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PubMedDate not supplied

ESR spectra of normal human serum after treatment with complement activating agents.

We describe the appearance of a free-radical signal in the ESR spectrum of normal human serum incubated with several complement activating agents. The intensity of this signal is dependent of dose of activating agents, time and temperature. Signals elicited by different complement activators differ in morphology and kinetics. Inhibition by treatment with EDTA and the presence of the signal in activated C 6-deficient rabbit serum suggest that the convertase forming steps of complement activation (C2 to 5) could be the source of free-radical containing molecules.

Blood Proteins↗
PubMed1980

Studies on the C2-deficiency gene in man.

A one-step haemolytic assay using cellular intermediates was used to determine C2 levels in 50 HLA-A25 and B18 positive blood donors and four families suspected to have the C2-deficiency gene. The method clearly discriminated between homozygous normals and heterozygous deficient individuals, and it was found that approx. 50% of individuals with the haplotype HLA-A25, B18 had low levels of functional C2. In the four families studied, the close linkage of the C2-deficiency gene and the haplotype HLA-A25, B18 was confirmed. Furthermore, the C2-deficiency gene was shown to be a silent or null allele at the structural locus.

Child↗
PubMed1977

Hereditary C7 deficiency. Diagnosis and HLA studies in a French-Canadian family.

The serum of a 44-yr-old woman of French-Canadian descent having a B-27 positive ankylosing spondylitis was deficient in the seventh component of complement (C7) as determined by hemolytic and immunochemical methods. No inhibitor against C7 was detected, and the levels of all other complement components were normal. No deficiency in the opsonic activity of the serum was found, and the results of basic coagulation studies of the plasma were normal. On investigation of the patient's family, two sisters were found to have the same deficiency but were otherwise in good health. The seven other siblings were heterozygous for C7 deficiency, while the paternal aunt had a normal C7 level. In the third generation, six children of the three homozygous sisters and five children of heterozygotes were available for testing. Studies of the HLA antigens in all the 22 subjects and in three spouses indicated no close linkage between the CM deficienty and the HLA system. In addition, the simultaneous occurrence of two hereditary complement deficiencies (C2 and C7) was discovered in one family of this remarkable kindred.

Adult↗
PubMed1991

A restriction fragment of the C2 gene is a unique marker for C2 deficiency and the uncommon C2 allele C2*B (a marker for type 1 diabetes).

There are three common C2 protein alleles in caucasians, C2*C, C2*B, and C2*Q0, with allele frequencies of 0.96, 0.03, and 0.01, as well as Sst I RFLP variants of 2.75, 2.7, 2.65, 2.55, and 2.4 kb, with frequencies of 0.017, 0.533, 0.358, 0.017, and 0.075. Thus, C2*C is informatively split by the RFLP. Of 94 nonrandomly ascertained caucasian complotypes, 77 contained C2*C, four contained C2*Q0, and 13 had C2*B. None of the C2*C-containing complotypes carried the 2.75 kb Sst I fragment and all of the complotypes with C2*B or C2*Q0 carried it. All of the C2*Q0 alleles were associated with C4A*4, C4B*2 in the complotype S042 as previously reported. C2*B was usually (9/13) in the complotype SB42, occasionally (1/13 each) in SB45, SB41, SB(4,3)0, and SB31. Thus, the association of the C2 2.75-kb fragment was with C2*B and C2*Q0, not with C4A*4, C4B*2, or even C4A*4 alone. The complotype SC42 was associated with the 2.65-kb Sst I fragment in four of five instances and in a single example with the 2.7-kb fragment. C2*B and C2*Q0 possibly had a common evolutionary ancestor complotype which carried the 2.75-kb Sst I fragment, and BF*S, C4A*4, and C4B*2. C2*B (particularly as the haplotype HLA-Bw62, SB42, DR4) is associated with type 1 diabetes but C2*Q0 is protective.

Alleles↗
PubMed1987

Strong association of HLA-DR3/DRw9 heterozygosity with early-onset insulin-dependent diabetes mellitus in Chinese.

Studies of Caucasian and Japanese patients with insulin-dependent diabetes mellitus (IDDM) have shown that heterozygosity for certain HLA-DR antigens confers a high risk of developing the disease. The HLA antigens of 75 Chinese patients and 100 Chinese controls in Hong Kong were studied to investigate the role of HLA-DR heterozygosity in Chinese individuals. Some of the patients and controls were also tested for allotypic variation in the complement components C2, C4, and BF. Three alleles, Aw33, B17, and DR3, had increased frequencies in patients compared with controls and frequently occurred together in the same phenotype, which suggested their existence as a haplotype. There were no statistically significant differences in complement allotype frequencies between patients and controls, although the C4B null allele seemed to be associated with Aw33, B17, and DR3. No other HLA-DR antigen appeared to be associated with IDDM. However, when the patients were separated on the basis of age at onset, the frequency of DR3/DRw9 heterozygosity was markedly increased in patients presenting in the first decade of life, but there was no increase in patients presenting at greater than 20 yr of age. DRw9 is strongly associated with autoimmune disease in Chinese, whereas DR3 is not. We suggest that the major IDDM susceptibility locus in Chinese is associated with HLA-DR3 and that patients with HLA-DR3 and HLA-DRw9 have an added predisposition to autoimmune disease and therefore develop IDDM earlier than patients without DRw9.

China↗
PubMed1986

[Absence of a connection between Alzheimer's disease and complement markers].

The hypothesis of a linkage between Alzheimer's disease (AD) (presenile dementia) and the complement components C2, C4, Bf linked to the Major Histocompatibility Complex has been investigated in a large family originating from Calabria, in which AD is transmitted as an autosomal dominant monogenic mendelian trait. The analysis of complotypes of 33 members of a pedigree, from which 10 individuals are affected, allowed to demonstrate that there wasn't any linkage between AD and those markers. Furthermore, no complete or partial deficiency in the C2, C4, Bf components has been observed in affected patients.

Alzheimer Disease↗
PubMed1982

Cerebro spinal fluid C2 and HLA system in multiple sclerosis.

C3 hemolytic activity has been measured in serum and C.S.F. of 67 multiple sclerosis (M.S.) patients classified in three evolutionary groups according to the index of progression of the disease and tested in HLA-A, B, C, DR and Bf. The median level of serum C2 is normal whether it is of the evolution or the HLA type. The average level of C.S.F. C2 is the same in the evolutionary groups and is low in patients bearing B 18 allele or B 18, DR2 haplotype. It seems that the median level of C.S.F. C2 is linked to the HLA types associated to the susceptibility gene(s) of the disease.

Alleles↗
PubMed1979

Plasma complement and histamine changes in atopic dermatitis.

Fifteen patients with atopic dermatitis were investigated to evaluate the total of complement and histamine. In five patients total serum complement haemolytic activity (CH50) was significantly decreased as was the haemolytic activity of complement components C2 (C2H50) and C3 (C3H50). By counter immunoelectrophoresis split products of C3 were detected. There was no evidence for alternative pathway activation or the presence of an activator of the alternative pathway. In three patients plasma histamine concentrations were elevated. The intensity of the complement and histamine changes observed seemed to be correlated to the severity of the disease.

Adolescent↗
PubMed2000

New structural motifs on the chymotrypsin fold and their potential roles in complement factor B.

Factor B and C2 are two central enzymes for complement activation. They are multidomain serine proteases and require cofactor binding for full expression of proteolytic activities. We present a 2.1 A crystal structure of the serine protease domain of factor B. It shows a number of structural motifs novel to the chymotrypsin fold, which by sequence homology are probably present in C2 as well. These motifs distribute characteristically on the protein surface. Six loops surround the active site, four of which shape substrate-binding pockets. Three loops next to the oxyanion hole, which typically mediate zymogen activation, are much shorter or absent. Three insertions including the linker to the preceding domain bulge from the side opposite to the active site. The catalytic triad and non-specific substrate-binding site display active conformations, but the oxyanion hole displays a zymogen-like conformation. The bottom of the S1 pocket has a negative charge at residue 226 instead of the typical 189 position. These unique structural features may play different roles in domain-domain interaction, cofactor binding and substrate binding.

Amino Acid Sequence↗
PubMed1981

Serum and cerebrospinal fluid C2 in multiple sclerosis.

C2 hemolytic activity was quantitated in the serum and cerebrospinal fluid of 46 MS patients studied twice at a 1-year interval. whereas serum C2 levels were found within the normal range, CSF C2 values were decreased (55 and 59% of normal) in patients with severe active disease. In contrast CSF C2 levels were normal in patients with stable or recently improved condition. CSF C2 fluctuations in individuals were found to closely parallel changes in the clinical course.

Complement C2↗
PubMed1997

C2 deficiency in blood donors and lupus patients: prevalence, clinical characteristics and HLA-associations in the Brazilian population.

The objective of the present study was to investigate the prevalence, clinical characteristics, and HLA association of C2 deficiency in the Brazilian population. The frequency of C2 deficiency profile (C2Q degree profile) was 2.2% among 1503 blood donors and 6.6% among 166 patients with systemic lupus erythematosus (SLE). A higher incidence of clinical manifestations possibly related to immune complex disease was observed among blood donors with C2Q degree profile and their relatives with C2Q degree profile when compared to the normal C2 relatives. The comparison of clinical and laboratory features between SLE patients with C2Q degree profile and those with normal C2 revealed earlier disease onset, higher frequency of oral ulcerations and lower frequency of anti-native DNA antibodies in the first group. The HLA study conducted on 18 individuals with C2Q degree profile (11 blood donors and 7 SLE patients) confirmed the previously reported association with the antigens HLA-A25, B18 and DR2, supporting the concept that probably most C2 deficiency cases, throughout the world, are due to a single mutation in the C2 gene in linkage disequilibrium with the A25B18DR2 haplotype.

Autoantibodies↗
PubMed1986

Heterozygous C2 deficiency associated with angioedema, myasthenia gravis, and systemic lupus erythematosus.

We describe a patient with myasthenia gravis, systemic lupus erythematosus, and angioedema associated with heterozygous complement factor 2 (C2) deficiency. The significance of this association is controversial, though the association of C2 deficiency with certain histocompatibility antigens suggests possible linkage to immune response genes. To our knowledge this is the first report of heterozygous C2 deficiency in association with this combination of 'autoimmune' disorders, and we discuss the aetiological implications.

Adult↗
PubMed1989

Successful plasma infusion treatment of a patient with C2 deficiency and systemic lupus erythematosus: clinical experience over forty-five months.

We describe a patient with C2 deficiency and severe systemic lupus erythematosus (SLE) that did not respond to conventional therapy. Over a period of 45 months, she was given 22 cycles of plasma therapy. For 6-8 weeks after each plasma infusion, there was a full clinical remission of the SLE, and a brief restoration of hemolytic complement activity. However, there were more prolonged increases in the activities of the complement components that are believed to be more directly involved in the clearance of immune complexes. Because of the theoretical risk that the infused complement might enhance inflammatory tissue damage, there has been some reluctance to try plasma replacement therapy in SLE patients with complement deficiency. We have not observed any adverse effects with the long-term use of this treatment, and our experience indicates that this therapeutic approach can be beneficial.

Adult↗
PubMed1985

Human monocyte recognition of complement-coated lymphoblastoid cells.

The macrophage system in man plays a significant role in the detection of foreign cells. The mechanisms by which macrophages recognize malignant cells, however, are not well understood. We used human monocytes and four lymphoblastoid cell (LC) lines derived from human acute lymphocytic leukemia to investigate the initial recognition of tumor cells by monocytes. IgM antibody mediated the binding of these cells to monocytes only in the presence of complement. The stepwise addition of complement components to IgM-coated LC indicated that C3 was necessary to monocyte binding. Similarly, monocyte recognition of IgM-coated LC was maximal in the presence of sera from patients with congenital C5 or C6 deficiency, but absent in the presence of sera deficient C4 or from a patient with congenital C2 deficiency. Complement activation was associated with C3 consumption and the deposition of substantial amounts of C3 on to LC. Although 3H-C3 bound to LC appeared stable for 2 hours, approximately 4.0 +/- 2 X 10(5) 3H-C3 per LC was necessary for monocyte recognition, compared to approximately 2.7 +/- 0.5 X 10(3) 3H-C3 per RBC. The data indicate that LC can be recognized by monocytes through complement by mechanisms similar to nonmalignant target cells. However, substantial amounts of C3 are necessary to induce monocyte recognition of IgM-coated LC and, thus, such complement mediated recognition may be inefficient.

Cell Communication↗
PubMed1997

Evolutionary significance of intra-genome duplications on human chromosomes.

Phylogenetic analyses indicated that a series of paralogous gene pairs, found in two extensive regions on human chromosomal bands 6p21.3 and 9q33-34, were created by at least two independent duplications. The duplicated genes on chromosomal band 6p21.3 include the genes for type 11 collagen alpha2 subunit (COL11A2), NOTCH4 (mouse int-3 homologue), 70 kDa heat shock protein (HSPA1A, HSPA1B, and HSPA1L), valyl-tRNA synthetase 2 (VARS2), complement components (C2 and C4), pre-B cell leukemia transcription factor 2 (PBX2), retinoid X receptor beta (RXRB), NAT/RING3, and four other proteins. Their paralogous genes on chromosomal band 9q33-34 are genes for type 5 collagen alpha1 subunit (COL5A1), NOTCH1, 78 kDa glucose-regulated protein (HSPA5), valyl-tRNA synthetase 1 (VARS1), complement component V (C5), PBX3, retinoid X receptor alpha (RXRA), ORFX/RING3L, and others. Among these, the genes for collagen, complement components, NAT/RING3, PBX, and RXR appear to have been duplicated around the time of vertebrate emergence, supporting the idea that they were duplicated simultaneously at that time. Another group of genes that includes NOTCH and HSP appear to have diverged long before that time. A comparison of the physical maps of these two regions revealed that the genes which duplicated in the same period were arranged in almost the same order in the two regions, with the assumption of a few chromosomal rearrangements. We propose a possible model for the evolution of these regions, taking into account the molecular mechanisms of regional duplication, gene duplication, translocation, and inversion. We also propose that a comparative mapping of paralogous genes within the human genome would be useful for identifying new genes.

Animals↗