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PubMed2001

Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1.

Angiogenesis is critical for the growth and proliferation of tumors as well as for normal development. We now describe a novel role for histidine-rich glycoprotein (HRGP) in the modulation of angiogenesis. HRGP is a plasma protein that circulates in relatively high concentrations (1.5 microM), but has no known function in vivo. We have shown previously that HRGP binds with high affinity to thrombospondin-1 (TSP-1), a homotrimeric glycoprotein that is a potent inhibitor of angiogenesis. The antiangiogenic activity of TSP-1 is mediated by the binding of properdin-like type I repeats to the receptor CD36. We found that binding of HRGP to TSP-1 was similarly mediated by TSP type I repeats. HRGP colocalized with TSP-1 in the stroma of human breast cancer specimens, and this interaction masked the antiangiogenic epitope of TSP-1. In assays performed in vitro of endothelial cell migration and tube formation, and in vivo corneal angiogenesis assays, HRGP inhibited the antiangiogenic effect of TSP-1. These studies suggest that HRGP can modulate the antiangiogenic activity of TSP-1, and identify a potential mechanism of resistance to the antiangiogenic effect of TSP-1.

Amino Acid Sequence↗
PubMed1988

Allelic variants for complement factors C3, C4, and B in acute necrotizing ulcerative gingivitis.

Impaired immune defense mechanisms and genetic factors appear to play a role in susceptibility to acute necrotizing ulcerative gingivitis (ANUG). Therefore, possible etiological mechanisms might involve genes at the Major Histocompatibility Complex, which include the complement factor loci. We have tested for a possible association between certain complement factor alleles and ANUG using a case-control study design. Specific alleles at complement factors C3 and C4, and properdin factor B (Bf) loci were determined indirectly by high voltage agarose gel electrophoresis in 58 subjects with a history of ANUG and in 58 age-sex-matched healthy controls. The highest relative risk of ANUG, as obtained by conditional logistic regression, for alleles at the C3 locus was 1.9 (90% confidence limits 0.8 to 4.8; p = 0.229) for C3*F-positive individuals. The highest relative risk for alleles at the C4 locus was 2.6 (0.5 to 14.9; p = 0.358) for C4A*3-positive individuals. There was no evidence for an association between Bf allotype and risk of ANUG, with a relative risk of 1.2 for Bf*F- and relative risk of 1.0 for B*S-positive individuals. None of our estimates was statistically significant. We conclude, therefore, that it is unlikely that there is any association between complement factor gene haplotype and susceptibility to ANUG.

Acute Disease↗
PubMed2006

Deficient alternative complement pathway activation due to factor D deficiency by 2 novel mutations in the complement factor D gene in a family with meningococcal infections.

The complement system is an essential element in our innate defense against infections with Neisseria meningitidis. We describe 2 cases of meningococcal septic shock, 1 of them fatal, in 2 children of a Turkish family. In the surviving patient, alternative pathway activation was absent and factor D plasma concentrations were undetectable. Concentrations of mannose-binding lectin (MBL), C1q, C4 and C3, factor B, properdin, factor H, and factor I were normal. Mutation analysis of the factor D gene revealed a T638 > G (Val213 > Gly) and a T640 > C (Cys214 > Arg) mutation in the genomic DNA from the patient, both in homozygous form. The consanguineous parents and an unaffected sister had these mutations in heterozygous form. In vitro incubation of factor-D-deficient plasma of the boy with serogroup B N meningitidis showed normal MBL-mediated complement activation but no formation of the alternative pathway C3-convertase C3bBbP, and severely decreased C3bc formation and terminal complement activation. The defect was restored after supplementation with factor D. In conclusion, this is the second report of a factor D gene mutation leading to factor D deficiency in a family with meningococcal disease. This deficiency abolishes alternative-pathway dependent complement activation by N meningitidis, and leads to an increased susceptibility to invasive meningococcal disease.

Amino Acid Substitution↗
PubMed1981

Hypocomplementemia in Reye syndrome: relationship to disease stage, circulating immune complexes, and C3b amplification loop protein synthesis.

Measurement of C1q, C2, C4, C5, C6, factor B, properdin, beta1H, and C3bINA were made in acute sera from 31 patients with Reye syndrome. Abnormalities were found in 18 patients. The magnitude of the complement component depression correlated with disease severity. Sera from patients with stage IV illness had significantly lower complement levels than did sera from patients with state I (P less than 0.001), II (P less than 0.05), and III (P less than 0.05) disease. Circulating immune complex measurements were performed on all 31 acute sera and were present in six (19%). However, from the results of the present study, it would appear that in the majority of the patients circulating immune complexes are not the cause of the lowered levels of, at least, C3 and factor B. Rather, these low levels could be explained as secondary to reductions in the levels of the C3b amplification loop control proteins beta1H and C3bINA.

Antigen-Antibody Complex↗
PubMed1996

Major histocompatibility complex class II and complement polymorphisms in postpartum thyroiditis.

The objective was to re-evaluate the association between class II HLA-DR and DQ MIIC antigens and postpartum thyroiditis (PPT) and to determine the prevalence of the class III complement allotypes of Properdin factor B (Bf), C4A and C4B in this condition. Two hundred and sixty-five (of 2897) pregnant women screened positive for thyroid autoantibody activity took part. Further blood samples were obtained for HLA class II (185) and complement (193) typing. The severity of the ensuing PPT was assessed by measuring thyroid function during the postpartum year. The HLA-DR and DQ phenotypes were assigned from restriction fragment length polymorphism analysis, and Bf, C4A and C4B allotypes were determined by immunofixation with anti-Bf or anti-C4 antibodies after electrophoresis. A weak association between the HLA class II antigens and PPT, as indicated by a reduced frequency of DR15 and DQ6 together with an increased frequency of-DR5 and DQ7, was confirmed. However, only the change in DR5 frequency remained significant after correction (corrected p < 0.05). Postpartum thyroiditis was also associated with frequency disturbances in BI and C4A allotypes but not C4B allotypes. Whilst this study has not provided evidence of a strong marker gene for PPT, it does not preclude the involvement of the MIIC in this condition. These data show disturbances in complement allotype frequencies, suggesting that the class III region may provide a useful focus for further study of this pathology.

Complement C4a↗
PubMed1981

Lymphocytotoxic antibodies and histocompatibility antigens in juvenile-onset diabetes mellitus.

Cold-reacting serum lymphocytotoxic antibodies (LCAs) were measured in sera from 230 insulin-dependent juvenile-onset diabetes mellitus (IDDM) patients and from 116 control subjects. LCAs were present in only 4% of control sera compared with 19% in IDDM patients. The most significant determinant of LCAs was time since onset of diabetes; within the first 12 mo, 55% of IDDM sera had LCAs, compared with 25% after one year and 15% after five years of diabetes. LCAs were absent in sera from patients with IDDM for 10 yr or more. Genetic factors were also implicated in susceptibility toi occurrence of LCAs. HLA antigen B8 and B18 were associated with an increased risk for LCAs, whereas HLA-B7 was associated with a decreased risk. The relative risk for LCAs in patients positive for HLA-B8 but not B7 was 2.3, compared with 0.0 in HLA-B7/B8 heterozygotes. In contrast, B7 did not provide protection from LCAs in B18/B7 IDDM patients. Properdin factor B (Bf) alleles, which are in linkage disequilibrium with alleles of the HLA-B locus, were also associated with LCAs, IDDM patients with alleles BfS1 or BfF hd a prevalence of LCAs of 7%, significantly less than the 39% in Bf-F1S or -F1 patients. LCAs were not identical or closely correlated to pancreatic islet cell antibodies. Our findings indicate genetic heterogeneity in, yet, another autoimmune process in IDDM.

Adolescent↗
PubMedDate not supplied

Insulin-resistant diabetes with insulin receptor autoantibodies in a male patient without acanghosis nigricans.

A 51-yr-old, nonobese, male patient presented with hyperglycemia and a recent 40-pound weight loss. Severe insulin resistance was documented in studies in which high amounts of insulin were infused using the Biostator GCIIS. Diabetic control was finally achieved with subcutaneous injections of 470 U of insulin per day. Positive laboratory findings included a mild pancytopenia, elevated erythrocyte sedimentation rate, decreased C3 and properdin, and increased IgA. Antinuclear or other autoantibodies were not present. Insulin antibody levels were within the range usually present in insulin-treated diabetic patients. Acanthosis nigricans was not present. Incubation of the patient's serum with IM-9 lymphoblastoid cells revealed that an insulin receptor antibody was present in a serum dilution of 1:80. Insulin-resistant diabetes mediated by insulin receptor antibodies may present in patients with immunologic findings but without overt dermatologic stigmata.

Acanthosis Nigricans↗
PubMed2003

Isolation and characterization of factor I of the bovine complement system.

OBJECTIVE: To isolate and characterize factor I of the bovine complement system. Sample Population-Serum obtained from the blood of beef cattle. PROCEDURES: Serum samples were fractionated to yield factor I by means of sequential precipitation, ion-exchange, and gel-filtration chromatography. The protein was identified throughout the procedure on the basis of its ability to degrade the alpha'-chain of bovine C3b in the presence of bovine factor H. Electrophoresis in polyacrylamide gels was used to assess the degradation of C3b and determine the molecular weights of factor I and its component polypeptide chains. RESULTS: Bovine factor I had an apparent molecular weight of 94 kd and consisted of 2 disulfide-bonded polypeptides that had apparent molecular weights of 51 and 42 kd (under reducing conditions). Factor H was required for the factor I cleavage of the alpha'-chain of bovine C3b into iC3b. A similar cofactor effect was provided by trypsinized bovine erythrocytes or erythrocyte ghosts. Bovine properdin was prepared and shown to be a single polypeptide chain of 58 kd in the reduced form. CONCLUSIONS AND CLINICAL RELEVANCE: Bovine factor I can be purified from serum by a simple 4-step procedure. It is structurally and functionally comparable to factor I of other species, and its purification completes the isolation and characterization of all the soluble components of the bovine alternative complement pathway.

Animals↗
PubMed1977

Eosinophilia and mast cell hyperplasia induced by parasite phospholipid.

Phospholipid preparations from the nematode Ascaris suum or cysts of Echinococcus granulosus (hydatid cysts) induced an eosinophilia when injected into the peritoneal cavity of rats. Peritoneal eosinophilia persisted throughout 21 days of daily injections of Ascaris lipid and was accompanied by blood eosinophilia, mast cell granule lysis and mast cell hyperplasia. The active material consisted of lecithin and lecithin plasmalogen, and in aqueous suspension had a membrane-like appearance. Electron microscopy revealed that the phospholipid was ingested by all types of cells in the peritoneal cavity, including mast cells, and was rapidly broken down by eosinophils. Phagocytosis was found to be complement dependent. The lipid combined with properdin in human serum and stimulated complement breakdown via the alternative complement pathway.

Animals↗
PubMed1995

Complement analysis in adult patients with a history of bacteremic pneumococcal infections or recurrent pneumonia.

Complement deficiencies are known to be associated with increased susceptibility to bacterial infections. In the present study we investigated 80 patients with either a history of pneumococcal bacteremic infection, or recurrent pneumonia, or both. Hemolytic screening tests for complement deficiency were performed and serum concentrations of C1q, C1s, C2, C3, C4, C4 isotypes, factor B, factor D, and properdin were determined. Complete deficiencies of single complement proteins were not found. 10 patients (12%) had a C4 isotype deficiency, but the frequency of homozygous C4A and C4B deficiency was not significantly increased. Seven patients (9%) had hypocomplementemia with low concentrations of at least 2 complement proteins. One of these patients had profound depletion of classical pathway components and findings suggesting acquired C1 esterase inhibitor deficiency. 16 patients (20%) had minor complement aberrations. A majority of the patients with hypocomplementemia suffered from other conditions associated with pneumococcal infections. However, impaired complement function could be a significant predisposing factor in some patients with invasive pneumococcal infections or recurrent pneumonia.

Acute Disease↗
PubMed1993

Genetic deficiencies of the complement system and association with disease--early components.

Genetic deficiency of one of the early components of the classical pathway of complement (C1q, C1r, C1s, C4 and C2) is often associated with clinical symptoms and immunochemical abnormalities common in idiopathic autoimmune diseases, such as lupus erythematosus, but also with an increased incidence of various, local and generalized infections. These observations are consistent with the current view of the complement system's role in handling immune complexes and combating microbial invasion. However, the absence of absolute correlations in these experiments of nature suggests that genetic defects of the classical pathway act only epistatically to other host factors and the primary etiologies of the associated diseases. In contrast, the strong association of properdin and factor D deficiency with serious infections caused by encapsulated Gram-negative bacteria suggests a more immediate involvement of the alternative pathway in a specific segment of immunity and its pathology. This concept is also supported by the primordial role of the alternative pathway in the evolution of the complement system and the apparent lethality of factor B deficiency. The gene structures of most of these early components have now been elucidated providing the basis for detailed analyses of the defective alleles, the determination of carrier status, and prenatal diagnosis.

Complement C1↗
PubMed1988

Complement-fixing gastric parietal cell autoantibodies. A good marker for the identification of type A chronic atrophic gastritis.

Using an indirect immunofluorescence (IIF) technique, gastric parietal cell autoantibodies of IgG class (GPCA-IgG) were found in 2% of a normal population, in 5-26% of organ-specific autoimmune subjects and in 100% of patients with pernicious anaemia. With the exception of subjects with alopecia, there was a significantly increased prevalence of GPCA-IgG in autoimmune patients with respect to normal controls. GPCA of IgA class were detected in 22% of GPCA-IgG positive subjects, whereas GPCA of IgM class were uncommon. One-hundred and fifteen subjects underwent gastroscopy and body mucosal biopsy. Histopathological findings of chronic atrophic gastritis (CAG) were present in 71% of GPCA-IgG positive autoimmune patients without pernicious anaemia, in 100% of GPCA-IgG positive patients with pernicious anaemia, and in 20% of GPCA negative autoimmune patients. Complement-fixation test was performed in 46 GPCA-IgG positive subjects without pernicious anaemia using the IIF method. Twenty-nine patients (63%) were found to fix complement fractions till C9 (CF-GPCA) together with properdin factor, and in 25 of them (86%) the histological examination of body gastric mucosa disclosed a CAG (P = 0.0003 versus GPCA-IgG positive/CF negative controls). No significant difference was observed for the prevalence of CAG in GPCA-IgG positive/CF negative subjects with respect to GPCA-IgG negative control group. We conclude that the presence of CF-GPCA represents a useful immunological marker in the identification of CAG, while no predictive value seems to be associated with non-complement fixing GPCA-IgG.

Adolescent↗
PubMed1992

Hormonal profiles in Italian late-onset adrenal hyperplasia correlate with HLA class III polymorphisms.

To investigate the genetic polymorphisms of the HLA region in late-onset adrenal hyperplasia, 13 Italian patients affected by the disease were analyzed for: (1) HLA-A and -B typing; (2) restriction fragment length polymorphism (RFLP) of DR beta, DQ beta, DQ alpha, 21-hydroxylase A and B genes; (3) fourth complement fraction loci A and B (C4A and C4B), second complement fraction (C2) and properdin B factor (Bf) complement typing; (4) hormonal characteristics associated with some HLA haplotypes. HLA alleles B14 and DR beta 1 were found to be significantly more frequent in patients with respect to controls (relative risk: 8.7 and 7.2, p less than 0.001 and p less than 0.0001, respectively). Also C4B*2, 1 duplication was more frequent in patients than in normal subjects (23% vs. 1.5%, p less than 0.0001). Moreover, patients carrying a duplicated C4B (as well as those having the B14 antigen) showed higher 17-hydroxyprogesterone levels after ACTH stimulation. RFLP analysis of 21-hydroxylase genes with a specific probe revealed a duplication of 21-hydroxylase A gene in 40% of patients. All these individuals carried the C4A*2 B*2,1 phenotype and 75% of them displayed a clearly recognizable duplication at the C4B locus. These data support the hypothesis that in late-onset adrenal hyperplasia the 21-hydroxylase A pseudogene, even if inactive, may play a negative role in the regulation of 21-hydroxylase biosynthesis. Furthermore, we suggest analyzing class III phenotypes to screen the enzymatic defect.

17-alpha-Hydroxyprogesterone↗
PubMed2001

Early immunological defects in comatose patients after acute brain injury.

OBJECT: The aim of this prospective study was to evaluate the phagocytic, humoral, and cellular arms of the immune system in comatose patients shortly after severe brain injury and to compare the findings with those reported earlier in patients in a persistent vegetative state. The study was conducted in intensive care units and immunology laboratories of university-affiliated hospitals in central Israel. METHODS: The study group consisted of 14 men aged 16 to 65 years who were comatose as a result of acute brain injury due to mechanical trauma. All were studied within 72 hours of injury. Brain damage was severe in all cases (Glasgow Coma Scale score < 8). Healthy age- and sex-matched volunteers served as simultaneous controls. Infections arose in nine (75%) of the 12 patients in whom data were available; the cumulative mortality rate was 38% (five of 13 patients in whom outcome data were available). Every patient exhibited one or more defects in at least one arm of the immune system. Significant deficiencies were noted in neutrophil superoxide release, immunoglobulin (Ig)G, IgG1, IgM, C1q, C2, properdin, alternate C pathway, T cells, T helper cells, T suppressor cells, and natural killer cells. In an earlier series of patients examined by the authors months after the primary insult, these impairments were absent in most of the patients in the vegetative state. CONCLUSIONS: Significant deficiencies of the immune system, particularly the cellular arm, are precipitated by severe brain injury within 72 hours of the event. These impairments probably play a role in the high rate of complicating infections and multiple organ failure. Together with earlier findings, the results of this study indicate that if brain-injured patients survive these hazards, their immune system will eventually recover.

Adolescent↗
PubMed2000

Novel mechanism of antibody-independent complement neutralization of herpes simplex virus type 1.

The envelope surface glycoprotein C (gC) of HSV-1 interferes with the complement cascade by binding C3 and activation products C3b, iC3b, and C3c, and by blocking the interaction of C5 and properdin with C3b. Wild-type HSV-1 is resistant to Ab-independent complement neutralization; however, HSV-1 mutant virus lacking gC is highly susceptible to complement resulting in > or =100-fold reduction in virus titer. We evaluated the mechanisms by which complement inhibits HSV-1 gC null virus to better understand how gC protects against complement-mediated neutralization. C8-depleted serum prepared from an HSV-1 and -2 Ab-negative donor neutralized gC null virus comparable to complement-intact serum, indicating that C8 and terminal lytic activity are not required. In contrast, C5-depleted serum from the same donor failed to neutralize gC null virus, supporting a requirement for C5. EDTA-treated serum did not neutralize gC null virus, indicating that complement activation is required. Factor D-depleted and C6-depleted sera neutralized virus, suggesting that the alternative complement pathway and complement components beyond C5 are not required. Complement did not aggregate virus or block attachment to cells. However, complement inhibited infection before early viral gene expression, indicating that complement affects one or more of the following steps in virus replication: virus entry, uncoating, DNA transport to the nucleus, or immediate early gene expression. Therefore, in the absence of gC, HSV-1 is readily inhibited by complement by a C5-dependent mechanism that does not require viral lysis, aggregation, or blocking virus attachment.

Adult↗
PubMed2002

C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase.

Contact between blood and a biomaterial surface induces an immediate complement-mediated inflammatory response. Under these conditions, the alternative pathway of complement is often initiated and amplified on the biomaterial surface. Adsorption of a protein such as C3 to a polymer surface induces conformational changes in the protein. Based on the expression on adsorbed C3 of conformational neoepitopes specific for bound C3 fragments, we have hypothesized that adsorbed C3 is able to bind factor B and form a functional C3,Bb convertase. Using a quartz crystal microbalance to monitor binding of proteins to a polymer surface, we have demonstrated that a functional C3-containing alternative pathway convertase can be formed, in particular, in the presence of properdin. These data indicate that adsorption of C3 induces conformational changes that turn C3 into a C3b-like molecule that is able to participate in the functioning of the alternative convertase, and they suggest a new mechanism for complement activation on a biomaterial surface.

Adsorption↗
PubMed2005

Binding of the complement inhibitor C4bp to serogroup B Neisseria meningitidis.

Neisseria meningitidis (meningococcus) is an important cause of meningitis and sepsis. Currently, there is no effective vaccine against serogroup B meningococcal infection. Host defense against neisseriae requires the complement system (C) as indicated by the fact that individuals deficient in properdin or late C components (C6-9) have an increased susceptibility to recurrent neisserial infections. Because the classical pathway (CP) is required to initiate efficient complement activation on neisseriae, meningococci should be able to evade it to cause disease. To test this hypothesis, we studied the interactions of meningococci with the major CP inhibitor C4b-binding protein (C4bp). We tested C4bp binding to wild-type group B meningococcus strain (H44/76) and to 11 isogenic mutants thereof that differed in capsule expression, lipo-oligosaccharide sialylation, and/or expression of either porin (Por) A or PorB3. All strains expressing PorA bound radiolabeled C4bp, whereas the strains lacking PorA bound significantly less C4bp. Increased binding was observed under hypotonic conditions. Deleting PorB3 did not influence C4bp binding, but the presence of polysialic acid capsule reduced C4bp binding by 50%. Bound C4bp remained functionally active in that it promoted the inactivation of C4b by factor I. PorA-expressing strains were also more resistant to C lysis than PorA-negative strains in a serum bactericidal assay. Binding of C4bp thus helps Neisseria meningitidis to escape CP complement activation.

Amino Acid Sequence↗
PubMed2006

Homozygosity for the IgG2 subclass allotype G2M(n) protects against severe infection in hereditary C2 deficiency.

Homozygous C2 deficiency (C2D) is the most common deficiency of the classical complement pathway in Western countries. It is mostly found in patients with autoimmune disease or susceptibility to bacterial infections and in healthy persons. We wished to assess to what extent other immunological factors might explain differences of susceptibility to infections in C2D. For this reason, 44 Swedish patients with C2D were stratified with regard to the severity of documented infections. Investigations of IgG subclass levels, IgG subclass-specific GM allotypes, concentrations of factor B, properdin, and factor H, and polymorphisms of mannan-binding lectin and the Fc receptors FcgammaRIIa and FcgammaRIIIb were performed. Homozygosity for the G2M*n allele, which is known to promote Ab responses to polysaccharide Ags, was strongly associated with the absence of severe infections (p < 0.001) in the patients, suggesting a major protective role. The combination of mannan (or mannose)-binding lectin and C2 deficiency was found to be a minor susceptibility factor for invasive infection (p = 0.03). Low concentrations of IgG2 and factor B might sometimes contribute to susceptibility to infection. Other factors investigated did not appear to be important. In conclusion, the findings indicated that efficient Ab responses to polysaccharides are protective against severe infection in C2D. Implications with regard to vaccination should be considered.

Adult↗