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PubMed1976

[Evaluation of the changes of natural resistance in patients with diffuse peritonitis].

A suppression of humoral and cell mechanisms of natural nonspecific resistance was found in patients with diffuse peritonitis. A considerable degranulation of basophilic leucocytes was indicated by the direct Shelley reaction, that evidences alterations in the functional state of these cells. Postoperatively, there is a break in restoration of the activity of properdine and its cofactors, and a considerable suppression of the phagocytic capacity of microphages is noted, that leads inevitably to a reduction of immune reactivity.

Basophils↗

PubMed1989

Subacute cutaneous lupus erythematosus. Genetic markers and clinical and immunological findings in patients.

The role of HLA and complement genes was studied in 13 patients with subacute cutaneous lupus erythematosus. Genetic markers and by combining the major histocompatibility complex class I (HLA-A, -B, and -C), class II (HLA-DR), and class III (properdin factor B [BF] and C4) phenotyping with DNA level analysis of the C4 region. Of our patients, 54% had DR2 antigens and 50% had DR3 antigens, when the frequencies in the controls were 25% and 33%, respectively. The DR3 antigen was associated with annular skin lesions that were associated with a younger age at onset, whereas the DR2 antigen was associated with papulosquamous skin lesions and an older age at onset. The frequency of C4 null alleles was 83% in the patients and 50% in the controls. The null alleles were found in both C4A and C4B loci and were not associated with any special major histocompatibility complex haplotype. The DNA studies showed that the null phenotype mostly resulted from a gene deletion. A highly increased frequency of complement C4 null alleles may be a predisposing factor for cutaneous lupus erythematosus and especially of the subacute cutaneous type.

Adult↗

PubMed1981

Hereditary ataxia and the sixth chromosome.

Possible linkage of the gene or genes for dominant hereditary ataxia and three genetic markers on the short arm of the sixth chromosome (HLA, properdin factor B [Bf], and glyoxalase I) was investigated in five families. Logarithmic odds (lod scores) were calculated for the linkages and found to be either inconclusive or in favor of nonlinkage. Caution is advised in the summing of lod scores for separate families because of the wide spectrum of clinical and anatomical manifestations of dominant hereditary ataxia. Three families with recessive hereditary ataxia were also studied. Identical haplotypes occurred in affected and unaffected siblings. It did not appear likely that the recessive genes of the parents were transmitted in linkage with the markers on the short arm of the sixth chromosome.

Ataxia↗

PubMed2001

Complement factor I deficiency associated with recurrent meningitis coinciding with menstruation.

BACKGROUND: Complement (C) factor I deficiency is a rare immunodeficiency state frequently associated with recurrent pyogenic infections in early infancy. This deficiency causes a permanent uncontrolled activation of the alternative pathway resulting in massive consumption of C3. PATIENT: A 23-year-old woman with monthly recurrent meningitis episodes, mostly in the perimenstrual period, since August 1999. Previously, at age 16 years, she had meningococcal sepsis, also coinciding with menstruation. OBJECTIVES: To study the patient and her family to elucidate the molecular defects in the pedigree and to evaluate her clinical evolution. RESULTS: We describe clinical, immunological, and treatment follow-up during this period. First, we characterized the existence of a total complement factor I deficiency defined by undetectable levels by enzyme immunosorbent assay. This total deficiency was also found in her sister. Her parents and brother had approximately half of the normal levels. In addition, the patient had very low levels of C3; factor B; and an important reduction of factor H, properdin, C5, C7, and C8 complement components. Additional studies in the patient's sera evidenced high levels of immune complexes containing C1q and immunoglobulin (Ig) G, as well as C3b/factor H, C3b/properdin, C3b/IgG, and properdin/IgG complexes. Treatment with prophylactic antibiotics, antiestrogen medication, plasma infusions, or intravenous immunoglobulin has been unsuccessful in avoiding consecutive meningitis episodes. CONCLUSION: For the first time to our knowledge, these data present an unusual relationship between meningitis episodes and menstruation in factor I immunodeficiency.

Adolescent↗

PubMed1981

Deficient activity of the alternative pathway of complement in beta thalassemia major.

Patients with thalassemia major suffer frequent and serious infections, especially after splenectomy. To explore the basis for this susceptibility, we examined activity of the complement system in sera from 24 patients. All sera had normal or increased activity of the classic complement pathway. However, six of the 24 (three with and three without splenectomy) had abnormal alternative pathway function, and mean alternative pathway activity was significantly decreased in both splenectomized and nonsplenectomized patients. Mean concentrations of C3, factor B, properdin, and immunoglobulins were normal. Defective alternative pathway function, especially in conjunction with asplenia, could contribute to the propensity to infection that exists in thalassemia.

Adolescent↗

PubMed1996

Complement activation by IgG immobilized on methylated silicon.

Activation of the complement system by immobilized IgG on methylated silicon was studied by ellipsometry/antibody-, ELISA-, and RIA techniques after exposure to human serum at 37 degrees C for up to 1 h. The IgG-covered surfaces rapidly activated the complement system and the combined results suggest an initial classical pathway activation. Complement factor 1q (C1q) and IgG were antibody-detectable on the surfaces for serum incubations up to 5 min but not thereafter. Anti-C3c and anti-properdin bound to the surfaces at all serum incubation times. Experiments with 125I-IgG preadsorbed to surfaces, or added to normal-, EGTA-, and EDTA-sera, showed that IgG was not displaced from the protein film by serum.

CD4 Antigens↗

PubMed1997

Temporal studies on the deposition of complement on human colostrum IgA and serum IgG immobilized on methylated silicon.

The temporal deposition of selected complement proteins from human serum onto immobilized human colostrum immunoglobulin (Ig)A and human IgG on hydrophobic silicon was studied by ellipsometry-antibody techniques after incubations at 37 degrees C for up to 1 h. In parallel experiments the serum soluble iC3b, C4d, and Bb were detected by enzyme-linked immunosorbent assay techniques. The IgA-coated surfaces showed activation via the alternative pathway, and displayed a lag phase in the deposition of increased amounts of serum proteins, and anti-C3c and antiproperdin. Anti-IgG, -C1q, -C4, -factor H and -factor B were not deposited at any time to IgA surfaces. Upon coating of the surface with IgG, the classical pathway was rapidly activated and bound, then anti-C3c, antiproperdin, and after short serum incubation times, also anti-C1q and anti-IgG. When factor B-depleted or heat-treated sera were used, the observation was that properdin deposited onto IgG-coated surfaces from both. Ellipsometry and antibody techniques offer a convenient and rapid way to indicate the activation of the complement system on solid surfaces and facilitates a time-resolved determination of the activation pathway(s).

Biocompatible Materials↗

PubMed2001

Ellipsometric in vitro studies on blood plasma and serum adsorption to zirconium.

Ellipsometry/antibody techniques were used to study the adsorption of heparinized human blood plasma and serum onto spontaneously oxidized zirconium, and a colorimetric assay measured the formation of kallikrein by the surface in citrated plasma. After 10 min incubation in the blood plasma the protein film thickness was approximately 4.2 nm, and the film bound polyclonal antibodies mainly against high molecular weight kininogen (HMWK), immunoglobulin G (IgG) and fibrinogen. After 5 or 60 min of incubations in whole normal or EGTA sera, antibodies against complement factor 3 (C3) and complement factor 3d (C3d) deposited to the surface. Factor H and complement factor 1q (C1q) were detected similarly after 1 and 5 min of incubation in 1-10% normal serum in veronal buffer, respectively. The indications are that upon contact with blood plasma, zirconium activates the intrinsic pathway of coagulation and is opsonized with C3. The failure to detect properdin and transient presence of factor H at the surface suggest that complement binds to zirconium although the activation becomes quickly down-regulated.

Adsorption↗

PubMed1979

Temperature dependent activation of the alternate complement pathway by an IgG cryoglobulin.

A patient with chronic membranoproliferative glomerulonephritis is presented whose serum contains a monoclonal IgG3 cryoglobulin. The presence of persistent hypocomplementemia suggested the possibility that the cryoglobulin, upon cold-induced precipitation, was capable of activating the complement system. Because visible cryoprecipitation commenced in vitro at 30 degrees C, the patient's serum and normal serum had been added the isolated cryoglobulin were repeatedly cooled to 30 degrees C and rewarmed to 37 degrees C. This reproduction of the in vivo counterpart of blood circulating through an extremity exposed to the cold resulted in activation of C3-proactivator (properdin factor B), C3 cleavage, and a 78% reduction in total hemolytic complement. This study demonstrates that IgG is capable of activating complement via the alternate pathway and reveals a mechanism through which this can occur in vivo; namely, by means of temperature dependent polymerization. In addition, we postulate that episodic complement activation initiated by the cryoglobulin contributed to the development of glomerulonephritis in this patient.

Aged↗

PubMed1982

The HLAB18,BFF1 in haplotype in type 1 diabetes.

We have investigated the properdin factor B (BF) locus as a possible marker for Type 1 diabetes. The frequencies of the four BF alleles were determined among 70 Type 1 diabetics with onset before age 18 years. The frequency of BF F1 among the diabetics was increased compared with 206 controls (15.7 vs 3.4%). The relative risk (RR) associated with BF F1 was 5.30. The suggestion that BF is most strongly associated with onset of diabetes under 10 years of age was not supported. HBLA 18 was increased (RR = 4.91) and B7 was decreased in frequency (RR = 0.41) among the 62 diabetics tested compared with 238 controls. An association was observed between HLAB 18 and BF F1 among the diabetics. A study of 12 families in which BF*F1 was segregating suggested that BF*F1 and HLAB*18 are components of a haplotype associated with Type 1 diabetes in this population and that both haplotypes of an affected parent may contribute to the development of Type 1 diabetes.

Adolescent↗

PubMed1984

Linkage analysis in a large kindred with autosomal dominant transmission of polyglandular autoimmune disease type II (Schmidt syndrome).

Schmidt syndrome (PGA syndrome type II) is a rare condition characterized by polyglandular failure. It is an autosomal dominant trait with variable expressivity that was inherited over four generations in an the Indiana kindred. Association of HLA-B8 has been reported with Schmidt syndrome. Our proband is a 12-year-old boy with Addison disease, insulin dependent diabetes mellitus (IDDM), and vitiligo. Two of his eight sibs had either IDDM (sister) or vitiligo and hyperthyroidism (brother). His mother had hypothyroidism. Seven members of earlier generations apparently were also affected. We obtained peripheral blood for HLA and genetic analysis from 21 relatives in a family with 8 Schmidt syndrome individuals in three generations. HLA studies on 15 affected and unaffected relatives showed only 2 of 7 persons with B8-containing haplotypes. Therefore, no association exists between the B8-containing haplotype and the syndrome. We identified informative marker loci. No evidence for linkage of the Schmidt locus to any of the 14 markers was found and close linkage to esterase D and adenylate kinase and possibly properdin factor B was excluded.

Addison Disease↗

PubMed1984

Tissue culture demyelination by normal human serum.

Serum from all of 20 normal individuals induced some degree of demyelination when applied to well-myelinated mouse cerebellum cultures. An intact complement sequence through C5 is required. Demyelinating activity was heat labile at 56 degrees C for 30 minutes but was not destroyed at 50 degrees C for 30 minutes (which inhibits properdin factor B and alternate complement pathway activation, but not the classic complement pathway). Sera from patients with agammaglobulinemia, C4 deficiency, or C6 deficiency all induced demyelination. Our results suggest that tissue culture demyelination results from nonimmunoglobulin activation of the alternate complement pathway and is not limited to sera from patients with neurological disease.

Animals↗

PubMed1996

Regulation of alternative pathway activation and C3a production by adipose cells.

Adipose tissue is a major source of adpisin/factor D of the alternative pathway of complement. Adipose tissue also expresses the two other complement components which are involved in the first activation step of the alternative pathway, factor B and C3, and this step is activated in adipose tissue, producing C3a/Acylation Stimulating Protein (C3a/ASP), a stimulator of triglyceride synthesis. Complement activation is a highly regulated process, however, nothing is known about regulation of complement activation in adipose tissue. To gain insight into the nature of adipose complement activation and its regulation, we have now examined the expression of several complement activation regulatory genes, and analyzed the production of C3a/ASP in lean vs. obese, adpisin-deficient mice. We found that undifferentiated preadipocytes expressed the mRNAs encoding the negative regulatory proteins Crry and factor H, but expression of both genes was decreased upon differentiation. The positive regulator properdin, as well as Crry and factor H, were found in adipose tissue. None of these genes was regulated in murine genetic obesity. To investigate the relative levels of complement activation in lean vs. adpisin-deficient obese mice, we developed a radioimmunoassay for measurement of murine C3a/ASP in plasma. We report that there was no significant difference in the level of C3a in lean vs. obese plasma; however, we found a positive correlation between C3a and plasma triglyceride levels in normal lean mice.

Adipose Tissue↗

PubMed1985

Debridement and replantation of the spleen with microsurgical restoration of blood flow.

Splenectomy continues to be the most commonly chosen method of management of traumatic injury to the spleen. However, patients of all age groups who have undergone splenectomy have significant impairment of immune functions as demonstrated by decreased production of IGM, tufsin, and properdin. This immune deficiency has been clinically manifested by an increased incidence of postsplenectomy pneumonia and sepsis which is reduced but not eliminated by the use of pneumococcal vaccine and/or prophylactic antibiotics. This paper presents the results of a study of the feasibility of repair and replantation of injured spleens using microsurgical techniques. Twenty cats had their spleens removed, finger-fractured, and debrided. The cats were then assigned to one of four groups. Group I had the entire spleen replanted but only 75% of the parenchyma revascularized. Group II had 75% of the parenchyma revascularized and replanted. Group III had 50% revascularized and replanted, and Group IV 25% revascularized and replanted. Patency of the anastomoses was assessed by postoperative arteriography. Restoration of reticuloendothelial (filter) function was assessed by the use of technetium sulphur colloid scans which showed preservation of reticuloendothelial function of the revascularized segments but absence of function in nonrevascularized segments which had been replanted. Histologic examination of replanted spleens harvested at 8 weeks showed normal architecture of red and white pulp in all areas that had been revascularized. However, in those spleens where the entire spleen had been replanted but only partially revascularized, the nonrevascularized segments were degenerated and atrophic.

Animals↗

PubMed1995

Inhibition of angiogenesis by thrombospondin-2.

To assess the ability of proteins of the thrombospondin family to inhibit angiogenesis, recombinant murine thrombospondin-2, bovine thrombospondin-2/CISP and thrombospondin-5/COMP were purified and tested for ability to block the migration of capillary endothelial cells towards a variety of inducers and to inhibit neovascularization induced in the rat cornea. Both preparations of thrombospondin-2 were active inhibitors in vitro and in vivo whereas thrombospondin-5/COMP was inactive. These results define thrombospondin-2 as a newly identified naturally occurring inhibitor of angiogenesis and suggest that the properdin-like type 1 modules that it shares with antiangiogenic thrombospondin-1 and are missing in thrombospondin-5/COMP could contribute to this activity.

Adrenal Glands↗

PubMed1993

Isolation and characterization of the mouse thrombospondin 3 (Thbs3) gene.

The DNA sequence of the coding region of the mouse thrombospondin (TSP) 3 gene has been determined by analysis of both genomic and cDNA clones. Like TSP1 and TSP2, TSP3 has a homologous COOH-terminal domain and seven type III (Ca(2+)-binding) repeats. However, TSP3 contains four, rather than three, type II repeats and lacks the type I (TSP or properdin) repeats and procollagen homology characteristic of TSP1 and TSP2. In addition, the NH2-terminal domain of TSP3 differs markedly, both in sequence and in exon/intron structure, from that in TSP1 or TSP2. The gene is located on mouse chromosome 3, bands E3-F1, immediately upstream from the Muc1 (episialin) gene and is expressed in the developing mouse in a pattern that also differs from that of TSP1 or TSP2. Based on its structure, we suggest that TSP3 may play both a unique role in cell-matrix interactions and perform functions that overlap with those of TSP1 and TSP2.

Amino Acid Sequence↗

PubMed1994

The complete sequence and promoter activity of the human A-raf-1 gene (ARAF1).

The raf proto-oncogenes encode cytoplasmic protein serine/threonine kinases, which play a critical role in cell growth and development. One of these, A-raf-1 (human gene symbol, ARAF1), which is predominantly expressed in mouse urogenital tissues, has been mapped to an evolutionarily conserved linkage group composed of ARAF1, SYN1, TIMP, and properdin located at human chromosome Xp11.2. We have isolated human genomic DNA clones containing the expressed gene (ARAF1) on the X chromosome and a pseudogene (ARAF2) on chromosome 7p12-q11.21. Analysis of the nucleotide sequence from the ARAF1 genomic clones demonstrated that it consists of 16 exons encoded by minimally 10,776 nucleotides. The major transcriptional start site (+1) was determined by RNase protection and primer extension assays. Promoter activity was confirmed by functional assays using DNA fragments fused to a CAT reporter gene. The ARAF1 minimal promoter, located between nucleotides -59 and +93, has a low G + C content and lacks consensus TATA and Inr sequences but shows sequence similarity at position -1 to the E box that is known to interact with USF and TFII-I transcription factors.

3T3 Cells↗

PubMedDate not supplied

Molecular heterosis: a review.

Molecular heterosis occurs when subjects heterozygous for a specific genetic polymorphism show a significantly greater effect (positive heterosis) or lesser effect (negative heterosis) for a quantitative or dichotomous trait than subjects homozygous for either allele. At a molecular level heterosis appears counterintuitive to the expectation that if the 1 allele of a two-allele polymorphism is associated with a decrease in gene expression, those carrying the 11 genotype should show the greatest effect, 12 heterozygotes should be intermediate, and 22 homozygotes should show the least effect. We review the accumulating evidence that molecular heterosis is common in humans and may occur in up to 50% of all gene associations. A number of examples are reviewed, including those for the following genes: ADRA2C, C3 complement, DRD1, DRD2, DRD3, DRD4, ESR1, HP, HBB, HLA-DR DQ, HTR2A, properdin B, SLC6A4, PNMT, and secretor. Several examples are given in which the heterosis is gender-specific. Three explanations for molecular heterosis are proposed. The first is based on an inverted U-shaped response curve in which either to little or too much gene expression is deleterious, with optimal gene expression occurring in 12 heterozygotes. The second proposes an independent third factor causing a hidden stratification of the sample such that for in one set of subjects 11 homozygosity is associated with the highest phenotype score, while in the other set, 22 homozygosity is associated with the highest phenotype score. The third explanation suggests greater fitness in 12 heterozygotes because they show a broader range of gene expression than 11 or 22 homozygotes. Allele-based linkage techniques usually miss heterotic associations. Because up to 50% of association studies show a heterosis effect, this can significantly diminish the power of family-based linkage and association studies.

Alleles↗