New possibilities of treating acute angioedema caused by C1-inhibitor deficiency

The authors discuss diagnostic difficulties in 12 cases of hereditary angioneurotic edema due to C1-esterase inhibitor (C1-INH deficiency). Emphasis is on the treatment of the acute attacks with intravenous infusions of C1-inhibitor concentrate (Boehring, West Germany). This proved to be a very efficient and safe therapy, leading to a prompt disappearance of all clinical symptoms. Throughout 12 months following the infusions, indices of the liver function remained within the normal range, and anti-Hbs and anti-HIV tests were negative.     

Immunity markers in patients with Helicobacter pylori infection: effect of eradication

BACKGROUND: Helicobacter pylori is a microorganism able to stimulate a robust inflammatory and systemic immune response. AIM: The aim of our study was to evaluate autoimmune markers in dyspeptic patients positive for H. pylori infection compared to a control group of non-H. pylori-infected subjects. The kinetics of cryoglobulins and autoantibodies was evaluated after treatment of the infection. PATIENTS AND METHODS: Dyspeptic patients with active H. pylori infection and age- and sex-matched healthy H. pylori-negative controls were studied. Markers of immunity were compared, in H. pylori-infected patients before, 6 months and 1 year after the end of therapy. Results were also compared between those with and without successful eradication therapy. RESULTS: Eighty-six individual were entered (43 H. pylori-infected). H. pylori-infected patients had higher levels of IgG and/or IgA and/or IgM (22/43 versus 2/43). Circulating immune complexes and cryoglobulins were detected in patients more often than controls (p < .05 for both). Autoantibodies were observed in 13 patients (30% versus 5% in controls) and antithyroid antibodies in 12 (p < .04 versus controls). Lower levels of C3 and/or C4 complement fractions were observed in infected patients with respect to controls (7/43 versus 1/43; p = .014). After 1 year of follow-up, the markers of autoimmunity dramatically improved in patients eradicated for H. pylori infection compared to those in whom therapy failed. No patient developed a clinical autoimmune disorder. CONCLUSIONS: Additional studies are necessary to ascertain the clinical significance of the modifications of autoimmune markers in patients with H. pylori infection.     

Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry?

Autoimmune pancreatitis is a recently defined nosological entity, which accounts for 4.6-6% of all forms of chronic pancreatitis and is often associated with other autoimmune diseases, particularly Sjogren's syndrome. Possession of the HLA DRB1*0405-DQB1*0401 genotype confers a risk for the development of autoimmune pancreatitis. Autoantibodies against carbonic anhydrase II and lactoferrin are frequently present in affected subjects and are suspected to have a pathogenic role. A link between gastric infection by Helicobacter pylori and autoimmune pancreatitis has been hypothesized. We used in silico protein analysis and search for HLA binding motifs to verify this hypothesis. We found a significant homology between human carbonic anhydrase II and alpha-carbonic anhydrase of Helicobacter pylori, an enzyme which is fundamental for the survival and proliferation of the bacterium in the gastric environment. Moreover, the homologous segments contain the binding motif of the HLA molecule DRB1*0405. Our data strengthen the hypothesis that gastric Helicobacter pylori infection can trigger autoimmune pancreatitis in genetically predisposed subjects.     

A concept on the role of Helicobacter pylori infection in autoimmune pancreatitis

Autoimmune pancreatitis, an inflammatory process of the pancreas due to an autoimmune mechanism establishing etiology of chronic pancreatitis, is characterized by the presence of autoantibodies, hypergammaglobulinemia, pancreatic enlargement, pancreatic duct strictures, and pathologic features of fibrotic changes with intense, mainly lymphocytic infiltrations, which may contribute to tissue destruction probably by apoptosis. In almost 60% of the cases, this type of pancreatitis coexists with other autoimmune diseases such as Sjogren's syndrome, sclerosing extrahepatic cholangitis, primary biliary cirrhosis, autoimmune hepatitis, or other extrapancreatic disorders, and recently with gastric peptic ulceration. The diversity of extrapancreatic lesions with similar histopathologic findings suggests general involvement of the digestive system in this disease, although the presence of such involvement has not been fully elucidated. Similarly, Helicobacter pylori (H. pylori) infection, a well known cause of gastric ulcer, has been associated, via molecular mimicry of host structures by its constituents with the same autoimmune conditions, also characterized by fibrotic changes and/or lymphoplasmacytic inflammations, accompanied by aberrations of T cell apoptosis that contribute to hepatobiliary- or extrahepatic-tissue destruction. Considering that H. pylori is involved in the pathogenesis and pathophysiology of these autoimmune disorders, we propose that this organism might trigger autoimmune pancreatitis through induction of autoimmunity and apoptosis.     

Cytochrome P450 enzymes and UDP-Glucuronosyltransferases as hepatocellular autoantigens

Cytochromes P450 and UDP-Glucuronosyltransferases (UGT) are targets of microsomal autoantibodies in liver and kidney (LKM). LKM autoantibodies are observed in autoimmune hepatitis, in some patients with viral hepatitis, drug-induced hepatitis and autoimmune hepatitis as disease component of the autoimmune polyglandulars syndrome type 1 (APS-1). In autoimmune hepatitis LKM antibodies are markers of autoimmune hepatitis type 2. The major target of LKM-1 antibodies is cytochrome P450 2D6; a second less frequent target was the described UGTs of family 1. In autoimmune hepatitis LKM-1 autoantibodies are usually directed against small linear epitopes. LKM autoantibodies are also associated with infection with hepatitis viruses C and D. In hepatitis C about 1–2% of patients develop LKM-1 autoantibodies. About 60% of these autoantibodies are conformation dependent. The presence of LKM autoantibodies in hepatitis C may be associated with an increased risk in interferon treatment. LKM-3 autoantibodies are found in about 8% of patients with hepatitis D and are directed against conformational epitopes. Patients treated with certain drugs may develop drug induced hepatitis. In hepatitis induced by tienilic acid, tienilic acid is activated by and covalently bound to cytochrome P450 2C9. Activation of the immune system results in the formation of autoantibodies against cytochrome P450 2C9 (LKM-2) and infiltration of the liver with immune cells. A similar mechanism has been described for dihydralazine induced hepatitis, where autoantibodies are directed against P450 1A2 (LM). Autoantibodies directed against cytochrome P450 1A2 also are found in patients suffering from hepatitis as a disease component of APS-1.Abbreviations AIH autoimmune hepatitis - APS1 autoimmune polyendocrine syndrome type 1 - APS-1 autoimmune polyglandular syndrome type 1 - LKM microsomal autoantibodies in liver and kidney - HSV-1 herpes simplex virus type 1 - UGT UDP-glucuronosyltransferases     

The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders.

H. pylori infection is putatively associated with extra-digestive disorders and may also play a role in the development of autoimmune thyroid diseases (ATD). It was recently found that monoclonal antibodies to an H. pylori strain with cagA-positivity reacted with follicular cells of the thyroid gland, and that an H. pylori organism possessing the cag pathogenicity island carried a gene encoding for an endogenous peroxidase. The aims of this study was (1); To ascertain whether the infection by strains endowed with an increased inflammatory potential (those expressing CagA) could further enhance the risk of developing ATD (2); To verify the possible existence of an immune cross-reactivity between autoantibodies to peroxidase and thyroglobulin and H. pylori antigens (3). To establish whether thyroid colloid antigens could cross-react with an anti-H. pylori serum. The study was partly designed retrospectively. We examined 41 consecutive women with ATD, and, as a control, 33 consecutive age- and socio-economic class-matched women without autoimmune thyroid disorders, living in the same area as patients, occurred at the same institution in the same period (six months). Both patients and controls were examined serologically for H. pylori infection and CagA status by Western blotting. Some serum samples were absorbed with H. pylori to determine whether the antibody levels decreased. Colloid proteins were resolved electrophoretically and matched with a hyperimmune serum raised in rabbits against a CagA-positive H. pylori. Thirty-two patients (78.0%) tested seropositive for H. pylori infection, vs. 16 controls (48.4%) (P = 0.008, OR = 3.78, RR = 1.61). The prevalence of anti-CagA antibodies was 71.8% in infected patients, and 50% in infected controls (P = 0.161, n.s.). The overall prevalence of infection by CagA-positive H. pylori was significantly higher in patients with ATD (23/41, or 56.0%) than that in controls (8/33, or 24.2%) (P = 0.006, OR = 3.99, RR = 2.31). The other tests gave negative or inexplicable results. In conclusion: CagA-positive H. pylori infection increases the risk of ATD development.     

Antibody-independent activation of C1. I. Differences in the mechanism of C1 activation by nonimmune activators and by immune complexes: C1r-independent activation of C1s by cardiolipin vesicles

C1 activation is controlled by the regulatory protein C1-inhibitor (C1-INH). In contrast to immune-complex-induced activation, which is insensitive to C1-INH, antibody-independent activation of C1 is modulated by C1-INH. The mechanisms regulating nonimmune activation were studied with two phospholipids varying in their capacity to activate C1 in the presence of C1-INH: cardiolipin (CL) and phosphatidylglycerol (PG). Whereas C1-INH consistently suppressed activation by PG vesicles, a dose-dependent increase in C1 activation was measured with CL vesicles above 40 mole %. A similar dose-response binding of C1s requiring C1q, but not C1r, was detected only on CL vesicles, but neither on PG vesicles nor on immune complexes. This binding was Ca2+-dependent, suggesting that dimeric C1s is involved and was inhibited by spermine. The C1q-bound C1s was specifically cleaved at 37 degrees C into its active 58 kDa and 28 kDa chains, in the absence of C1r. On the addition of anti-CL antibodies, the C1q-mediated cleavage of C1s by CL vesicles was specifically inhibited. The cleavage of C1r on CL vesicles was also determined. When macromolecular C1 was offered in the presence of C1-INH, C1r cleavage was detected; however, the presence of C1s was a critical factor for C1r activation, because it was required on CL vesicles, but not on immune complexes. These results show that nonimmune activation of C1 presents specific features which distinguish it from immune complex-induced activation. These characteristics varied with the capacity of antibody-independent activators to activate C1 in the presence of C1-INH.     

Helicobacter pylori infection and skin diseases.

There is increasing evidence for systemic effects of gastric H. pylori infection which may result in extragastrointestinal disorders. This review summarizes the available medical literature up to September 1999, identified through a MEDLINE research including own studies, regarding H. pylori and skin diseases. Due to current knowledge best evidence for a potential link of H. pylori infection exists for chronic urticaria although the data are still conflicting. Thus, the search for H. pylori should be included in the diagnostic management of chronic urticaria. With regard to other skin diseases such as rosacea, hereditary or acquired angioedema due to C1-esterase inhibitor deficiency, systemic sclerosis, Sch?nlein-Henoch purpura, Sj?gren's syndrome, sweet's syndrome, and atopic dermatitis only single of few cases have been reported so far. Thus, we clearly need further randomized, double-blind and placebo-controlled studies including adequate diagnostic schedules, sufficient eradication treatment protocols, confirmation of eradication, and adequate control groups to establish a role of H. pylori in skin diseases. Caution must be taken not to accuse H. pylori as the infectious agent responsible for every disease, particularly since H. pylori infection is very common. Although from an epidemiological and morphological view the skin diseases to which H. pylori has been linked seem to be completely different it is striking that in most of them an autoimmune pathogenesis is suspected or considerable vascular impairment can be found.     

The humoral immuneresponse to Helicobacter pylori infection in children with gastrointestinal symptoms

The prevalence of Helicobacter pylori is high in Eastern Europe. The purpose of this study was to estimate the prevalence of H. pylori in symptomatic Lithuanian children and to identify the infection by clinicopathological and serological analyses. One hundred sixteen symptomatic children (age 8-16) with gastritis and duodenal ulcer were included. Biopsies were histologically assessed according to the Sydney-System. Serum IgG antibodies against H. pylori were detected by an enzyme-linked immunosorbent assay (ELISA), using low molecular mass antigen. The western blot technique was used to detect serum antibodies against the cytotoxin-associated protein (CagA) using whole cell antigen. Histologically the prevalence of H. pylori infection was 79% and not influenced by demographic factors. Mucosal inflammation and atrophy were associated with a H. pylori infection. Intestinal metaplasia was found in eight children, suggesting early H. pylori acquisition in life. Increased levels of IgG antibodies were detected in 57% of children. The prevalence of IgG antibodies was significantly higher in patients with duodenal ulcer compared to children with gastritis. Forty-four (67%) H. pylori-seropositive children had antibodies against CagA. Low molecular weight-ELISA and whole cell-western blot results were significantly associated with histopathology, the presence of duodenal ulcer and the CagA status. A high number of false seronegative cases were due to poor immunological responses in children and poor locally validated tests. The prevalence of H. pylori infection in Lithuanian children is higher compared to Western Europe. The infection is acquired in early life. Diagnosing H. pylori infection, serology is helpful, but endoscopy/histology remains as gold standard.     

Organ-specific autoantibodies in children with Helicobacter pylori infection

BACKGROUND: We compared the prevalence of organ-specific autoantibodies in a group of Helicobacter pylori infected children and a group of uninfected children and investigated the relationship between the presence of relevant autoantibodies and the status of the target organs. PATIENTS AND METHODS: One hundred and twenty-four children with dyspepsia (54 boys, 70 girls; mean age 10.5 years; range 4-19) underwent gastroscopy: 56 had H. pylori infection (31 girls, 25 boys), while 68 (37 girls and 31 boys), were H. pylori-negative. All sera were tested for the presence of: parietal cell autoantibodies (PCA), intrinsic factor autoantibodies (IFA), microsomial autoantibodies, thyroglobulin autoantibodies, islet cell autoantibodies, glutamic acid decarboxylase autoantibodies, adrenal cortex autoantibodies, steroid-producing cell autoantibodies; gastrin, pepsinogen A, pepsinogen C and anti-H. pylori antibodies. The histological features and the ureA and cagA genes were also considered. RESULTS: The frequency of organ-specific autoantibodies was higher in patients with H. pylori infection than in uninfected patients (chi2-test p < .0001). Specifically gastric autoantibodies were significantly higher: seven of the 56 H. pylori-positive children were PCA-positive and one was IFA-positive (chi2-test p = .0004). The presence of autoantibodies was not associated with any clinical or biohumoral signs of disease. CONCLUSIONS: Our study detected a relationship between H. pylori infection in childhood and the presence of organ-specific autoantibodies unassociated with any clinical or biohumoral signs of disease. Helicobacter pylori infection in childhood could trigger the onset of clinical autoimmune gastritis, and/or other clinical autoimmune diseases.     

Anti-Lewis X IgM and IgG in H. pylori infections in children and adults

A role of autoimmune processes in the pathology of Helicobacter pylori infections has been suggested. The Lewis determinants present in LPS molecule of H. pylori bacteria have been indicated as the cause of antigenic mimicry. In this study, the prevalence of IgM and IgG antibodies to Lewis X antigen in the sera from children and adults, with or without dyspepsia, infected or not infected with H. pylori, seropositive and seronegative for anti-H. pylori IgG were determined immuno-enzymatically (ELISA). Our results revealed that humans may produce anti-Lewis X antibodies, particularly of IgM class, in the absence of H. pylori infection or H. pylori independent dyspepsia. The production of such antibodies, by healthy children who had never been infected with H. pylori suggested that anti-Lewis X antibodies may occur naturally.     

Features of a newly cloned pig C1 esterase inhibitor

The pig cDNA encoding C1 esterase inhibitor (C1-INH) was isolated and the homology of the sequence was compared with that from other animals. The structure of pig C1-INH contains a two disulfide bridge pattern identical to the human C1-INH. In the amino acid sequence of the first Cys-91 to the C-terminal end, the pigC1-INH has a 76.2% homology with the human protein, and the sequence of the reactive site is close to the human. A surface-bound form of pig and human C1-INH, pC1-INH-PI and hC1-INH, respectively, were next constructed. Stable Chinese hamster ovarian tumor (CHO) cell lines and pig endothelial cell (PEC) lines expressing these C1-INH-PI were prepared by transfection. The basic function and the species specificity of pCI-INH were then investigated using these transfectants. pC1-INH and hC1-INH have almost the same suppressive effect on pig, human, dog and rabbit sera in complement-dependent cell lysis, indicating little species specificity.     

Contiguous deletion and duplication mutations resulting in type 1 hereditary angioneurotic edema

Mutations that cause low antigenic and functional levels of C1 inhibitor protein result in type 1 hereditary angioneurotic edema. This disease is characterized by episodic edema leading to considerable morbidity and sometimes death. We present here two novel mutations in the reactive center coding region. One mutation is a deletion of an imperfect palindrome encompassing nucleotides 1395–1428 and the other is a direct duplication of nucleotides 1414–1433. These mutations do not depend on improper pairing of direct repeats, but may form as a consequence of a peculiar consensus sequence or an alternative secondary structure.     

Potentiation of C1-esterase inhibitor by heparin and interactions with C1s protease as assessed by surface plasmon resonance

Background

Human C1-esterase inhibitor (C1-INH) is a multifunctional plasma protein with a wide range of inhibitory and non-inhibitory properties, mainly recognized as a key down-regulator of the complement and contact cascades. The potentiation of C1-INH by heparin and other glycosaminoglycans (GAGs) regulates a broad spectrum of C1-INH activities in vivo both in normal and disease states.

Scope of research

We have studied the potentiation of human C1-INH by heparin using Surface Plasmon Resonance (SPR), circular dichroism (CD) and a functional assay. To advance a SPR for multiple-unit interaction studies of C1-INH we have developed a novel (consecutive double capture) approach exploring different immobilization and layout.

Major conclusions

Our SPR experiments conducted in three different design versions showed marked acceleration in C1-INH interactions with complement protease C1s as a result of potentiation of C1-INH by heparin (from 5- to 11-fold increase of the association rate). Far-UV CD studies suggested that heparin binding did not alter C1-INH secondary structure. Functional assay using chromogenic substrate confirmed that heparin does not affect the amidolytic activity of C1s, but does accelerate its consumption due to C1-INH potentiation.

General significance

This is the first report that directly demonstrates a significant acceleration of the C1-INH interactions with C1s due to heparin by using a consecutive double capture SPR approach. The results of this study may be useful for further C-INH therapeutic development, ultimately for the enhancement of current C1-INH replacement therapies.     

Characterization of the StcE protease activity of Escherichia coli O157:H7

The StcE zinc metalloprotease is secreted by enterohemorrhagic Escherichia coli (EHEC) O157:H7 and contributes to intimate adherence of this bacterium to host cells, a process essential for mammalian colonization. StcE has also been shown to localize the inflammatory regulator C1 esterase inhibitor (C1-INH) to cell membranes. We tried to more fully characterize StcE activity to better understand its role in EHEC pathogenesis. StcE was active at pH 6.1 to 9.0, in the presence of NaCl concentrations ranging from 0 to 600 mM, and at 4 degrees C to 55 degrees C. Interestingly, antisera against StcE or C1-INH did not eliminate StcE cleavage of C1-INH. Treatment of StcE with the proteases trypsin, chymotrypsin, human neutrophil elastase, and Pseudomonas aeruginosa elastase did not eliminate StcE activity against C1-INH. After StcE was kept at 23 degrees C for 65 days, it exhibited full proteolytic activity, and it retained 30% of its original activity after incubation for 8 days at 37 degrees C. Together, these results show the StcE protease is a stable enzyme that is probably active in the environment of the colon. Additionally, k(cat)/K(m) data showed that StcE proteolytic activity was 2.5-fold more efficient with the secreted mucin MUC7 than with the complement regulator C1-INH. This evidence supports a model which includes two roles for StcE during infection, in which StcE acts first as a mucinase and then as an anti-inflammatory agent by localizing C1-INH to cell membranes.     

StcE,a metalloprotease secreted by Escherichia coli O157:H7, specifically cleaves C1 esterase inhibitor

Escherichia coli O157:H7 causes diarrhoea, haemorrhagic colitis, and the haemolytic uraemic syndrome. We have identified a protein of previously unknown function encoded on the pO157 virulence plasmid of E. coli O157:H7, which is the first described protease that specifically cleaves C1 esterase inhibitor (C1-INH), a member of the serine protease inhibitor family. The protein, named StcE for secreted protease of C1 esterase inhibitor from EHEC (formerly Tagn), cleaves C1-INH to produce (unique) approximately 60-65 kDa fragments. StcE does not digest other serine protease inhibitors, extracellular matrix proteins or universal protease targets. We also observed that StcE causes the aggregation of cultured human T cells but not macrophage-like cells or B cells. Substitution of aspartic acid for glutamic acid at StcE position 435 within the consensus metalloprotease active site ablates its abilities to digest C1-INH and to aggregate T cells. StcE is secreted by the etp type II secretion pathway encoded on pO157, and extracellular StcE levels are positively regulated by the LEE-encoded regulator, Ler. StcE antigen and activity were detected in the faeces of a child with an E. coli O157:H7 infection, demonstrating the expression of StcE during human disease. Cleavage of C1-INH by StcE could plausibly cause localized pro-inflammatory and coagulation responses resulting in tissue damage, intestinal oedema and thrombotic abnormalities.     

Study of the effect of high molecular weight kininogen upon the fluid-phase inactivation of kallikrein by C1 inhibitor

Plasma kallikrein and factor XIa circulate bound to high molecular weight kininogen, and such binding has been reported to protect these enzymes from inactivation by their respective inhibitors. However, this observation is controversial, and the effect of high molecular weight kininogen upon the interaction between kallikrein and C1 inhibitor (C1-INH) has been questioned. We have re-evaluated this reaction and studied the rate of inhibition of kallikrein by C1-INH in the presence and absence of high molecular weight kininogen. The second-order rate constant of inhibition of kallikrein by C1-INH was unaffected by saturating concentrations of high molecular weight kininogen. Our results suggest that although high molecular weight kininogen clearly augments the rate of formation of kallikrein and other enzymes of the contact activation pathway, it has no effect on the rate of enzyme inhibition by C1-INH.     

Cysteine Proteinase from Streptococcus pyogenes Enables Evasion of Innate Immunity via Degradation of Complement Factors

Streptococcus pyogenes is an important human pathogen that causes invasive diseases such as necrotizing fasciitis, sepsis, and streptococcal toxic shock syndrome. We investigated the function of a major cysteine protease from S. pyogenes that affects the amount of C1-esterase inhibitor (C1-INH) and other complement factors and aimed to elucidate the mechanism involved in occurrence of streptococcal toxic shock syndrome from the aspect of the complement system. First, we revealed that culture supernatant of a given S. pyogenes strain and recombinant SpeB degraded the C1-INH. Then, we determined the N-terminal sequence of the C1-INH fragment degraded by recombinant SpeB. Interestingly, the region containing one of the identified cleavage sites is not present in patients with C1-INH deficiency. Scanning electron microscopy of the speB mutant incubated in human serum showed the abnormal superficial architecture and irregular oval structure. Furthermore, unlike the wild-type strain, that mutant strain showed lower survival capacity than normal as compared with heat-inactivated serum, whereas it had a significantly higher survival rate in serum without the C1-INH than in normal serum. Also, SpeB degraded multiple complement factors and the membrane attack complex. Flow cytometric analyses revealed deposition of C9, one of the components of membrane the attack complex, in greater amounts on the surface of the speB mutant, whereas lower amounts of C9 were bound to the wild-type strain surface. These results suggest that SpeB can interrupt the human complement system via degrading the C1-INH, thus enabling S. pyogenes to evade eradication in a hostile environment.     

Inhibition of H. pylori colonization and prevention of gastritis in murine model

Helicobacter pylori is a Gram-negative spiral bacterium that colonizes human gastric mucosa causing infection. In this study aiming at inhibition of H. pylori infection we made an attempt to evaluate immunogenicity of the total (UreC) and C-terminal (UreCc) fragments of H. pylori urease. Total UreC and its C-terminal fragment were expressed in E. coli. Recombinant proteins were analyzed by SDS-PAGE and western blot and then purified by Ni-NTA affinity chromatography. Female C57BL6/j mice were immunized with the purified proteins (UreC and UreCc). Antibody titers from isolated sera were measured by ELISA. Immunized mice were then challenged by oral gavage with live H. pylori Sydney strain SS1. Total of 109 CFU were inoculated into stomach of immunized and unimmunized healthy mice three times each at one day interval. Eight weeks after the last inoculation, the blood sample was collected and the serum antibody titer was estimated by ELISA. Stomach tissues from control and experimental animal groups were studied histopathologically. UreC and UreCc yielded recombinant proteins of 61 and 31 kDa respectively. ELIZA confirmed establishment of immunity and the antibodies produced thereby efficiently recognized H. pylori and inhibited its colonization in vivo. Pathological analysis did not reveal established infection in immunized mice challenged with H. pylori. The results support the idea that UreC and UreCc specific antibodies contribute to protection against H. pylori infections.     

Binding of activated Factor XII to endothelial cells affects its inactivation by the C1-esterase inhibitor.

It is well known that activated Factor XII (FXIIa) and kallikrein are rapidly inactivated in plasma as a result of reaction with endogenous inhibitors. The purpose of this may be to prevent uncontrolled deleterious spreading and activation of target zymogens. Both FXII and the complex plasma prekallikrein/high molecular mass kininogen become activated when they bind, in a Zn2+-dependent manner, to receptors on human umbilical vein endothelial cells (HUVEC). The C1-esterase inhibitor (C1-INH) is by far the most efficient inhibitor of FXIIa. In the present study it has been investigated whether binding of FXIIa to HUVEC might offer protection against inactivation by C1-INH. It appeared that the relative amidolytic activity of purified FXIIa bound to the surface of HUVEC decreased according to the concentration of C1-INH in medium; however, the decrease was smaller than that measured for inactivation of FXIIa in solution. The secondary rate constant for the inactivation was 3-10-fold lower for cell-bound than for soluble FXIIa. The inactivation was found to be caused by C1-INH binding to cell-bound FXIIa. Accordingly, the amidolytic activity of saturated amounts of cell-bound FXIIa was reduced in the presence of C1-INH and was theoretically nonexistent at physiological C1-INH concentrations. Amidolytic activity was, however, present on HUVEC incubated with plasma indicating that the endogenous C1-INH did not completely abolish the activity of FXIIa generated during the incubation period. This supports the hypothesis that binding to endothelial cells protects the activated FXII against inactivation by its major endogenous inhibitor. Hence, the function of FXII may be localized at cellular surfaces.