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PubMedDate not supplied

The role of complement and activated microglia in the pathogenesis of Alzheimer's disease.

A variety of inflammatory mediators including complement activation products, protease inhibitors, and cytokines are colocalized with beta-amyloid (A beta) deposits in the Alzeimer's disease (AD) brain. Activation products of the early complement components C1, C4, and C3 are always found in neuritic plaques and to a lesser extent in varying numbers of diffuse plaques. In contrast to these findings, no immunohistochemical evidence was obtained for the presence of the late complement components C7 and C9 and the complement membrane attack complex in the neuropathological lesions in AD brains. The mRNA encoding the late complement components C7 and C9 appears to be hardly or not detectable. These findings indicate that in AD the complement system does not act as an inflammatory mediator through membrane attack complex formation, but through the actions of the early complement products. In this review we focus on the role of complement in the pathological amyloid cascade in AD. In our opinion, the early complement activation products play a crucial role as mediators between the A beta deposits and the inflammatory responses leading to neurotoxicity.

Alzheimer Disease↗
PubMed1999

Septic shock after liver transplantation for Caroli's disease: clinical improvement after treatment with C1-esterase inhibitor.

The extent of complement and contact activation is related to outcome in sepsis. A low functional index of their main blocker C1-esterase inhibitor (C1-INH) is considered as a relative deficiency of C1-INH and might contribute to the development of fatal complications in the intensive care unit. The first results of therapeutic intervention with C1-INH concentrate in septic shock are promising. We report on our experience of C1-INH concentrate administration in a young woman with Caroli's disease as ultimate rescue therapy for septic shock with capillary leakage syndrome after combined liver and kidney transplantation. No focus of infection was detectable and thus surgical intervention was not indicated. Antibiotic therapy at that time included vancomycin, tobramycin, meropenem and fluconazol. Hemodynamic stabilization occurred within hours after administration of C1-INH concentrate. Simultaneously a reduction in vasopressor medication was possible and negative fluid balance was achieved.

Adult↗
PubMed2006

Complement deficiency and disease: an update.

Complement deficiencies are probably vastly under-diagnosed within clinical medicine. Judging from a Swedish study of C2 deficiency, a deficiency with an estimated prevalence of about 1/20,000 in Western countries, less than 10% of the deficiencies of the classical and alternative pathways and the late complement components are identified in Sweden. C1 inhibitor deficiency and deficiencies of MBL and MASP-2 were not included in the assessment. The introduction of new screening methods should facilitate detection of complement deficiencies in clinical practice. In our study of C2 deficiency (n=40), 57% of the patients had a history of invasive infection with encapsulated bacteria, mainly Streptococcus pneumoniae. This emphasizes the importance of the classical and/or the lectin pathway in defence against severe infection. Rheumatological disease, mainly systemic lupus erythematosus was present in 43% of the patients. In addition, a significant association was found between C2 deficiency and atherosclerosis. Complement-dependent disease mechanisms are discussed together with the potential importance of non-complement genes for disease expression in complement deficiencies. Analysis of larger patient groups is required in order to establish guidelines for investigation and treatment of patients with complement deficiency.

Atherosclerosis↗
PubMed1997

[Ascites and suspected acute abdomen in hereditary angioedema due to C1 inhibitor deficiency].

HISTORY AND CLINICAL FINDINGS: A 35-year-old man, for 8 years known to have hereditary angio-oedema with recurrent cutaneous swellings and occasional attacks of gastrointestinal pain, developed very painful, colic-like upper abdominal symptoms and frequent vomiting. INVESTIGATIONS: Routine laboratory tests were normal, except for leucocytosis of 18,200 WBC/microliter. The plasma concentrations of C1-esterase inhibitor (5.6 mg/dl) and of complement factor C4 (10.0 mg/dl) were reduced. Computed tomography revealed about 500 ml free fluid, a perihepatic effusion and definite oedematous thickening of the ileal wall. TREATMENT AND COURSE: During conservative treatment with infusions and no food by mouth the symptoms regressed. Abdominal ultrasonography was normal (no free intraabdominal fluid). Since discharge (now more than 15 months ago) the patient has been on danazole medication (200 mg/d). CONCLUSION: Recurrent gastrointestinal colics are typical of for hereditary angio-oedema and can imitate an acute abdomen. Concurrent ascites has only recently been described. Appropriate instruction of the patient and his/her medical practitioner is important to avoid unnecessary laparotomy.

Abdomen, Acute↗
PubMed1993

Transinhibition of C1 inhibitor synthesis in type I hereditary angioneurotic edema.

To ascertain the mechanism for decreased synthesis of C1 inhibitor (C1 INH) in certain patients with the autosomal dominant disorder hereditary angioneurotic edema, we studied expression of C1 INH in fibroblasts in which the mutant and wild type mRNA and protein could be distinguished because of deletion of exon 7 (delta Ex7). In the HANE delta Ex7 cells, the amount of wild type mRNA (2.1 kb) was expressed at 52 +/- 2% (n = 5) of normal, whereas the mutant mRNA was 17 +/- 1% (n = 5) of normal. Rates of synthesis of both wild type and mutant proteins (11 +/- 3 and 3 +/- 1% of normal, respectively) were lower than predicted from the mRNA levels. There was no evidence of increased C1 INH protein catabolism. These data indicate that there are multiple levels of control of C1 INH synthesis in type I hereditary angioneurotic edema. Pretranslational regulation results in < 50% of the mutant truncated 1.9-kb mRNA. In addition, translational regulation results in decreased synthesis of both wild type and mutatn C1 INH proteins. These data suggest a transinhibition of wild type C1 INH translation by mutant mRNA and/or protein.

Adult↗
PubMed1998

Values of complement, T- and B-lymphocytes and immune complexes in patients with skin allergies.

The aim of this pilot study was to determine the values of total complement, C3 and C4 fractions, C1-esterase inhibitor, T- and B-lymphocytes, and immune complexes in our patients with skin allergic disease. The purpose was to investigate the probability of type III hypersensitivity reaction in the development and onset of skin allergies. The values of these parameters were determined in ten patients with atopic dermatitis and ten patients with chronic allergic urticaria. Results showed most of the study subjects with atopic dermatitis (7/10) to have increased CH50 values, a finding not observed in the patients with chronic allergic urticaria (2/10) and healthy controls (0/10). No major changes in other parameteres were found in any of the patient groups. A statistically significant difference (p < 0.05) was found among the three groups in CH50 and C4 values.

Adolescent↗
PubMed1982

Exacerbation of a lupus-erythematosus-like syndrome during treatment of non-C1-esterase-inhibitor-dependent angioedema with danazol.

A 70-yr-old man presented with symptoms of angioedema and a lupus erythematosus-like syndrome. Because initial studies showed a functional deficiency of C1 esterase inhibitor and low C4 levels, he was treated with danazol, an attenuated androgen that has proven to be effective in the treatment of angioedema associated with C1 esterase inhibitor deficiency. After treatment, the patient's C4 levels returned to normal and his angioedema resolved, but concurrently he experienced clinical and laboratory exacerbations of his lupuslike illness. Specifically, on two occasions after danazol treatment he developed arthralgias, myalgias, hematuria, and pleuritic chest pain, accompanied by increased titers of antinuclear antibodies and circulating immune complexes. Serum testosterone levels were decreased during these episodes. Because treatment with danazol was temporally associated with recurrent exacerbations of a lupuslike illness and low serum testosterone levels, we believe that this case is an example of sex hormonal modulation of a lupuslike disease in man.

Aged↗
PubMed1993

C1 inhibitor functional deficiency in systemic lupus erythematosus (SLE).

C1 inhibitor (C1-inh) was assayed in eight SLE patients presenting with consistently low levels of intact C4. C1-inh antigenic levels were normal in all patients; however, the function of the C1-inh tested against C1s and C1r was variable and outside the normal functional range in seven of the eight patients. The molecular weight of patients' C1-inh protein was 105 kD, corresponding to the size of the intact molecule. The C1-inh gene was analysed in all patients. Restriction fragments generated with TaqI, PstI and HgiAI gave no indication of a major C1-inh gene rearrangement. Direct genomic sequencing of exon VIII revealed three polymorphic point mutations, but there were no changes from the normal gene in or around the reactive-centre residue of C1-inh. Furthermore, we found no evidence for a C1-inh autoantibody in patients which could affect normal C1-inh function in vitro. These results indicate that the etiology of C1-inh dysfunction in SLE is heterogeneous and distinct from that reported in either hereditary or acquired angioedema.

Base Sequence↗
PubMed1996

[Disseminated intravascular coagulations].

Disseminated intravascular coagulation (DIC) syndromes can be defined as the formation of fibrin deposits within the microcirculation, occurring in definite clinical situations. Their biological counterpart is a consumption coagulopathy. The clinical profiles of DIC have been well known for decades, are multiform and range from latency to overwhelming haemorrhagic diatheses, including also characteristic but rare situations, such as purpura fulminans, acral cyanosis and pictures resembling thrombotic thrombocytopenic purpura or haemolytic-uraemic syndrome. Biological tests of DIC show a consumption coagulopathy, displayed on the standard haemostasis sheet; along with signs of paracoagulation and/or of secondary fibrinolysis (FDP). New tests have recently been introduced: D-dimers are specific and sensible; Antithrombin-III, protein C and alpha 2-antiplasmin also can sometimes be useful. The knowledge of the pathophysiology of DIC has made advances with passing years. Fibrin deposits may be non-occlusive, and indeed they are swiftly removed by a secondary fibrinolysis. Except in very rare situations, such as those leading to a cortical renal necrosis, and perhaps in some ARDS, there is little evidence relating DIC to organ failure syndromes. Moreover, there is no clear relationship between the severity of the consumption coagulopathy and the prognosis. For instance, the mortality is much lower in abruptio placentae, where the coagulopathy is very severe, than in septic shock, where it is usually moderate. In septic shock, the disorders of haemostasis were related initially to a platelet activation, then to an activation of the contact system (releasing kinins and triggering complement cascade), and nowadays to the activation of the extrinsic coagulation system. The treatment of DIC is mainly the treatment of its cause. Indications for heparin therapy should be strictly limited to a few exceptional circumstances. When haemorrhagic diathesis threatens, FPC and/or platelet transfusion may be indicated. Aprotinin can be useful in rare cases of overwhelming secondary fibrinolysis. Trials with antithrombin-III or C1-esterase inhibitors are in progress.

Blood Coagulation↗
PubMed1994

A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2.

In a pilot study six patients received 4 days' treatment with interleukin 2 (IL-2) [cumulative dose (CD) 264 +/- 26 x 10(6) IU m-2] and C1 esterase inhibitor (C1-INH) (loading dose 2,000 U, followed by 500-1,000 U twice daily). Toxicity was compared with that in patients given 4 days' treatment with standard (CD 66 +/- 12 x 10(6) IU m-2) or escalating-dose (CD 99 +/- 8 x 10(6) IU m-2) IL-2. IL-2-induced hypotension was equivalent and complement activation was less after IL-2 + C1-INH (C3a = 10.5 +/- 3.2 nmol l-1) than following standard (14.1 +/- 8.4 nmol l-1) or escalating-dose (18.3 +/- 2.9 nmol l-1) IL-2. This study demonstrates that C1-INH administration during IL-2 treatment is safe and warrants further study to evaluate its ability to ameliorate IL-2-induced toxicity.

Adult↗
PubMedDate not supplied

Humoral and cellular immunity in chronic urticaria.

In chronic recurrent urticaria of months' or years' duration, it is difficult to identify the causative factor. From an immunological point of view, various authors have attempted to demonstrate alterations in levels of immunoglobulins and complement fractions. We do not know of any previous studies of cellular immunity in this disorder. Fifty-one patients with chronic urticaria were studied, 22 females and 29 males, with ages ranging from 8 to 70 years. The patients were considered to be affected by recurrent or chronic urticaria with no clear allergic etiology. In all subjects a determination was made of serum levels of immunoglobulins G, A, M and E and of the complement fractions: C1 inhibitor, C1q, C3, C4 and C5. In addition, a study of cellular immunity was carried out on these patients. The results of tests of humoral immunity in the group of chronic urticarial patients studied showed only an increase of IgM in 41.7%. No significant changes were noted among the complement fractions. The study of cellular immunity gave normal figures for total and for B and T lymphocytes. The only finding which may be worthy of is a slight decrease in active T lymphocytes. The lymphocyte transformation test also gave a normal response to PHA and overall a normal cellular immunity was shown in these patients. At present we do not consider that the increased IgM in 40 to 45% of the cases has any pathogenic diagnostic value.

Adolescent↗
PubMed2002

[Complement system in patients with IgE related and non IgE related bronchial asthma].

The studies were performed in 32 patients in the age range of 17-58 years suffering from bronchial asthma in the exacerbation period of their illness. 16 patients suffered from IgE related/atopic and 16 from IgE non IgE related/nonatopic bronchial asthma. The complement haemolytic activity (CH50) and the activity of C1 inhibitor (C1 INH) were measured in the plasma. In 60% of patients with IgE related asthma and in 45% of patients with non IgE related asthma we stated decrease of CH50. The activity of C1INH also was decreased in 80% of patients with atopic asthma and in 40% of patients with nonatopic asthma. The observed changes were not related to aspirin tolerance as well as to IgE mediation of their illness. Control examinations of these parameters repeated during remission of asthma symptoms in 11 patients with low values during the exacerbation of the illness (in 5 patients with atopic and in 6 with non-atopic asthma) revealed an increase of their values; however without features of normalisation.

Adolescent↗
PubMed1985

[Effect of Expafusion (HES 40/0.5) on the corpuscular elements of blood and inhibitors of blood coagulation].

The present study reports on an investigation of 32 normal subjects who were given intravenously 500 ml of hydroxyethyl starch (HES) over 30 min. In 16 normal subjects, 500 ml of blood had been previously withdrawn over 20 min. Tolerance proved to be good. Side effects such as hyperergic reactions, influence on circulatory or cardiac function were not observed. Changes in corpuscular elements of blood did not exceed the dilution effect and mostly returned to the initial value 60 min after termination of HES infusion. The change in thrombocyte function, immunoglobulins and the inhibitors alpha 1-antitrypsin, alpha 2-macroglobulin, as well as C1-inactivator and C3-activator only slightly, but not more pronounced than it could have been expected by the dilution effect. A favorable effect could be recorded in erythrocyte filtration according to Schmidt-Schoenbein. Here, we found an improved flow property which exceeded the hemodilution effect and lasted over the 4-hour test period. In addition, thrombocyte aggregation during ADP administration in the Born chamber did not show any change which suggests that a clinically relevant effect on thrombocyte function and thus the danger of hemorrhage during HES administration can be excluded.

Adolescent↗
PubMed2001

Increased systemic activation of neutrophils but not complement in preeclampsia.

OBJECTIVE: To investigate whether neutrophils and systemic complement are activated in pregnancies complicated by preeclampsia more than in normal pregnancies. METHODS: We measured native complement components and activation products in plasma by enzyme immunoassays in 19 women with uncomplicated pregnancies, 15 with preeclampsia before cesarean deliveries, and 16 nonpregnant women. Neutrophil activation was measured by specific enzyme immunoassays for myeloperoxidase and lactoferrin. RESULTS: Myeloperoxidase was significantly higher in women with preeclampsia (197 microg/L, 95% confidence interval [CI] 94, 646) than in women with uncomplicated pregnancies (124 microg/L, 95% CI 70, 289; P =.009), whereas lactoferrin did not differ between groups. C4 was decreased in preeclamptic women (0.16 g/L, 95% CI 0.07, 0.48) compared with women with uncomplicated pregnancies (0.21, 95% CI 0.10, 0.30, P <.001). There were no differences for the other native complement components. There was a significant decrease in C1rs-C1 inhibitor, 13 AU/mL (95% CI 9, 34) versus 19 (95% CI 13, 38) (P < or =.001) in normal pregnant women compared with nonpregnant women. There also was an increase in C3, C4, C9 (data not shown), C4bp, 132% (95% CI 94%, 161%) versus 91% (95% CI 57%, 128%); C3bc (7.4 AU/mL, 95% CI 4.2, 10.7) versus 4.8 AU/mL (95% CI 3.2, 7.3) and C4bc (8.6 AU/mL, 95% CI 5.7, 14.0) versus 3.5 AU/mL (95% CI 2.2, 6.7) in normal pregnant women compared with nonpregnant women (P < or =.001). CONCLUSION: Neutrophil activation in preeclampsia was shown by systemic increases in myeloperoxidase. Except for a decrease in C4, systemic complement activation could not be detected in preeclampsia.

Adult↗
PubMed1995

What do dysfunctional serpins tell us about molecular mobility and disease?

Proteinase inhibitors of the serpin family have a unique ability to regulate their activity by changing the conformation of their reactive-centre loop. Although this may explain their evolutionary success, the dependence of function on structural mobility makes the serpins vulnerable to the effects of mutations. Here, we describe how studies of dysfunctional variants, together with crystal structures of serpins in different forms, provide insights into the molecular functions and remarkable folding properties of this family. In particular, comparisons of variants affecting different serpins allow us to define the domains which control this folding and show how spontaneous but inappropriate changes in conformation cause diverse diseases.

Angioedema↗
PubMed1993

Hereditary angioedema: uncomplicated maxillofacial surgery using short-term C1 inhibitor replacement therapy.

We report on the successful use of a pasteurized C1 inhibitor (C1-INH) concentrate during dental surgery of a patient affected by hereditary angioedema. The patient recovered fully without complications or side effects. Within 30 min, the first 1,000 U of C1-INH concentrate raised C1-INH concentration from 19 to 55% and function from 40 to 90% of the normal mean. When measured 4 h after the second injection, a further increase of the C1-INH concentration to 86% and a function of 106% relative to the normal mean was observed. Within 2 weeks C1-INH concentration returned to pretreatment level, while the function remained above this value. Serum liver enzyme values did not change and no anti-C1-INH alloantibodies were detected 10 months post-replacement therapy. We conclude that in patients affected by C1-INH deficiency, dental surgery and likely other traumatic procedures can be safely performed in conjunction with C1-INH replacement therapy even without preliminary treatment.

Adolescent↗
PubMedDate not supplied

Activation of the complement pathway: comparison of normal pregnancy, preeclampsia, and systemic lupus erythematosus during pregnancy.

To evaluate a flare of systemic lupus erythematosus (SLE) during pregnancy and to differentiate it from diseases of pregnancy, serological parameters are often utilized. However, there are conflicting reports regarding the merit of conventional measurements of complement and activation products. While in normal pregnancy the levels of serum C3, C4, and CH50 gradually rise, a decline in these levels occurs during the course of pregnancy in selected SLE patients. There is controversy regarding whether such falls represent decreases in the overall synthesis of complement or activation, the former theory being supported by a report of normal levels of the C1s-C1 inhibitor complex. During normal pregnancies, increases of complement split products, such as plasma C3a, may occur, and these correlate positively with elevations of C3. In pregnancies complicated by lupus, increases of C3a are often accompanied by a decline in total C3 and CH50. In a minority of non-SLE patients, preeclampsia has been associated with elevations of a variety of complement split products. Ba, C3a, C4d, SC5b-9, indicating activation of both the classical and alternative pathways. The CH50 levels tend to remain normal in these patients. In contrast, elevations of complement split products frequently accompany disease flares in patients with SLE. A high ratio of CH50/Ba may differentiate patients with preeclampsia from those with active SLE. A decline in conventional measures of C3, C4, or CH50 which is accompanied by elevations of complement split products appears to differentiate a lupus flare from non-SLE diseases of pregnancy.

Complement Activation↗
PubMed1993

A de novo deletion in the C1 inhibitor gene in a case of sporadic hereditary angioneurotic edema.

A sporadic case of hereditary angioneurotic edema (HANE) is reported here. The patient was a 15-year-old girl who for 4 years had suffered recurrent episodes of urticaria-like erythema, followed by vomiting with abdominal pain. She was diagnosed as having Sjögren syndrome by results of sialography and serological studies, and moreover, it was also observed that the C1 inhibitor (C1-INH) activity in her plasma was very low during these episodes of urticarial erythema. Diagnosis of acquired angioneurotic edema (AANE) was excluded because the patient's plasma had no inhibitory effect on the C1-INH activity of normal individuals. Although neither of her parents had a history of HANE, we were able to show that the patient had HANE by Southern blot analysis using C1-INH cDNA as a probe. One of the patient's C1-INH gene alleles was revealed to have at least a 17-kb-length deletion including exons 5-8. Neither her parents nor her healthy brother showed any abnormalities on Southern blot analysis. The parent-child relationship in this family was confirmed by an HLA-typing study of all family members.

Adolescent↗