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PubMed2001

Extended HLA haplotypes in a Carib Amerindian population: the Yucpa of the Perija Range.

Eleven MHC loci haplotypes have been defined among a Carib speaking Amerindian population; the Yucpa, inhabiting the northern section of the Perija Range, on the limits between Colombia and Venezuela. This tribe has been known with the name of "Motilones mansos" and is located close to the Chibcha-Paeze speaking Bari or "Motilones bravos." Seventy-three full blooded Yucpa living at the villages of Aroy, Marewa, and Peraya, were selected using a genealogy previously collected by an anthropologist and tested for Bf-C4AB complement allotypes and by serology, high resolution PCR-SSO and SBT typing for HLA class 1 and class 2 alleles. Combinations of 6 HLA-A, 6 HLA-B, 5 HLA-C, 1 Bf, 3 C4AB, 3 DQA1, 3DQB1 and 2 DPA1 and 2 DPB1 alleles present in this population originate 17 different haplotypes, 3 of which represent 63% of the haplotypic constitution of the tribe. The presence of 13 individuals homozygous for 11-loci haplotypes corroborates the existence of the following allelic combinations: DRB1*0411 DQA1*03011 DQB1*0302 DPA1*01 DPB1*0402 with HLA-A*6801 C*0702 B*3909 BfS C4 32 (f = 0.3372) or with A*0204 C*0702 B*3905 (f = 0.1977) and a third haplotype which differs only in DRB1*0403 and A*2402 (f = 0.0930). The results demonstrate the isolation of the tribe and the existence of high frequencies of a reduced number of "Amerindian" ancestral and novel class 1 and class 2 alleles (B*1522, DRB1*0807) with significant linkage disequilibria. These results will be useful to test the hypothesis that differentiation of Amerindian tribal groups will have to rely on haplotypes and micropolymorphism rather than allelic lineage frequencies due to the uniformity shown thus far by the putative descendants of the original Paleo-Indians.

Colombia↗
PubMed1990

C4B deficiency in two siblings with IgA nephropathy.

The development of IgA nephropathy in first degree relatives is a well-described, yet relatively uncommon, occurrence. The association of a C4 isotype deficiency or partial deficiency of another complement protein has been previously documented for patients with IgA nephropathy. The present report describes a family in which two siblings and their father had biopsy-confirmed IgA nephropathy; both siblings were deficient for the C4B isotype. In addition, one of the biopsied siblings and a third sibling with microscopic hematuria but no renal biopsy apparently had a partial deficiency of the complement regulatory protein, I. The findings in this family may be compatible with the hypothesis that a C4 isotype deficiency and/or a partial deficiency of an individual complement protein allows clinical expression of IgA nephropathy in an individual with a genetic susceptibility for the disease.

Adolescent↗
PubMed1983

Anaphylatoxin formation during hemodialysis: effects of different dialyzer membranes.

Measurable complement activation resulting in the formation of both C3a and C5a anaphylatoxins was observed in 12 patients undergoing maintenance dialysis treatment with cuprophan hollow fiber dialyzers. Specific radioimmunoassay measurements demonstrated that these patients displayed significantly elevated levels of C3a antigen in the venous (outflow) line of the dialyzer after only 2 min of dialysis. During hemodialysis, venous plasma C3a levels continued to increase and became maximally elevated after 15 min. Thereafter, C3a concentrations gradually declined, suggesting that the rate of complement activation abates with continued cuprophan hemodialysis. Complement activation, as judged by venous plasma C3a levels, was also temporally correlated with hemodialysis leukopenia. The factor believed to be responsible for pulmonary vascular leukosequestration, C5a, could also be detected in venous plasma, but levels of this antigen were not strikingly elevated until the later stages of dialysis. By contrast, six patients dialyzed with polyacrylonitrile dialyzers failed to exhibit hemodialysis leukopenia and displayed only very modest increases in their plasma C3a levels during the initial phases of hemodialysis. These observations provide direct evidence that anaphylatoxin formation during hemodialysis is a transient phenomenon and indicate that the biocompatibility of dialysis membranes, as reflected by their complement activating potential, may be significantly different.

Acrylic Resins↗
PubMed1992

Influence of C4B null genes on cytomegalovirus antibody titers in healthy blood donors.

C4B null genes (C4B*Q0) have been found with increased frequency in persons with viral diseases, including hepatitis and human immunodeficiency virus infection. Whether a relationship might exist between the presence of C4B*Q0 and antibodies to cytomegalovirus (CMV) was investigated. Fifty blood donors who were seropositive for CMV antibodies and 101 healthy nondonors were C4-allotyped with electrophoresis immunofixation. CMV-seropositive sera were titrated for CMV IgG-specific antibody by enzyme-linked immunosorbent assay, and serum IgG levels were assayed by rate nephelometry. C4B*Q0 was higher in the CMV antibody-positive group than in nondonors (p = 0.05), but the increase was most significant (p = 0.028) in donors with the highest titers of CMV antibodies. There was poor correlation (r = 0.015) between CMV titers and plasma IgG levels. Serum C4B levels were lower in CMV antibody-positive donors with one C4B null gene than in matched nondonors or nondonors not having any null genes.

Antibodies, Viral↗
PubMed1984

Complement activation and hypersensitivity reactions to dialysis membranes.

Certain patients receiving hemodialysis experience recurrent chest pain, dyspnea, and hypotension during exposure to new cuprophane-membrane dialyzers (the "first-use syndrome"). Because activation of complement may be involved in these events, we examined in vivo complement activation with new cuprophane membranes and in vitro activation by zymosan in 6 such patients, and compared them with 10 patients who did not have symptoms during dialysis. All patients with the first-use syndrome had maximal complement activation 10 minutes after initiation of dialysis, with C3a des-arginine (desArg), the stable metabolite of C3 activation, equal to 8533 +/- 157 ng per milliliter (mean +/- S.E.M.). In asymptomatic patients the maximal C3a desArg value occurred at 15 minutes and was only 2907 +/- 372 ng per milliliter (P less than or equal to 0.0001). At a concentration of 3.8 x 10(-5) g of zymosan per milliliter, patients with the first-use syndrome had a C3a desArg level of 29.6 +/- 1.4 micrograms per milliliter, whereas it was only 16.6 +/- 2.3 micrograms per milliliter in asymptomatic patients (P less than or equal to 0.0001). Two other patients, who experienced cardiopulmonary collapse during the first two minutes of dialysis, had a C3a desArg level of 18,900 and 7800 ng per milliliter, respectively. We conclude that the occurrence of adverse symptoms associated with new cuprophane-membrane dialyzers correlates with complement activation.

Adult↗
PubMed1985

Human genes for three complement components that regulate the activation of C3 are tightly linked.

A new cluster of complement component genes, including C4BP, C3bR, and FH, is described. Family segregation data indicate that FH is linked to the genes for C4-bp and C4bR, previously reported to be linked and to maintain linkage disequilibrium. This cluster is not linked to the major histocompatibility complex, which contains the genes for the complement components, C4, C2, and factor B, or to the C3 locus. These data further suggest that the organization of genes for functionally related proteins in clusters may be a rule for the complement system.

Carrier Proteins↗
PubMed1989

Structure of the human RD gene: a highly conserved gene in the class III region of the major histocompatibility complex.

We cloned and determined the DNA sequence of a novel gene (termed RD or D6S45) situated in the class III region of the human major histocompatibility complex (HLA) between the Bf and C4A complement genes. The coding region of the gene is contained in 10 exons spread over approximately 6 kb of DNA. The encoded protein is predicted to contain 371 amino acid residues with a molecular weight of 41,000. The predicted amino acid sequence is notable for a central region containing 24 consecutive pairs of alternating basic (Arg) and acidic (Asp or Glu) residues similar to, but more strictly alternating than, those seen in the 70K protein of the U1 small nuclear ribonucleoprotein (snRNP). There is a high degree of homology both at the amino acid and DNA level between the human RD gene and its murine homology. Although the central region is highly repetitious and contains a high proportion (13%) of CpG dinucleotides-both features that might predispose to frequent mutations-sequence analysis of this region in genes amplified from six individuals revealed no polymorphism.

Amino Acid Sequence↗
PubMed1987

Multiple sclerosis in north-east Scotland. An association with HLA-DQw1.

This study reports the frequencies of HLA antigens and the polymorphic variants of C4, C2, and Bf for 200 patients with multiple sclerosis (MS) living in the Grampian region of Scotland, an area of high disease prevalence. A group of 128 normal subjects from the same region were typed for comparison. Although the frequencies of HLA-B7 and DR2 in the patient group (43.3% and 49.4%, respectively) were found to be similar to those reported for other Northern European HLA studies on patients with MS, high frequencies of these antigens were also observed in the group of normal Grampian subjects (38.3% and 40.6%) the differences were not statistically significant. However, a significant association was found between the recently defined Class II HLA antigen, DQw1, and MS (P less than 0.006) when compared with controls. There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf when the group of patients with MS was compared with the control group of normal subjects. The patients were subdivided according to disease severity, remittent versus progressive clinical course, age of onset of the disease and initial symptoms. The frequencies of the HLA and complement polymorphisms (C4, C2, and Bf) were analysed in these subdivisions. DQw1 was found with similar frequency in severe and benign disease (78% and 80%, respectively) but DR2 was most frequent in the group of patients with remittent disease (54%). There were no significant differences in frequency of the polymorphisms of C4, C2, and Bf between the above subgroups of patients and overall no significant HLA associations were found with age of onset of disease or initial symptoms. The findings suggest that in an area of high prevalence of MS, the disease is more closely associated with DQw1 than DR2. Furthermore, there was no evidence to support the hypothesis that the HLA region complement gene polymorphisms show significant association with a putative HLA-linked MS susceptibility gene.

Complement C4↗
PubMed1987

C5a and thromboxane generation associated with pulmonary vaso- and broncho-constriction during protamine reversal of heparin.

The authors conducted a study in humans to determine the mediators associated with acute pulmonary vaso- and broncho-constriction occurring episodically with protamine reversal of heparin anticoagulation. Of 48 adult patients investigated prospectively after termination of cardiopulmonary bypass, two presented a sudden increase of airway pressure, acute pulmonary hypertension, and systemic hypotension 1-3 min after right atrial protamine injection. In these two subjects, plasma levels of C5a increased from 0.7 and 2.2 to 9.8 and 9.9 ng/ml, respectively, and thromboxane B2 increased from 0.26 and 0.34 to 7.5 and 16.2 ng/ml 1 minute after drug injection. A third subject not identified prospectively had an identical reaction and mediator profile (C5a, 10.2 ng/ml; TxB2, 18.6 ng/ml at 1 min). The plasma levels of these mediators were unchanged in the remaining patients (C5a, 0.7 +/- 1.1 [x +/- S.D.] to 0.6 +/- 0.9 ng/ml; TxB2, 0.16 +/- 0.12 to 0.15 +/- 0.07 ng/ml). Plasma histamine was not involved in this type of reaction, but increased from 0.7-10.4 ng/ml in a fourth patient who became hypotensive without acute pulmonary hypertension, bronchoconstriction, or elevation of C5a or TxB2. The authors' data indicate that the generation of high plasma levels of C5a anaphylatoxins and thromboxane is associated with pulmonary vaso- and broncho-constriction induced by protamine reversal of heparin in humans.

Adult↗
PubMed1987

Psoriasis and leukocyte chemotaxis.

Transepidermal migration of leukocytes, with resultant formation of microscopic or macroscopic sterile subcorneal pustules is a phenomenon characteristically noted in psoriasis and related sterile pustular dermatoses. It is natural to assume the presence of potent neutrophil chemotactic substances in the subcorneal portion of the lesional epidermis, because this location is the target of the in vivo leukocyte chemotaxis. In fact, crude psoriasis scale extracts show remarkably high neutrophil chemotactic and activating properties as compared with those of other non-psoriatic inflammatory dermatoses. We isolated a psoriatic leukotactic factor (PLF) having a molecular mass of around 12 kD, distinct from those common to other inflammatory changes involving the skin or those released by bacteria. Further analysis of PLF identified C5 cleavage fragments, together with other chemotactic peptides, such as those derived from monocytes. Likewise, potent low-molecular-mass chemotactic factors, including cell membrane lipid derived chemotactic factor, e.g. leukotriene B4, are also increased in psoriatic lesions, as in other nonpsoriatic inflammatory dermatoses. However, their activity to stimulate the generation of oxygen radicals in neutrophils was found to be much weaker than that of PLF. The peripheral blood leukocytes from active psoriatic patients show enhanced function in chemotaxis, phagocytosis, active oxygen production, and enzyme release; patients' sera contain substances such as anaphylatoxins that activate leukocyte function. Further research is required for clearer understanding of the series of events resulting in the leukocyte chemotaxis, as well as for the elucidation of the background immunoregulatory mechanisms.

Cell Movement↗
PubMed2005

Common variable immunodeficiency and the complement system; low mannose-binding lectin levels are associated with bronchiectasis.

The importance of the innate immune system, including mannose-binding lectin and the complement system, in common variable immunodeficiency is unclear. The objective of this study was to evaluate mannose-binding lectin and the complement system in relation to clinical and immunological parameters in patients with common variable immunodeficiency. Circulating levels of mannose-binding lectin, complement components, complement activation products and functional capacity of complement pathways were correlated to clinical features within 71 patients and compared with 30 healthy controls. The main findings were; the patients had signs of increased complement activation significantly associated with signs of autoimmunity and immunological hyperactivity; there were no signs of deficiencies of the classical and alternative complement pathways in the patient group; the prevalence of lectin pathway deficiency was the same in patients and controls, but patients with increased frequency of lower respiratory tract infections or bronchiectasis had lower capacity of the lectin pathway than patients without these features (P = 0.002 and 0.004, respectively); the serum concentration of mannose-binding lectin was inversely correlated to the frequency of lower respiratory tract infections (P = 0.002) and bronchiectasis (P = 0.01). We conclude that patients with common variable immunodeficiency have no increased frequency of complement deficiencies but signs of increased complement activation. Our findings suggest that mannose-binding lectin and the lectin complement pathway may protect against lower respiratory tract infection and bronhiectasis in patients with common variable immunodeficiency.

Adult↗
PubMed2006

Inhibition of classical complement activation attenuates liver ischaemia and reperfusion injury in a rat model.

Activation of the complement system contributes to the pathogenesis of ischaemia/reperfusion (I/R) injury. We evaluated inhibition of the classical pathway of complement using C1-inhibitor (C1-inh) in a model of 70% partial liver I/R injury in male Wistar rats (n = 35). C1-inh was administered at 100, 200 or 400 IU/kg bodyweight, 5 min before 60 min ischaemia (pre-I) or 5 min before 24 h reperfusion (end-I). One hundred IU/kg bodyweight significantly reduced the increase of plasma levels of activated C4 as compared to albumin-treated control rats and attenuated the increase of alanine aminotransferase (ALT). These effects were not better with higher doses of C1-inh. Administration of C1-inh pre-I resulted in lower ALT levels and higher bile secretion after 24 h of reperfusion than administration at end-I. Immunohistochemical assessment indicated that activated C3, the membrane attack complex C5b9 and C-reactive protein (CRP) colocalized in hepatocytes within midzonal areas, suggesting CRP is a mediator of I/R-induced, classical complement activation in rats. Pre-ischaemic administration of C1-inh is an effective pharmacological intervention to protect against liver I/R injury.

Alanine Transaminase↗
PubMed1992

Genetic risk factors for perinatally acquired HIV-1 infection.

This study evaluates genetic influence on susceptibility to perinatal HIV-1 infection among 106 Black infants from New York and San Francisco born to mothers infected with HIV-1. Genes tested by molecular techniques are HLA class II loci DRB1, DPB1 and DQA1; HLA class III loci complement C4A and C4B; alpha and beta interferons; and the constant region of the T-cell receptor beta chain. Of the 106 infants analysed, 54 are infected with HIV and 52 remain uninfected at age 15 months and older. Genotypes in the HLA region appear to influence risk of HIV infection. Specifically, infants with the amino acid sequence -asp-glu-ala-val- at DPB1 positions #84-87 are more likely to be infected (P = 0.001) and infants with the allele DQA1*0102 are less likely to be infected (P = 0.031). Combinations of these two risk factors show a strong dose response (P = 0.0005). HLA DPB1 and DQA1 may play a direct role in immune response associated with HIV-1 infection, or the critical region may be located between these two genes. Characterisation of other class II HLA genes in these infants will allow more precise determination of the role of HLA loci in susceptibility to HIV-1 infection.

Alleles↗
PubMed1988

Italian extended HLA haplotypes in congenital adrenal hyperplasia.

In order to complete the data on human 21-Hydroxylase deficiency, we present a study on HLA markers in 35 Italian families (14 from Northern, eight from Central and 13 from Southern Italy) with one affected child. Three children from the issue of first cousin marriages were homozygous for the whole HLA haplotype. Extended haplotypes shared by unrelated patients were not found, and a total absence of the HLA Bw47 allele among the haplotypes carrying the disease as well as normal haplotypes was observed. The absence of A1 Cw7 B8 BfS C4AQ0 C4B1 DR3 extended haplotype was instead confirmed. Allele frequencies in the different clinical forms were analyzed: BfSO7 allele frequency was significantly increased on haplotypes of the salt-wasting form (p less than 0.01). We noticed two duplications (C4B1-2) of C4B genes, on haplotypes involved in the disease. Allele distribution in the regions studied showed that Bw22 (w55), Cw3 and DR2 were characteristic of Northern patients, while B15 was found in patients from Central Italy.

Adrenal Hyperplasia, Congenital↗
PubMed1986

An immunogenetic study of juvenile chronic arthritis.

Ninety-seven patients from Western Australia and Victoria suffering from juvenile chronic arthritis (JCA) for longer than 1 year were studied with particular reference to immunogenetic markers in the sub-groups of the disease. In the pauci-articular group, the antigens DR5, DR8 and BW35 were increased in frequency. The phenotypes within the sub-groups appeared distinctive despite the absence of any increase in the frequency of single antigens. Complement allotyping did not prove to be different from controls or within the sub-groups for JCA. This study supports the concept that patients with JCA have specific genetic characteristics and that sub-groups of the disease are genetically distinct.

Arthritis, Juvenile↗