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PubMed1983

A comparison of the effects of heat-aggregated and chemically cross-linked IgG on monocyte C2 production.

Heat or alkali-aggregated IgG was found to inhibit C2 production by monocytes, whereas chemically cross-linked IgG and antigen-antibody complexes stimulated C2 synthesis. Chemically cross-linked IgG was shown to inhibit monocyte EA-rosette formation presumably because it blocked monocyte Fc receptors. Furthermore stimulation of C2 synthesis was limited to polymers of the IgG1 and IgG3 subclasses. In contrast, heat-aggregated IgG failed to inhibit monocyte EA-rosette formation significantly, and all the heat-aggregated IgG subclasses inhibited C2 production. It therefore appears that physically aggregated IgG does not bind effectively to Fc receptors. As the effects of physically aggregated IgG C2 production are similar to those of the hydrophobic proteins casein and alkali-denatured human serum albumin (HSA), it is suggested that hydrophobic residues in the aggregates bind preferentially to the lipid component of the cell membrane.

Animals↗
PubMed1980

Heterozygous C2-deficiency and myasthenia gravis.

Complement deficiency states in myasthenia gravis (MG) have not been reported previously. We describe a 19-year-old woman with typical MG and heterozygous C2 deficiency, along with HLA typing of the patient and her immediate family.

Acetylcholine↗
PubMed1989

Association of HLA-DR4 with ocular cicatricial pemphigoid.

HLA typing for A, B, and C locus antigens was performed on 70 patients with ocular cicatricial pemphigoid (OCP) and on 1849 controls. Additionally, typing for DR and DQ antigens and for the complement proteins (C2, factor B, C4A, and C4B) was performed on 63 patients and on the same control population. A significantly higher incidence of the following antigens was found in the OCP patients when compared to the control population: DR4 (43% in patients compared to 18% in controls, p = 0.0001); DR5 (41% compared to 16%, p = 0.0001); DQw3 (57% compared to 31%, p = 0.0010); A2 (60% compared to 28%, p = 0.0001); B8 (24% compared to 13%, p = 0.0086); B35 (19% compared to 9%, p = 0.0097); and B49 (7% compared to 2%, p = 0.0052). The complement types SC01, SC30, SC32, SC41, and SC42 were also significantly increased in patients compared to controls. No significant differences were found based on ethnic background, involvement of multiple mucous membranes, history of glaucoma, or deposition of specific immunoreactants in conjunctival biopsy samples. These findings may provide further insights into the pathogenesis of OCP and may help to localize a susceptibility gene for this autoimmune disease.

Complement Fixation Tests↗
PubMed1977

Opsonic requirements for phagocytosis of Streptococcus pneumoniae types VI, XVIII, XXIII, and XXV.

An assay system employing radiolabeled, heat-killed Streptococcus pneumoniae and human polymorphonuclear leukocytes was utilized to study serum pneumococcal opsonic requirements. Comparing the kinetics of phagocytosis in normal serum, heat-inactivated serum, immunoglobulin G (IgG)-deficient serum, C2-deficient serum, and magnesium dichloride ethyleneglycol-tetraacetic acid (MgEGTA)-chelated serum allowed definition of the opsonic requirements for four pneumococcal serotypes: VI XVIII, XXIII, and XXV. All four serotypes were efficiently opsonized in 10% normal serum. Only type XVIII was opsonized in heat-inactivated serum. All four were also opsonized in IgG-deficient serum but not as efficiently as in normal serum. Opsonization via the alternative pathway was diminished for all four serotypes in 10% MgEGTA-chelated and C2-deficient serum. Furthermore, by varying the concentration of MgEGTA-chelated serum, it was found that type XXV was least efficiently opsonized via the alternative pathway. The quantitative nature of this assay system will permit measurement of bacterial and host factors that may contribute to host susceptibility to pneumococcal infection.

Blood↗
PubMed1984

HLA-linked complement markers in Alzheimer's and Parkinson's disease: C4 variant (C4B2) a possible marker for senile dementia of the Alzheimer type.

We determined the gene frequencies for the alleles of the HLA-linked complement markers C2, properdin factor B (BF), C4A (Rodgers) and C4B (Chido), and the red cell enzyme glyoxalase-I in 38 unrelated patients with senile dementia of the Alzheimer type, 42 patients with idiopathic Parkinson's disease, and 59 unaffected, aged-matched control blood donors. In senile dementia of the Alzheimer type and in Parkinson's disease, no significant difference was found in the gene frequencies of alleles at either the BF, C2, or GLO-I locus compared with those of age-matched controls. In senile dementia of the Alzheimer type, a striking increase in the frequency of the rare C4B locus allele, C4*B2, was apparent, resulting in the high relative risk of RR = 8.8 (p less than 0.0001) for this disorder.

Alleles↗
PubMed1996

Multifocal stenosing ulcerations of the small intestine revealing vasculitis associated with C2 deficiency.

A patient with cryptogenic multifocal ulcerous stenosing enteritis characterized by repeated bouts of intestinal obstruction, ulcerative stenosis of the small bowel relapsing after surgical resection, and steroid sensitivity is described. Fourteen strictures of the jejunum were found at laparotomy. Despite resection, abdominal pain persisted. Steroid therapy was effective but led to dependence. In our patient, cryptogenic multifocal ulcerous stenosing enteritis was associated with fever, asthma, Raynaud's phenomenon, sicca syndrome, heterozygous type I C2 deficiency (28-base pair gene deletion), stenosis, and aneurysms in selective mesenteric angiography. It is hypothesized that cryptogenic multifocal ulcerous stenosing enteritis might be related to a particular form of polyarteritis nodosa with mainly intestinal expression or to a yet unclassified independent vasculitis.

Adult↗
PubMed1987

Desensitization to factor VIII in a patient with classic hemophilia and C2 deficiency.

Factor VIII therapy has been reported to cause anaphylactic reactions in patients with hemophilia. Desensitization attempts have been complicated by severe allergic reactions that have prevented the achievement of protective factor VIII levels. We report successful administration of factor VIII by a graded dose desensitization protocol in a 36-year-old man with hemophilia A who had previously experienced anaphylactic reactions to factor VIII infusions. The reactions were manifested by urticaria, choking, and bronchospasm and were not prevented by pretreatment with antihistamines and corticosteroids. Intradermal skin test with factor VIII was positive. Serum levels of circulating immune complexes were slightly elevated. Persistently low serum C2 levels were consistent with genetic C2 deficiency. These findings suggest the possibility of Type I (IgE mediated) and Type III (immune complex) immunopathogenic mechanisms. Our experience suggests that administration of factor VIII by graded dose desensitization protocol may offer a practical therapeutic approach for management of hemorrhage in patients with classic hemophilia who are allergic to factor VIII.

Adult↗
PubMed1982

[Immunological changes following heart surgery under extracorporeal circulation (author's transl)].

Post-operative immunological changes were studied in 40 patients undergoing heart surgery. Tty-five patients were operated upon under extracorporeal circulation (ECC), and 15 without ECC. Immunological investigations were performed before, immediately after the operation and again 7 days later. The post-operative changes recorded were early decrease in IgG and IgM followed by a rise in IgM, transient lymphocytopenia affecting mainly T lymphocytes and delayed increase in complement (CH50, C2, C3). These changes were comparable in both groups of patients and therefore seemed to relate to the operation itself rather than to the ECC. It may be concluded that ECC does not appear to increase the risk of post-operative infection by depressing immune defence mechanisms.

Adolescent↗
PubMed2002

Sodium bicarbonate treatment and ubiquitin gene expression in acidotic human subjects with chronic renal failure.

BACKGROUND: In chronic renal failure, metabolic acidosis is associated with increased whole body protein degradation. In rats this effect of acidosis occurs in skeletal muscle and is associated with increased ubiquitin mRNA expression. This has not been demonstrated in humans. MATERIALS AND METHODS: Six patients with chronic renal failure and acidosis underwent muscle biopsy before and after 1 month's treatment with sodium bicarbonate. RNA was extracted from the biopsy, and the expression of the genes for ubiquitin and the proteasome component, C2, were measured by Northern blotting. RESULTS AND CONCLUSIONS: There was no significant difference in the expression of ubiquitin or C2 after bicarbonate treatment. This is contrast with results from animal models of acidosis and some other catabolic conditions in humans. This may reflect the complexity of the ubiquitin-dependent pathway, and it may be that changes in ubiquitin expression are only seen with more severe and/or acute changes in pH.

Acidosis↗
PubMed2000

Hypoxia increases the sensitivity of the L-type Ca(2+) current to beta-adrenergic receptor stimulation via a C2 region-containing protein kinase C isoform.

The effects of hypoxia on the L-type Ca(2+) current (I:(Ca-L)) in the absence and presence of the ss-adrenergic receptor agonist isoproterenol (Iso) were examined. Exposing guinea pig ventricular myocytes to hypoxia alone resulted in a reversible inhibition of basal I:(Ca-L). When cells were exposed to Iso in the presence of hypoxia, the K:(0.5) for activation of I:(Ca-L) by Iso was significantly decreased from 5.3+/-0.7 to 1.6+/-0.1 nmol/L. The membrane-impermeant thiol-specific oxidizing compound 5, 5'-dithio-bis(2-nitrobenzoic acid) (DTNB) attenuated the inhibition of basal I:(Ca-L) by hypoxia 81.3+/-9.4% but had no effect on the increase in sensitivity of I:(Ca-L) to Iso. In addition, DTT mimicked the effects of hypoxia on basal I:(Ca-L) and the increase in sensitivity to Iso. Neither the inhibitors of guanylate cyclase LY-83583 or methylene blue nor the NO synthase inhibitor N:(G)-monomethyl-L-arginine monoacetate had any effect on the basal inhibition of I:(Ca-L) or the decrease in K:(0.5) for activation of I:(Ca-L) by Iso during hypoxia. However, the protein kinase C (PKC) inhibitors bisindolylmaleimide I and Gö 7874 significantly attenuated the increase in sensitivity of I:(Ca-L) to Iso. More specifically, the response was attenuated when cells were dialyzed with a peptide inhibitor of the C2 region-containing classical PKC isoforms. The same effect was not observed with the PKCepsilon peptide inhibitor. These results suggest that hypoxia regulates I:(Ca-L) through the following 2 distinct mechanisms: direct inhibition of basal I:(Ca-L) and an indirect effect on the sensitivity of the channel to ss-adrenergic receptor stimulation that is mediated through a classical PKC isoform.

Animals↗
PubMed2004

Characterization of recombinant mannan-binding lectin-associated serine protease (MASP)-3 suggests an activation mechanism different from that of MASP-1 and MASP-2.

Mannan-binding lectin (MBL)-associated serine proteases (MASP-1, -2, and -3) are homologous modular proteases that each associate with MBL and L- and H-ficolins, which are oligomeric serum lectins involved in innate immunity. To investigate its physicochemical, interaction, and enzymatic properties, human MASP-3 was expressed in insect cells. Ultracentrifugation analysis indicated that rMASP-3 sedimented as a homodimer (s(20,w) = 6.2 +/- 0.1 S) in the presence of Ca(2+), and as a monomer (s(20,w) = 4.6 +/- 0.1 S) in EDTA. As shown by surface plasmon resonance spectroscopy, it associated with both MBL (K(D) = 2.6 nM) and L-ficolin (K(D) = 7.2 nM). The protease was produced in a single-chain, proenzyme form, but underwent slow activation upon prolonged storage at 4 degrees C, resulting from cleavage at the Arg(430)-Ile(431) activation site. Activation was prevented in the presence of protease inhibitors iodoacetamide and 1,10-phenanthroline but was not abolished upon substitution of Ala for the active site Ser(645) of MASP-3, indicating extrinsic proteolysis. In contrast, the corresponding mutations Ser(627)-->Ala in MASP-1 and Ser(618)-->Ala in MASP-2 stabilized the latter in their proenzyme form. Likewise, the MASP-1 and MASP-2 mutants were each activated by their active counterparts, but MASP-3 S645A was not. Activated MASP-3 did not react with C1 inhibitor; had no activity on complement proteins C2, C4, and C3; and only cleaved the N-carboxybenzyloxyglycine-L-arginine thiobenzyl ester substrate to a significant extent. Based on these observations, it is postulated that MASP-3 activation and control involve mechanisms that are different from those of MASP-1 and -2.

Alanine↗
PubMed1985

Sex influences transmission of the supratype associated with the C2 deficiency allele: a possible mechanism for the maintenance of heterozygosity and disease susceptibility.

We have examined the transmission of the supratype associated with C2 deficiency (C2Q0) using our own and many published pedigrees in order to determine whether nonrandom transmission may contribute to the stability of disease-associated supratypes. Unexpectedly, we found that C2Q0 may be preferentially transmitted to the opposite sex and therefore propose that such "zig-zag" transmission may result in the preservation of recessive disease susceptibility genes and in the maintenance of heterozygosity. Further pedigrees are required to verify our findings.

Alleles↗
PubMed1985

Molecular organization and in vitro expression of murine class III genes.

These experiments demonstrate that at least two types of gene duplications have occurred during the evolution of the S region. The first type, which produced the C2 and factor B genes, involved a short segment of the chromosome encompassing a single gene. The related products have subsequently diverged yielding sequences which do not cross-hybridize. Further duplication of these genes has not been observed. The second type of duplication consisted of a much longer primordial sequence, spanning approximately 55 kb of genomic DNA and including at least two genes, C4/Slp and 21-hydroxylase. The duplicated sequences are separated by a segment of single copy sequence of as yet undefined length. These duplicated sequences have been relatively conserved. There is evidence that further duplication of this region is possible (as seen in the H-2w7 strain) although the exact nature of the increase in gene number has not been fully characterized. Detailed analysis of cosmid clones which span these two duplications has permitted the assignment of a new pair of loci to the S region, encoding 21-hydroxylase A and B. The advantage conferred by linkage of the gene encoding this adrenal steroid biosynthesis enzyme to the genes encoding complement components C2, factor B, and C4 is unclear, as is the advantage of the association of all of the class III genes with the remainder of the MHC. The availability of cloned sequences containing all of the class III genes permits further study of the factors which govern the tissue specificity of their expression and which confer androgen responsiveness on certain of the Slp alleles.

Animals↗
PubMed1998

Molecular cloning of XNLRR-1, a Xenopus homolog of mouse neuronal leucine-rich repeat protein expressed in the developing Xenopus nervous system.

We report the isolation and characterization of a Xenopus sequence, XNLRR-1, that is closely related to a gene for mouse neuronal leucine-rich repeat protein (NLRR-1). The cDNA clone is 4179 bp long and encodes a putative transmembrane glycoprotein of 718 amino acids, containing 12 leucine-rich repeats followed by one C2-type immunoglobulin-like domain and one fibronectin type-III repeat. XNLRR-1 is transcribed mainly in the developing eye area and the ventricular zone from diencephalon to hindbrain and slightly in spinal cord in Xenopus tadpoles. The similarity of the XNLRR-1 gene to other known cell adhesion molecules, together with the expression pattern, suggests that XNLRR-1 is involved in interactions at the neuronal cell surface.

Amino Acid Sequence↗
PubMed1991

[Angioedema due to acquired complement-C1-inhibitor deficiency in a female patient with non-Hodgkin lymphoma and autoimmune hemolytic anemia].

A case of angioedema due to acquired deficiency of the regulatory protein C1-esterase-inhibitor (C1-INH) is reported. The edematous attack occurred 3 1/2 weeks after initiation of successful therapy for autoimmune-hemolytic anemia in the course of long-standing non-Hodgkin's lymphoma. At the time of acute edema the complement profile was typical: virtual absence of C1-INH function was associated with diminished concentrations of the components of the classical pathway of complement (C1q, C1r, C1s, C2, C4) and reduced complement hemolytic activity (CH50). Anti-C1-INH-autoantibodies were not detected. The angioedema lasted for about one week, and no further attacks occurred during the five-months follow-up period. Although there was only a minor adjustment to the therapy, the C1q, C2, C4 and CH50 values gradually increased to levels close to the lower limit of the normal range, while C1r and C1s showed normal values. In contrast to most other reports, this case was characterized by angioedema which was precipitated only after initiation of appropriate treatment for the underlying disease rather than before therapy or even diagnosis of the underlying disease.

Aged↗
PubMed2001

Genetics of human complement component C4 and evolution the central MHC.

The two classes of human complement component C4 proteins C4A and C4B manifest differential chemical reactivities and binding affinities towards target surfaces and complement receptor CR1. There are multiple, polymorphic allotypes of C4A and C4B proteins. A complex multiplication pattern of C4A and C4B genes with variations in gene size, gene dosage and flanking genes exists in the population. This is probably driven by the selection pressure to respond to a great variety of parasites efficiently and effectively, which the bony fish achieved through the multiplication and diversification of the related complement C3 proteins. Complement C4, C3 and C5 belong to the alpha2 macroglobulin protein family but acquired specific features that include an anaphylatoxin domain, a netrin (NTR) domain, and stretches of basic residues for proteolytic processings to form multiple chain structures. Complement C3 and C4 are important in the innate immune response as they opsonize parasites for phagocytosis. The emergence of complement C3 predates proteins involved in the adaptive immune response as C3 is present in deuterostome invertebrates such as echinoderms. The human C4 genes are located in the central MHC at chromosome 6p21.3. C3 and C5 are located at chromosome 19 and 9, respectively, with representatives of the other groups of genes paralogous to the MHC at 19p13.1-p13.3, 1q21-25, and 9q33-34. The central MHC also contains genes for complement components C2 and Bf. These genes appear to have similar evolutionary histories to C3/C4/C5 and are used here to illustrate stepwise processes resulting in co-location of diverse domains, chromosomal duplication, local segmental duplication and divergence of sequence and function. This model of evolution is useful in the investigation of innate and acquired immunity and in seeking explanations for diseases associated with MHC ancestral haplotypes.

Amino Acid Sequence↗
PubMed2001

[New developments in immunosuppressive therapy].

A highly effective immunosuppressive therapy with as few side effects as possible can only be achieved by a reliable drug monitoring. For neoral monitoring of the C2 level is essential while for tacrolimus measuring of the trough level is sufficient. Due to the different immunogenicity of the organ transplants the type and intensity of the immunosuppressive therapy should be organ-specific. Sirolimus is highly effective in combination with calcineurin antagonists in immunologically high-risk patients. In addition in case of severe side effects sirolimus can substitute for the calcineurin antagonists. Il-2 receptor antibodies are characterized by minimal side effects and have been shown to be a highly effective new therapeutic principle for immunosuppressive induction therapy.

Antibodies↗
PubMed1976

Complement component profiles in urticaria, dermatitis herpetiformis, and alopecia areata.

Insignificant variation was noted in the mean levels of the complement components CIQ, C4, C2, C3, C5 and C3PA between various groups of sera from patients with urticaria, angio-oedema, dermatitis herpetiformis, alopecia areata, or hay fever. No deficiencies were found. Elevated C9 levels in chronic urticaria and angio-oedema reflected its nature as an acute phase protein. The assessment of C components in single or sequential serum samples revealed only marginal variations. Similar results were recorded for plasminogen the immunoglobulins, G, A and M. Some evidence is provided for the primary involvement of the kallikrein-kinin system in urticaria.

Alopecia Areata↗