this drug. Furthermore in the subsequent years it was withdrawn from the Italian market because it was extracted from parotids of cows and thus it fell into the restriction applied to reduce the risk of cows’ related infections. Anti-fibrinolytic agents are sometimes useful for non life-threatening acute attacks of angioedema. We obtained satisfactory results with high doses of tranexamic acid (1 g every 3–4 h), given orally over a period of 12–15 h. Their administration early in the attacks is critical and no effect can be expected when the edema has already spread. However, these data rely just on the authors’ personal experience and no controlled study has been ever performed

3. Acquired angioedema Acquired angioedema (AAE) is a rare syndrome, clinically undistinguishable from HAE. The characteristics that allow to differentiate AAE from HAE are a late onset of symptoms (usually after 40 years), the absence of family history of angioedema, low C2/C4/ C1-Inh plasma levels, usually associated with low C1q levels (Agostoni and Cicardi, 1992). The first case of AAE was described by Caldwell et al. (1972), who gave full account of a patient with lymphosarcoma, recurrent attacks of angioedema and the complement profile now known as diagnostic for AAE. From that moment on, several cases of AAE associated with lymphoproliferative disorders of B cells and, less frequently, with other malignancies or with autoimmune or infectious diseases, have been reported, and in 1986 the presence of an autoantibody to C1-Inh was discovered in a patient with AAE (Jackson et al., 1986).

3.1. Ethiopathogenesis Studying the first AAE patient, Caldwell found that his serum, incubated at 37 °C with a normal one, consumed C1q. He hypothesized that patient’s serum contained something able to fix and to activate the complement classical pathway. Accordingly, in vivo turnover studies performed some years later (Melamed et al., 1986) demonstrated that patients with AAE had an increased fractional catabolic rate of C1q and C1Inh. Within the 30 years passed from Caldwell’s paper, several attempts have been made to identify the mechanism(s) responsible for the consumption of C1-Inh and for the tremendous activation of the classical complement pathway that characterize AAE. In the following paragraphs, we will try to briefly review the main

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

contributions to ethiopathogenesis.

the

understanding

of

AAE

3.1.1. Cryoglobulins Hauptmann et al. (1975) described a patient with AAE, lymphosarcoma and cold urticaria. Cryoglobulins (monoclonal IgGk), present in serum of this patient, reacted with C1q activating the classical pathway complement components. Casali et al. (1978) studied complement consumption in five patients with mixed cryoglobulinemia and C1-Inh deficiency, two of these patients also presented angioedema symptoms. They provided evidence that cryoprecipitating immunecomplexes activated complement and that C1-Inh consumption followed C1 activation. 3.1.2. 7S IgM Several authors (Oberling et al., 1975; Casali et al., 1978; Hauptmann et al., 1979) have reported the presence of a low molecular weight IgM in subjects with AAE and lymphoproliferative diseases. They suggested that this 7S IgM, usually found in cord blood but not in normal adult, could activate the classical pathway, leading to C1-Inh consumption. Against this hypothesis Hauptmann et al. (1976) showed that the 7S IgM subunits, obtained by fragmentation of 19S IgM, had much less capacity to activate C1 compared with the normal protein. He also called attention on the fact that in other pathological conditions (i.e. SLE, ataxia teleangectasia, Rheumatoid Arthritis) the 7S IgMs were present but there were not the complement abnormalities characteristic of AAE. 3.1.3. Cellular abnormalities In one patient with AAE and lymphoproliferative disease, Schreiber et al. (1976) demonstrated that peripheral blood mononuclear cells, but not plasma, could deplete C1 and C1-Inh from normal compatible sera. Those mononuclear cells had a B-lymphocyte phenotype in terms of membrane receptor and membrane Ig (mostly IgM), but they had also phagocytic activity. These studies lead to the hypothesis of a relatively independent binding of C1-Inh and C1 to the cells: bound activated C1 in turn depleted C2 and C4. Similar experiments performed by Cohen et al. (1978) with lymphocytes from a patient with rectal carcinoma and AAE, failed to show complement activation or C1-Inh binding. 3.1.4. Serum and cellular abnormalities Hauptmann et al. (1979) described a patient with AAE and poorly differentiated lymphocytic lymphoma, whose serum, blood mononuclear cells and cells from neoplastic tissue consumed C1 and C1-Inh from homologous plasma.

167

3.1.5. Idiotype–anti-idiotypes antibodies Geha et al. (1985) identified, in patients with AAE and B cell lymphoproliferative diseases, anti-idiotypic IgG reacting with the monoclonal immunoglobulins. He showed that the patient’s own IgG bound to the patient’s IgM, differently from control IgG preparations. Similarly the patient’s IgG bound to the patient’s B cells and also to autologous bone marrow and spleen cells, but not to cells from control preparations. Later it was shown that one of the patients of Geha’s study also had an autoantibody against C1-Inh in his serum (Cicardi et al., 1993). The possibility that anti-idiotype and anti-C1-Inh autoantibody could represent two specificities of the same immunoglobulins has never been defined. 3.1.6. Extra6ascular consumption A different situation is described by Schifferli et al. (1987) in four patients with AAE and paraproteinemia, who had neither serum nor cellular complement binding activities. Complement was consumed nearly exclusively in extravascular compartment, mostly in the liver or in the spleen, where it was demonstrated rapid accumulation and fast catabolism of 125I-C1q. 3.1.7. Anti-C1 -Inh autoantibodies Jackson et al. (1986) described for the first time an autoantibody (IgG) to C1-Inh in a patient with AAE. The inhibitory effect of that autoantibody was mediated by the Fab-region and it had the characteristic restricted mobility of a monoclonal antibody. Interestingly the patient’s IgG did not cause significant decrease in CH50, indicating that the immune complexes autoantibody-C1-Inh did not fix complement. Autoantibodies to C1-Inh seem rather specific of AAE and in these patients they usually are not associated with other autoantibodies (Cicardi et al., 1993). In the same year, but prior of availability of a test for detecting anti-C1Inh autoantibodies, Zuraw and Curd (1986) found three different forms of C1-Inh in plasma of AAE patients. These forms corresponded to: C1-Inh complexed with its proteases (190–210 kD), native C1-Inh (105–110 kD), modified inactive C1-Inh (94–96 kD). This last form accounted for 92% of total C1-Inh in AAE patients, 28% in HAE patients and only 1.2% in normal controls. It could be generated in vitro by activation of contact system. Alsenz et al. (1987) demonstrated that native C1-Inh was degraded to its cleaved form of 96 kD when incubated in serum of patients with AAE and anti-C1-Inh autoantibodies: such a degradation was caused by activated C1s. In their experiments anti-C1-Inh antibodies bind to free C1-Inh but not to C1-Inh already complexed with activated C1s: they concluded that the epitopes recognized by these autoantibodies were not accessible in C1s –C1-Inh complexes. Addressing the same question,

168

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

Jackson and Feighery (1988) and Jackson et al. (1989) suggested that normal C1-Inh bound to anti-C1-Inh autoantibodies could still react with its target proteases, but the resulting complex was highly unstable with the consequent release of cleaved 96 kD C1-Inh. Whatever the mechanism of formation, generation of the 96 kD C1-Inh appears to depend on the presence of anti-C1Inh autoantibodies: its accumulation causes a discrepancy between antigenic (nearly normal) and functional (almost undetectable) C1-Inh plasma levels. This condition is similar to what is found in HAE type II. Based on this finding and on the fact that the first patients with anti-C1-Inh autoantibodies had no associated disease, while typical AAE patients had lymphoproliferative disorders, it was concluded that two different forms of AEE existed. Accordingly, autoantibody-associated AAE was named type II and type I the AAE associated with lymphoprolyferative disorders (Alsenz et al., 1989). This classification turned out to be largely inaccurate. Antibody screening in patients putatively type I was frequently positive and antigenic C1Inh levels are frequently low also in presence of anti-C1-Inh autoantibodies (Cicardi et al., 1993, 1996; Whaley et al., 1996; D’Incan et al., 1999). According to the view that AAE depends on accelerated C1-Inh consumption, Malbran et al. (1988) demonstrated that monocytes from patients with autoantibodies to C1-Inh secreted at normal rate antigenically and functionally normal 105 kD C1-Inh. They shed further light on the mechanism of action of the anti-C1-Inh autoantibodies providing some evidence that they bind epitope(s) within or nearby the reactive site of C1-Inh. Evidence that the epitopes recognized by anti-C1-Inh autoantibodies mapped around its reactive center was brought by different authors (Mandle et al., 1994; Donaldson et al., 1996; He et al., 1996). In one patient Mandle et al. (1994) showed that the autoantibody bound to C1-Inh reactive center (residues 430– 441) sterically inhibiting the interaction of C1-Inh with the activated C1s. In this patient C1-Inh was not cleaved. He et al. (1996) studied the autoantibodies of 6 AAE patients with 3 synthetic peptides and found that the autoantibodies recognized 2 peptides which spanned the reactive center of C1-Inh. They concluded that there are 2 potential epitopes in C1-Inh capable of binding to C1-Inh autoantibodies. The autoantibodies to C1-Inh bind native and cleaved C1-Inh with different affinities. This was clearly demonstrated by two patients: one had ten times more C1-Inh –anti-C1-Inh complexes than the other, who had four times higher titer and an almost identical concentration of C1-Inh in its plasma (Alsenz and Loos, 1989). Agostoni and Cicardi (1992) called attention on the fact that anti-C1-Inh autoantobodies do not explain massive C1 activation. This is understandable if a dis-

ease associated with AAE causes massive C1 activation first and C1-Inh consumption as a secondary event. But anti-C1-Inh autoantibodies, theoretically, should consume C1-Inh first, creating a condition very similar to HAE where C1 is normal. Thus, other still unknown factor(s) or maybe the autoantibody-C1-Inh immunecomplex should intervene producing massive C1 consumption.

3.2. The course of lymphoproliferati6e disorders The existence of a close relationship between AAE and B cell proliferation has been clear since the first description of this syndrome. Introduction of the distinction between AAE type I and type II suggested that the latter was characterized by absence of associated lymphoproliferative disease. Such a clear-cut distinction does not actually reflect the high degree of variability among patients, particularly without a clear definition of what is considered as lymphoprolyferative disease. If we limit this term to clinically overt lymphoma or CLL, very few cases of AAE with autoantibodies to C1-Inh occur in association (Holme and Whaley, 1990; Chevailler et al., 1996). On the other hand, an apparently benign monoclonal gammopathy (sign of a minor B cell clonal proliferation) is present in most of the patients with AAE and anti-C1-Inh autoantibodies. Thus, the limits between the 2 AAE subtypes are blurred. During the past 24 years, we observed 19 subjects with AAE: and 16 of them have an autoantibody to C1-Inh. The key question in this disease is whether B cell clones producing autoantibodies to C1-Inh tend to become neoplastic. Four of our 19 patients developed overt lymphoproliferative diseases (1 CLL, 1 Waldenstro¨ m disease, 2 NHL), but we have no evidence that the neoplastic clone originate from those producing immunoglobulins against C1-Inh.

3.3. The therapy The therapeutic approach to AAE patients is empiric due to the fact that reports are scattered, sometimes conflicting and always based on one or few patients. However, based on the literature and on our own experience, it is possible to summarize the therapy of AAE diving it into attempts to remove the cause of C1-Inh deficiency and attempts to prevent or to revert symptoms. (1) Cure of the underlying disease has induced the clinical remission of angioedema symptoms, with partial correction of complement abnormalities in several cases (Gelfand et al., 1979; Hauptmann et al., 1979; Cicardi et al., 1985; Rodriguez et al., 1988). Immunosuppressive regimens (cyclophosfamide, alone or with steroids) have been successful in suppressing anti-C1-

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

Inh autoantibodies in isolated cases of patients with AAE and overt lymphoproliferative disease (Jackson et al., 1989; Donaldson et al., 1992; Wasserfallen et al., 1995; Chevailler et al., 1996). This kind of therapy should be carefully weighted considering the possible side effects of immunosuppression: it is highly questionable its indication and efficacy in absence of malignancy (Ordi-Ros et al., 1997). (2) Long term prophylaxis with attenuated androgens (Danazol/Stanozolol) increases C1-Inh plasma levels and effectively cures HAE, while this approach is usually ineffective in AAE patients with autoantibodies to C1-Inh. It is likely that the increased production of C1-Inh stimulated by androgens is immediately neutralized by the autoantibodies. In some patients normalization of complement parameters along with clinical effectiveness has been initially registered (Hauptmann et al., 1977; Frigas, 1989; Bain et al., 1993; Chevailler et al., 1996; Malcolm and Prather, 1999; Bouillet et al., 2000). These patients usually develop a kind of refractoriness to the treatment within the following months (Cohen and Koethe, 1978; Cohen et al., 1978; Nilsen and Matre, 1980; Cicardi et al., 1993). Long term prophylaxis with antifibrinolytic agents (tranexamic acid) seems the first choice for AAE (Gelfand et al., 1979; Cicardi et al., 1985). Since these drugs do not relay on C1-Inh levels, their efficacy is not influenced by its rapid catabolism. Their mechanism of action is not fully understood. Patients with AAE have signs of activation of fibrinolysis already in basal conditions, and tranexamic acid could counteract this situation by its antiplasmin activity (Cugno et al., 1994). Attention should be paid to patients with concomitant cardiovascular risk. In two of our patients, who were in prophylaxis with tranexamic acid, it has been necessary to associate oral anticoagulant therapy to lower the thrombotic risk. (3) As in HAE, C1-Inh concentrate remains the treatment of choice for life-threatening attacks also in AAE patients. The response has been always favorable in our experience. However some patient with autoantibodies becomes highly resistant and the doses have to be increased several times in order to obtain a clinical response. In one of these patients we obtained the clinical response injecting 12,000 U of concentrate and still without detecting any significant increase of C1-Inh activity in plasma. Autoantibodies neutralizing C1-Inh are likely to be responsible for this behavior.

References Agostoni, A., Bergamaschini, L., Martignoni, G., Cicardi, M., Marasini, B., 1980a. Treatment of acute attacks of hereditary angioedema with C1-inhibitor concentrate. Ann. Aller. 44, 299 – 301.

169

Agostoni, A., Cicardi, M., 1992. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 71, 206 – 215. Agostoni, A., Cicardi, M., Martignoni, G.C., Bergamaschini, L., Marasini, B., 1980b. Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. J. Aller. Clin. Immunol. 65, 75 – 79. Alsenz, J., Bork, K., Loos, M., 1987. Autoantibody-mediated acquired deficiency of C1 inhibitor. N. Engl. J. Med. 316, 1360 – 1366. Alsenz, J., Lambris, J.D., Bork, K., Loos, M., 1989. Acquired C1 inhibitor (C1-Inh) deficiency type II. Replacement therapy with C1-INH and analysis of patients’ C1-INH and anti-C1-INH autoantibodies. J. Clin. Invest. 83, 1794 – 1799. Alsenz, J., Loos, M., 1989. The acquired C1-INH deficiencies with autoantibodies (AAE type II). Behring Inst Mitt 165 – 172. Andriole, G.L., Brickman, C., Lack, E.E., Sesterhenn, I.A., Javadpour, N., Linehan, W.M., Frank, M.M., 1986. Danazol-induced cystitis: an undescribed source of hematuria in patients with hereditary angioneurotic edema. J. Urol. 135, 44 – 46. Ariga, T., Carter, P.E., Davis, A.E.d., 1990. Recombinations between Alu repeat sequences that result in partial deletions within the C1 inhibitor gene. Genomics 8, 607 – 613. Ariga, T., Igarashi, T., Ramesh, N., Parad, R., Cicardi, M., Davis, A.E.d., 1989. Type I C1 inhibitor deficiency with a small messenger RNA resulting from deletion of one exon. J. Clin. Invest. 83, 1888 – 1893. Atkinson, J.P., 1979. Diagnosis and management of hereditary angioedema (HAE). Ann. Aller. 42, 348 – 352. Aulak, K.S., Cicardi, M., Harrison, R.A., 1990. Identification of a new P1 residue mutation (444Arg — Ser) in a dysfunctional C1 inhibitor protein contained in a type II hereditary angioedema plasma. FEBS Lett. 266, 13 – 16. Aulak, K.S., Eldering, E., Hack, C.E., Lubbers, Y.P., Harrison, R.A., Mast, A., Cicardi, M., Davis, A.E.d., 1993. A hinge region mutation in C1-inhibitor (Ala436 “ Thr) results in nonsubstratelike behavior and in polymerization of the molecule. J. Biol. Chem. 268, 18088 – 18094. Aulak, K.S., Harrison, R.S., 1990. Rapid and sensitive techniques for identification and analysis of ‘reactive-centre’ mutants of C1-inhibitor proteins contained in type II hereditary angio-oedema plasmas. Biochem. J. 271, 565 – 569. Bain, B.J., Catovsky, D., Ewan, P.W., 1993. Acquired angioedema as the presenting feature of lymphoproliferative disorders of mature B-lymphocytes. Cancer 72, 3318 – 3322. Barakat, A., Castaldo, A.J., 1993. Hereditary angioedema: danazol therapy in a 5-year-old child. Am. J. Dis. Child. 147, 931 –932 Letter. Binkley, K.E., Davis III, A.E., 2000. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J. Allergy Clin. Immunol. 106, 546 –550. Bissler, J.J., Aulak, K.S., Donaldson, V.H., Rosen, F.S., Cicardi, M., Harrison, R.A., Davis, A.E. III, 1997. Molecular defects in hereditary angioneurotic edema. Proc. Assoc. Am. Phys. 109, 164 –173. Blohme, G., 1972. Treatment of hereditary angioneurotic oedema with tranexamic acid. A random double-blind cross-over study. Acta Med. Scand. 192, 293 – 298. Bock, S.C., Skriver, K., Nielsen, E., Thogersen, H.C., Wiman, B., Donaldson, V.H., Eddy, R.L., Marrinan, J., Radziejewska, E., Huber, R., et al., 1986. Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization. Biochemistry 25, 4292 – 4301. Bork, K., Barnstedt, S.E., 2001. Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema. Arch. Intern. Med. 161, 714 – 718. Bork, K., Barnstedt, S.-E., Kock, P., Traupe, H., 2000. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356, 213 – 217.

170

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

Bork, K., et al., 1999. Hepatocellular adenomas in patients taking danazol for hereditary angiooedema. Lancet 353, 1066 –1067. Bouillet, L., Ponard, D., Drouet, C., Dumestre, C., Pernollet, M., Bonerandi, J.J., Caillaud, D., D’Incan, M., Hacini, M., Harle, J.R., de Wazieres, B., Colomb, M., Massot, C., 2000. Acquired angioneurotic edema. Clinical and biological characteristics in 9 patients. Presse Med. 29, 640 –644. Branco-Ferreira, M., Pedro, E., Barbosa, M.A., Carlos, A.G., 1998. Ascites in hereditary angioedema. Allergy 53, 543 –545. Bretza, J.A., Novey, H.S., Vaziri, N.D., Warner, A.S., 1980. Hypertension: a complication of danazol therapy. Arch. Intern. Med. 140, 1379 – 1380. Caldwell, J.R., Ruddy, S., Schur, P.H., Austen, K.F., 1972. Acquired C1 inhibitor deficiency in lymphosarcoma. Clin. Immunol. Immunopathol. 1, 39– 52. Carter, P.E., Dunbar, B., Fothergill, J.E., 1988. Genomic and cDNA cloning of the human C1 inhibitor. Intron-exon junctions and comparison with other serpins. Eur. J. Biochem. 173, 163 – 169. Carter, P.E., Duponchel, C., Tosi, M., Fothergill, J.E., 1991. Complete nucleotide sequence of the gene for human C1 inhibitor with an unusually high density of Alu elements. Eur. J. Biochem. 197, 301 – 308. Casali, P., Borzini, P., Pioltelli, P., Invernizzi, F., Zanussi, C., 1978. Acquired C1-inhibitor deficiency in essential cryoglobulinemia and macrocryoglobulinemia. Acta Haematol. 59, 277 – 284. Chevailler, A., Arlaud, G., Ponard, D., Pernollet, M., Carrere, F., Renier, G., Drouet, M., Hurez, D., Gardais, J., 1996. C-1-inhibitor binding monoclonal immunoglobins in three patients with acquired angioneurotic edema. J. Aller. Clin. Immunol. 97, 998 – 1008. Cicardi, M., Beretta, A., Colombo, M., Gioffre, D., Cugno, M., Agostoni, A., 1996. Relevance of lymphoproliferative disorders and of anti-C1 inhibitor autoantibodies in acquired angiooedema. Clin. Exp. Immunol. 106, 475 – 480. Cicardi, M., Bergamaschini, L., Cugno, M., Hack, E., Agostoni, G., Agostoni, A., 1991. Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience. J. Aller. Clin. Immunol. 87, 768 – 773. Cicardi, M., Bisiani, G., Cugno, M., Spath, P., Agostoni, A., 1993. Autoimmune C1 inhibitor deficiency: report of eight patients. Am. J. Med. 95, 169 – 175. Cicardi, M., Castelli, R., Zingale, L.C., Agostoni, A., 1997. Side effects of long-term prophylaxis with attenuated androgens in hereditary angioedema: comparison of treated and untreated patients. J. Aller. Clin. Immunol. 99, 194 –196. Cicardi, M., Frangi, D., Bergamaschini, L., Gardinali, M., Sacchi, G., Agostoni, A., 1985. Acquired C1 inhibitor deficiency with angioedema symptoms in a patient infected with Echinococcus granulosus. Complement 2, 133–139. Cicardi, M., Igarashi, T., Kim, M.S., Frangi, D., Agostoni, A., Davis, A.E.d., 1987a. Restriction fragment length polymorphism of the C1 inhibitor gene in hereditary angioneurotic edema. J. Clin. Invest. 80, 1640 –1643. Cicardi, M., Igarashi, T., Rosen, F.S., Davis, A.E.d., 1987b. Molecular basis for the deficiency of complement 1 inhibitor in type I hereditary angioneurotic edema. J. Clin. Invest. 79, 698 –702. Cicardi, M., Mannucci, P.M., Castelli, R., Rumi, M.G., Agostoni, A., 1995. Reduction in transmission of hepatitis C after the introduction of a heat-treatment step in the production of C1-inhibitor concentrate. Transfusion 35, 209 – 212 See comments. Cohen, S.H., Koethe, S.M., 1978. Danazol and C1 esterase inhibitor deficiency. Ann. Intern. Med. 88, 429 Letter. Cohen, S.H., Koethe, S.M., Kozin, F., Rodey, G., Arkins, J.A., Fink, J.N., 1978. Acquired angioedema associated with rectal carcinoma and its response to danazol therapy. Acquired angioedema treated with danazol. J. Aller. Clin. Immunol. 62, 217 – 221.

Crampon, D., Barnoud, R., Durand, M., Ponard, D., Jacquot, C., Sotto, J.J., Letoublon, C., Zarski, J.P., 1998. Danazol therapy: an unusual aetiology of hepatocellular carcinoma. J. Hepatol. 29, 1035 – 1036 Letter. Crowder, J.R., Crowder, T.R., 1917. Five generations of angioneurotic edema. Arch. Inter. Med. 20, 840 – 852. Cugno, M., Cicardi, M., Agostoni, A., 1994. Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid. J. Aller. Clin. Immunol. 93, 870 – 876. Cugno, M., Hack, C.E., de Boer, J.P., Eerenberg, A.J., Agostoni, A., Cicardi, M., 1993. Generation of plasmin during acute attacks of hereditary angioedema. J. Lab. Clin. Med. 121, 38 – 43. Davis, A.E.d., 1988. C1 inhibitor and hereditary angioneurotic edema. Annu. Rev. Immunol. 6, 595 – 628. Davis, A.E.d., Aulak, K., Parad, R.B., Stecklein, H.P., Eldering, E., Hack, C.E., Kramer, J., Strunk, R.C., Bissler, J., Rosen, F.S., 1992. C1 inhibitor hinge region mutations produce dysfunction by different mechanisms. Nat. Genet. 1, 354 – 358. Davis A.E.d., Bissler J.J., Cicardi M., 1993. Mutations in the C1 inhibitor gene that result in hereditary angioneurotic edema. Behring Inst Mitt 313 – 320. Davis, A.E.d., Whitehead, A.S., Harrison, R.A., Dauphinais, A., Bruns, G.A., Cicardi, M., Rosen, F.S., 1986. Human inhibitor of the first component of complement, C1: characterization of cDNA clones and localization of the gene to chromosome 11. Proc. Natl. Acad. Sci. USA 83, 3161 – 3165. Davis, T.L., Firulli, A.B., Kinniburgh, A.J., 1989. Ribonucleoprotein and protein factors bind to an H-DNA-forming c-myc DNA element: possible regulators of the c-myc gene. Proc. Natl. Acad. Sci. USA 86, 9682 – 9686. D’Incan, M., Tridon, A., Ponard, D., Dumestre-Perard, C., FerrierLe Bouedec, M., Betail, G., Souteyrand, P., Caillaud, D., 1999. Acquired angioedema with C1 inhibitor deficiency: is the distinction between type I and type II still relevant? Dermatology 199, 227 – 230. Dinkel, H.P., Maroske, J., Schrod, L., 2001. Sonographic appearances of the abdominal manifestations of hereditary angioedema. Pediatr. Radiol. 31, 296 – 298. Donaldson, V.H., Bernstein, D.I., Wagner, C.J., Mitchell, B.H., Scinto, J., Bernstein, I.L., 1992. Angioneurotic edema with acquired C1-inhibitor deficiency and autoantibody to C1-inhibitor: response to plasmapheresis and cytotoxic therapy. J. Lab. Clin. Med. 119, 397 – 406. Donaldson, V.H., Evans, R.R., 1963. A biochemical abnormality in herediatry angioneurotic edema: absence of serum inhibitor of C% 1-esterase. Am. J. Sci. 31, 37 – 44. Donaldson, V.H., Rosen, F.S., Bing, D.H., 1977. Role of the second component of complement (C2) and plasmin in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma. Trans. Assoc. Am. Phys. 90, 174 – 183. Donaldson, V.H., Wagner, C.J., Davis, A.E. III, 1996. An autoantibody to C1-inhibitor recognizes the reactive center of the inhibitor. J. Lab. Clin. Med. 127, 229 – 232. Douglas, C.H., Blitzer, J.R., 1957. Familial paroxismal dysfunction of the autonomic nervous system (a periodic disease), often precipitated by emotional stress. Pediatrics 18, 782 – 793. Duponchel, C., Di Rocco, C., Cicardi, M., Tosi, M., 2001. Rapid detection by fluorescent multiplex PCR of exon deletions and duplications in the C1 inhibitor gene of hereditary angioedema patients. Hum. Mutat. 17, 61 – 70. Eggert, J., Zachariae, H., Svejgaard, E., Svejgaard, A., KissmeyerNielsen, F., 1982. Hereditary angioneurotic edema and HLA types in two Danish families. Arch. Dermatol. Res. 273, 347 –348. Falus, A., Feher, K.G., Walcz, E., Brozik, M., Fust, G., Hidvegi, T., Feher, T., Meretey, K., 1990a. Hormonal regulation of complement biosynthesis in human cell lines – I. Androgens and g-inter-

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173 feron stimulate the biosynthesis and gene expression of C1 inhibitor in human cell lines U937 and HepG2. Mol. Immunol. 27, 191 – 195. Falus, A., Rokita, H., Walcz, E., Brozik, M., Hidvegi, T., Meretey, K., 1990b. Hormonal regulation of complement biosynthesis in human cell lines – II. Upregulation of the biosynthesis of complement components C3, factor B and C1 inhibitor by interleukin-6 and interleukin-1 in human hepatoma cell line. Mol. Immunol. 27, 197 – 201. Farrell, G.C., Joshua, D.E., Uren, R.F., Baird, P.J., Perkins, K.W., Kronenberg, H., 1975. Androgen-induced hepatoma. Lancet 1, 430 – 432. Ford, I., Li, T.C., Cooke, I.D., Preston, F.E., 1994. Changes in haematological indices, blood viscosity and inhibitors of coagulation during treatment of endometriosis with danazol. Thromb. Haemost. 72, 218 – 221. Frangi, D., Aulak, K.S., Cicardi, M., Harrison, R.A., Davis, A.E.d., 1992. A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444 “ Leu). FEBS Lett. 301, 34 –36. Frangi, D., Cicardi, M., Sica, A., Colotta, F., Agostoni, A., Davis, A.E.d., 1991. Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema. J. Clin. Invest. 88, 755 –759. Frank, M.M., Gelfand, J.A., Atkinson, J.P., 1976. Hereditary angioedema: the clinical syndrome and its management. Ann. Intern. Med. 84, 580 – 593. Frank, M.M., Sergent, J.S., Kane, M.A., Alling, D.W., 1972. Epsilon aminocaproic acid therapy of hereditary angioneurotic edema. A double-blind study. N. Engl. J. Med. 286, 808 –812. Frigas, E., 1989. Angioedema with acquired deficiency of the C1 inhibitor: a constellation of syndromes. Mayo. Clin. Proc. 64, 1269 – 1275. Gadek, J.E., Hosea, S.W., Gelfand, J.A., Santaella, M., Wickerhauser, M., Triantaphyllopoulos, D.C., Frank, M.M., 1980. Replacement therapy in hereditary angioedema: successful treatment of acute episodes of angioedema with partly purified C1 inhibitor. N. Engl. J. Med. 302, 542 –546. Geha, R.S., Quinti, I., Austen, K.F., Cicardi, M., Sheffer, A., Rosen, F.S., 1985. Acquired C1-inhibitor deficiency associated with antiidiotypic antibody to monoclonal immunoglobulins. N. Engl. J. Med. 312, 534 – 540. Gelfand, J.A., Boss, G.R., Conley, C.L., Reinhart, R., Frank, M.M., 1979. Acquired C1 esterase inhibitor deficiency and angioedema: a review. Medicine (Baltimore) 58, 321 –328. Gelfand, J.A., Sherins, R.J., Alling, D.W., Frank, M.M., 1976. Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N. Engl. J. Med. 295, 1444 – 1448. Hamilton, A.O., Jones, L., Morrison, L., Whaley, K., 1987. Modulation of monocyte complement synthesis by interferons. Biochem. J. 242, 809 – 815. Harrison, R.A., 1983. Human C1 inhibitor: improved isolation and preliminary structural characterization. Biochemistry 22, 5001 – 5007. Hauptmann, G., Lang, J.M., North, M.L., Oberling, F., Mayer, G., Lachmann, P., 1976. Acquired c1-inhibitor deficiencies in lymphoproliferative diseases with serum immunoglobulin abnormalities. A study of three cases. Blut 32, 195 – 206. Hauptmann, G., Lang, J.M., North, M.L., Oberling, F., Mayer, G., Lachmann, P.J., 1975. Lymphosarcoma, cold urticaria, IgG1 monoclonal cryoglobulin and complement abnormalities. Scand. J. Haematol. 15, 22 – 26. Hauptmann, G., Mayer, S., Lang, J.M., Oberling, F., Mayer, G., 1977. Treatment of acquired C1-inhibitor deficiency with danazol. Ann. Intern. Med. 87, 577 –578. Hauptmann, G., Petitjean, F., Lang, J.M., Oberling, F., 1979. Acquired C1 inhibitor deficiency in a case of lymphosarcoma of the

171

spleen. Reversal of complement abnormalities after splenectomy. Clin. Exp. Immunol. 37, 523 – 531. He, S., Tsang, S., North, J., Chohan, N., Sim, R.B., Whaley, K., 1996. Epitope mapping of C1 inhibitor autoantibodies from patients with acquired C1 inhibitor deficiency. J. Immunol. 156, 2009 – 2013. Heda, G.D., Mardente, S., Weiner, L., Schmaier, A.H., 1990. Interferon-g increases in vitro and in vivo expression of C1 inhibitor. Blood 75, 2401 – 2407. Holme, E.R., Whaley, K., 1990. Monoclonal antibodies to C1 inhibitor in acquired angioedema. Complement Inflam. 7, 144. Hosea, S.W., Frank, M.M., 1980. Danazole in the treatment of hereditary angioedema. Drugs 19, 370 – 372. Ishak, K.G., Zimmerman, H.J., 1987. Hepatotoxic effects of the anabolic/androgenic steroids. Semin. Liver. Dis. 7, 230 –236. Jackson, J., Feighery, C., 1988. Autoantibody-mediated acquired deficiency of C1 inhibitor. N. Engl. J. Med. 318, 122 – 123 Letter. Jackson, J., Sim, R.B., Whaley, K., Feighery, C., 1989. Autoantibody facilitated cleavage of C1-inhibitor in autoimmune angioedema. J. Clin. Invest. 83, 698 – 707. Jackson, J., Sim, R.B., Whelan, A., Feighery, C., 1986. An IgG autoantibody which inactivates C1-inhibitor. Nature 323, 722 – 724. Johnson, F.L., Lerner, K.G., Siegel, M., Feagler, J.R., Majerus, P.W., Hartmann, J.R., Thomas, E.D., 1972. Association of androgenic-anabolic steroid therapy with development of hepatocellular carcinoma. Lancet 2, 1273 – 1276. Katz, Y., Strunk, R.C., 1989. Synthesis and regulation of C1 inhibitor in human skin fibroblasts. J. Immunol. 142, 2041 –2045. Kramer, J., Katz, Y., Rosen, F.S., Davis, A.E.d., Strunk, R.C., 1991. Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema. J. Clin. Invest. 87, 1614 – 1620. Kunschak, M., Engl, W., Maritsch, F., Rosen, F.S., Eder, G., Zerlauth, G., Schwarz, H.P., 1998. A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 38, 540 – 549. Lappin, D.F., Guc, D., Hill, A., McShane, T., Whaley, K., 1992. Effect of interferon-g on complement gene expression in different cell types. Biochem. J. 281, 437 – 442. Lappin, D.F., McPhaden, A.R., Yap, P.L., Carter, P.E., Birnie, G.D., Fothergill, J.E., Whaley, K., 1989. Monocyte C1-inhibitor synthesis in patients with C1-inhibitor deficiency. Eur. J. Clin. Invest. 19, 45 – 52. Laurent, J., Guinnepain, M.T., 1996. Hereditary angioedema with ascites. J. Aller. Clin. Immunol. 98, 999 Letter; comment. Lener, M., Vinci, G., Duponchel, C., Meo, T., Tosi, M., 1998. Molecular cloning, gene structure and expression profile of mouse C1 inhibitor. Eur. J. Biochem. 254, 117 – 122. Levy, L.R., Lepow, I.H., 1959. Assay and properties of serum inhibitor of C1 esterase. Proc. Soc. Exp. Biol. Med. 101, 608 –611. Levy, N.J., Ramesh, N., Cicardi, M., Harrison, R.A., Davis, A.E.d., 1990. Type II hereditary angioneurotic edema that may result from a single nucleotide change in the codon for alanine-436 in the C1 inhibitor gene. Proc. Natl. Acad. Sci. USA 87, 265 –268. Malbran, A., Hammer, C.H., Frank, M.M., Fries, L.F., 1988. Acquired angioedema: observations on the mechanism of action of autoantibodies directed against C1 esterase inhibitor. J. Aller. Clin. Immunol. 81, 1199 – 1204. Malcolm, A., Prather, C.M., 1999. Intestinal angioedema mimicking Crohn’s disease. Med. J. Aust. 171, 418 – 420. Mandle, R., Baron, C., Roux, E., Sundel, R., Gelfand, J., Aulak, K., Davis, A.E. III, Rosen, F.S., Bing, D.H., 1994. Acquired C1 inhibitor deficiency as a result of an autoantibody to the reactive center region of C1 inhibitor. J. Immunol. 152, 4680 – 4685. Marasini, B., Cicardi, M., Martignoni, G.C., Agostoni, A., 1978. Treatment of hereditary angioedema. Klin. Wochenschr. 56, 819 – 823.

172

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173

McPhaden, A.R., Birnie, G.D., Whaley, K., 1991. Restriction fragment length polymorphism analysis of the C1-inhibitor gene in hereditary C1-inhibitor deficiency. Clin. Genet. 39, 161 – 171. Melamed, J., Alper, C.A., Cicardi, M., Rosen, F.S., 1986. The metabolism of C1 inhibitor and C1q in patients with acquired C1inhibitor deficiency. J. Aller. Clin. Immunol. 77, 322 –326. Morris, G.E., Slavin, B.M., Browse, N.L., 1987. Hereditary angioneurotic oedema: a neglected diagnosis. J. Clin. Pathol. 40, 516 – 517. Nielsen, E.W., Johansen, H.T., Holt, J., Mollnes, T.E., 1994. C1 inhibitor and diagnosis of hereditary angioedema in newborns. Pediatr. Res. 35, 184 –187. Nilsen, A., Matre, R., 1980. Acquired angioedema and hypocompleentemia in a patient with myelofibrosis. Effect of danazol treatment. Acta Med. Scand. 207, 123 – 125. Nilsson, T., Back, O., 1985. Elevated plasmin-a 2-antiplasmin complex levels in hereditary angioedema: evidence for the in vivo efficiency of the intrinsic fibrinolytic system. Thromb. Res. 40, 817 – 821. Oberling, F., Hauptmann, G., Lang, J.M., Bergerat, J.P., Mayer, G., Batzenschlager, A., Hammann, B., Gillet, B., 1975. Acquired C1-esterase inhibitor deficiencies during lymphoid syndromes. Nouv. Presse. Med. 4, 2705 –2708. Ocejo-Vinyals, J.G., Leyva-Cobian, F., Fernandez-Luna, J.L., 1995. A mutation unique in serine protease inhibitors (serpins) identified in a family with type II hereditary angioneurotic edema. Mol. Med. 1, 700 – 705. Ohela, K., Tiilikainen, A., Kaakinen, A., Rasanen, J., 1977. Hereditary angioneurotic edema (HANE): lack of close linkage between HLA haplotypes and C1 esterase inhibitor deficiency. Tissue Antigens 9, 90 – 95. Ordi-Ros, J., Paredes, J., Detarsio, G., Vilardell, M., 1997. Autoantibodies to C1 inhibitor in patients with lupus disease. J. Rheumatol. 24, 1856 – 1858 Letter. Osler, W., 1888. Hereditary angio-neurotic oedema. Am. J. Med. Sci. 95, 362 – 367. Pappalardo, E., Cicardi, M., Duponchel, C., Carugati, A., Choquet, S., Agostoni, A., Tosi, M., 2000. Frequent de novo mutations and exon deletions in the C1-inhibitor gene of patients with angioedema. J. Aller. Clin. Immunol. 106, 1147 –1154. Parad, R.B., Kramer, J., Strunk, R.C., Rosen, F.S., Davis, A.E.d., 1990. Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site. Proc. Natl. Acad. Sci. USA 87, 6786 – 6790. Pensky, J., Levy, L.R., Lepow, I.H., 1961. Partial purification of a serum inhibitor of C1 esterase. J. Biol. Chem. 236, 1674 – 1679. Pickering, R.J., Good, R.A., Kelly, J.R., Gewurz, H., 1969. Replacement therapy in hereditary angioedema. Successful treatment of two patients with fresh frozen plasma. Lancet 1, 326 –330. Pitts, J.S., Donaldson, V.H., Forristal, J., Wyatt, R.J., 1978. 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. J. Lab. Clin. Med. 92, 501 –507. Robson, E.B., Lachmann, P.J., Hobart, M.J., Johnston, A.W., 1979. Linkage studies in hereditary angio-oedema. J. Med. Genet. 16, 347 – 350. Rodriguez, M., Ancochea, J., De Buen, C., Merino, J.L., Marques, G., Vivanco, F., 1988. Acquired C1-inhibitor deficiency associated with a lupus-like anticoagulant activity. Annu. Aller. 61, 348 – 350. Rosen, F.S., Pensky, J., Donaldson, V., Charache, P., 1965. Hereditary angioneurotic edema: two genetic variants. Science 148, 957 – 958. Russell, J.A., Whaley, K., Heaphy, S., 1997. The sequence of a cDNA encoding functional murine C1-inhibitor protein. Biochim. Biophys. Acta 1352, 156 –160.

Schifferli, J.A., Pascual, M., Steiger, G., Schapira, M., Ryser, J.E., Estreicher, J., Dash, A., 1987. Fast liver catabolism of C1q in patients with paraproteinaemia and depletion of the classical pathway of complement. Clin. Exp. Immunol. 69, 188 – 197. Schreiber, A.D., Zweiman, B., Atkins, P., Goldwein, F., Pietra, G., Atkinson, B., Abdou, N.I., 1976. Acquired angioedema with lymphoproliferative disorder: association of C1 inhibitor deficiency with cellular abnormality. Blood 48, 567 – 580. Shah, T.J., Knowles, W.O., McGeady, S.J., 1995. Hereditary angioedema with recurrent abdominal pain and ascites. J. Aller. Clin. Immunol. 96, 259 – 261 See comments. Sheffer, A.L., Austen, K.F., Rosen, F.S., 1972. Tranexamic acid therapy in hereditary angioneurotic edema. N. Engl. J. Med. 287, 452 – 454. Sheffer, A.L., Fearon, D.T., Austen, K.F., 1977. Methyltestosterone therapy in hereditary angioedema. Ann. Intern. Med. 86, 306 – 308. Sheffer, A.L., Fearon, D.T., Austen, K.F., 1987. Hereditary angioedema: a decade of management with stanozolol. J. Aller. Clin. Immunol. 80, 855 – 860. Siddique, Z., McPhaden, A.R., Lappin, D.F., Whaley, K., 1991. An RNA splice site mutation in the C1-inhibitor gene causes type I hereditary angio-oedema. Hum. Genet. 88, 231 – 232. Siddique, Z., McPhaden, A.R., Whaley, K., 1992. Type II hereditary angio-oedema associated with two mutations in one allele of the C1-inhibitor gene around the reactive-site coding region. Hum. Hered. 42, 298 – 301. Skriver, K., Radziejewska, E., Silbermann, J.A., Donaldson, V.H., Bock, S.C., 1989. CpG mutations in the reactive site of human C1 inhibitor. J. Biol. Chem. 264, 3066 – 3071. Skriver, K., Wikoff, W.R., Patston, P.A., Tausk, F., Schapira, M., Kaplan, A.P., Bock, S.C., 1991. Substrate properties of C1 inhibitor Ma (alanine 434 —glutamic acid). Genetic and structural evidence suggesting that the P12-region contains critical determinants of serine protease inhibitor/substrate status. J. Biol. Chem. 266, 9216 – 9221. Sofia, S., Casali, A., Bolondi, L., 1999. Sonographic findings in abdominal hereditary angioedema. J. Clin. Ultrasound 27, 537 – 540. Spaulding, W.B., 1960. Methyltestosterone therapy for hereditary episodic edema (hereditary angioneurotic edema). Ann. Intern. Med. 53, 739 – 745. Stewart, G.J., Basten, A., Kirk, R.L., Serjeantson, S.W., 1979. Hereditary angioedema: lack of close linkage with markers on chromosome 6, with data on other markers. Clin. Genet. 16, 369 –375. Stoppa-Lyonnet, D., Carter, P.E., Meo, T., Tosi, M., 1990. Clusters of intragenic Alu repeats predispose the human C1 inhibitor locus to deleterious rearrangements. Proc. Natl. Acad. Sci. USA 87, 1551 – 1555. Stoppa-Lyonnet, D., Duponchel, C., Meo, T., Laurent, J., Carter, P.E., Arala-Chaves, M., Cohen, J.H., Dewald, G., Goetz, J., Hauptmann, G., et al., 1991. Recombinational biases in the rearranged C1-inhibitor genes of hereditary angioedema patients. Am. J. Hum. Genet. 49, 1055 – 1062. Stoppa-Lyonnet, D., Tosi, M., Laurent, J., Sobel, A., Lagrue, G., Meo, T., 1987. Altered C1 inhibitor genes in type I hereditary angioedema. N. Engl. J. Med. 317, 1 – 6 Published erratum appears in N. Engl. J. Med. 1987 Sep 3; 317(10), 641. Talavera, A., Larraona, J.L., Ramos, J.L., Lopez, T., Maraver, A., Arias, J., Barrios, A., 1995. Hereditary angioedema: an infrequent cause of abdominal pain with ascites. Am. J. Gastroenterol. 90, 471 – 474. Tosi, M., 1998. Molecular genetics of C1 inhibitor. Immunobiology 199, 358 – 365. Tosi, M., Duponchel, C., Bourgarel, P., Colomb, M., Meo, T., 1986. Molecular cloning of human C1 inhibitor: sequence homologies with a1-antitrypsin and other members of the serpins superfamily. Gene 42, 265 – 272.

A. Carugati et al. / Molecular Immunology 38 (2001) 161–173 Veit, V., Hardwigsen, J., Bernit, E., Gachon, J., Kaplanski, G., Schlienger, J.L., Le Treut, Y.P., Harle´ , J.R., 1999. Traitment par danazol, une e´ tiologie exceptionnelle d’he´ patocarcinome: a` propos d’une observation. Rev. Me´ d. Interne. 20, 634S. Verpy, E., Biasotto, M., Brai, M., Misiano, G., Meo, T., Tosi, M., 1996. Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema. Am. J. Hum. Genet. 59, 308 –319 See comments. Verpy, E., Biasotto, M., Meo, T., Tosi, M., 1994. Efficient detection of point mutations on color-coded strands of target DNA. Proc. Natl. Acad. Sci. USA 91, 1873 –1877. Verpy, E., Couture-Tosi, E., Eldering, E., Lopez-Trascasa, M., Spath, P., Meo, T., Tosi, M., 1995. Crucial residues in the carboxy-terminal end of C1 inhibitor revealed by pathogenic mutants impaired in secretion or function. J. Clin. Invest. 95, 350 –359. Warin, A.P., Greaves, M.W., Gatecliff, M., Williamson, D.M., Warin, R.P., 1980. Treatment of hereditary angio-oedema by low dose attenuated androgens: disassociation of clinical response from levels of C1 esterase inhibitor and C4. Br. J. Dermatol. 103, 405 – 409. Wasserfallen, J.B., Spaeth, P., Guillou, L., Pecoud, A.R., 1995. Acquired deficiency in C1-inhibitor associated with signet ring cell gastric adenocarcinoma: a probable connection of antitumor-associated antibodies, hemolytic anemia, and complement turnover. J. Aller. Clin. Immunol. 95, 124 –131. Waytes, A.T., Rosen, F.S., Frank, M.M., 1996. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N. Engl. J. Med. 334, 1630 –1634 See comments.

173

Whaley, K., Sim, R.B., He, S., 1996. Autoimmune C1-inhibitor deficiency. Clin. Exp. Immunol. 106, 423 – 426 Editorial. Zahedi, K., Prada, A.E., Davis, A.E. III, 1994. Transcriptional regulation of the C1 inhibitor gene by g-interferon. J. Biol. Chem. 269, 9669 – 9674. Zahedi, K., Prada, A.E., Prada, J.A., Davis, A.E. III, 1997a. Characterization of the IFN-g-responsive element in the 5% flanking region of the C1 inhibitor gene. J. Immunol. 159, 6091 – 6096. Zahedi, R., Bissler, J.J., Davis, A.E., Andreadis, C., Wisnieski, J.J. III, 1995. Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443 “Val substitution and functional analysis of the recombinant mutant protein. J. Clin. Invest. 95, 1299 – 1305. Zahedi, R., Wisnieski, J., Davis, A.E. III, 1997b. Role of the P2 residue of complement 1 inhibitor (Ala443) in determination of target protease specificity: inhibition of complement and contact system proteases. J. Immunol. 159, 983 – 988. Zuraw, B.L., Curd, J.G., 1986. Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients. J. Clin. Invest. 78, 567 – 575. Zuraw, B.L., Herschbach, J., 2000. Detection of C1 inhibitor mutations in patients with hereditary angioedema. J. Aller. Clin. Immunol. 105, 541 – 546. Zuraw, B.L., Lotz, M., 1990. Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon-g. J. Biol. Chem. 265, 12664 – 12670. Zurlo, J.J., Frank, M.M., 1990. The long-term safety of danazol in women with hereditary angioedema. Fertil. Steril. 54, 64 – 72.

.