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PubMed1988

Diagnostic validity of multivariate combinations of biochemical analytes as markers for rejection and infection in the follow-up of patients with heart transplants.

The diagnostic validity of multivariate combinations of alpha 1-antitrypsin, alpha 2-macroglobulin, C-reactive protein, complement C3, complement C4, neopterin in serum, and neopterin in urine as markers for acute cardiac allograft rejection and for differential diagnosis of rejection and infections was investigated in the follow-up of 37 patients with heart transplants. Rejection was diagnosed by endomyocardial biopsy. Infections were classified as 'no infection', 'viral infection', and 'bacterial, fungal or mixed infections'. Although there are significant differences between the mean levels of analytes, multivariate discriminant analysis does not provide an adequate discrimination of rejection and infection states. In separate rejection diagnosis, multivariate combinations of analytes cannot replace endomyocardial biopsy. However, a multivariate combination of alpha 1-antitrypsin, alpha 2-macroglobulin, C-reactive protein, C3, C4 in serum, and neopterin in urine can be used as a screening procedure to reduce the number of endomyocardial biopsies.

Adolescent↗

PubMed1994

Antiphospholipid and anti-beta 2 glycoprotein I antibodies in monozygotic twin sisters.

We describe an 18-year-old woman with primary antiphospholipid syndrome whose monozygotic twin sister is as yet an asymptomatic carrier of the lupus anticoagulant, anticardiolipin, and anti-beta 2 glycoprotein I (beta 2GPI) antibodies. Serum concentrations of beta 2GPI were normal in the patient and elevated in her sister. HLA and complement C4 phenotypes showed the presence of class II antigens DR7 and DRw53 and of a C4AQ0 allele. This supports the theory that a genetic predisposition may influence the appearance of these autoantibodies.

Adolescent↗

PubMed1982

Amino acid sequence homologies and glycosylation differences between the fourth component of murine complement and sex-limited protein.

Limited primary sequence data have been obtained for all three subunits of the fourth component of murine complement (C4) and its related homologue, the sex-limited protein (Slp). These data show a high degree of NH2-terminal homology between C4 and Slp: four of the six residues identified for the alpha chain, seven of eight for the beta chain, and four of four for the gamma chain. This suggests that apparent molecular weight differences between C4 and Slp subunits are not, as previously suggested, due to a shift in the proteolytic processing sites in the pro-Slp polypeptide molecule. Chemical deglycosylation (apparently complete) of the C4 and Slp alpha chains with trifluoromethanesulfonic acid removes the molecular weight difference between them, suggesting that acquisition of extra glycosylation sites in the latter is responsible for this difference.

Amino Acid Sequence↗

PubMed1978

Two HLA-linked loci controlling the fourth component of human complement.

An electrophoretic polymorphism of the fourth component of human complement (C4) is described. Three patterns of bands of C4 were observed in EDTA plasma from a panel of unrelated blood donors and family members by using the technique of immunofixation electrophoresis. These patterns consisted of four fast-moving anodal bands (F), four slow-moving cathodal bands (S), or a combination of both the F and S bands (FS). The C4 patterns of bands were observed in EDTA plasma and not in serum. Family studies showed that this polymorphism of C4 did not segregate with HLA histocompatibility genes in a fashion governed by two codominant alleles at a single genetic locus. The family data are in agreement with the hypothesis that two different genetic loci control the electrophoretic patterns of C4. One locus controls the presence (F) or absence (f0) of the four anodal (F) bands and the other controls the presence (S) or absence (s0) of the four cathodal (S) bands. The C4F and C4S loci are both closely linked to HLA-B.

Complement C4↗

PubMed1981

Sequence determination of the thiolester site of the fourth component of human complement.

The fourth component of complement (C4) is inactivated by treatment with methylamine. This property is shared wit the third component (C3) and with alpha 2-macroglobulin. In each instance, the reaction with methylamine is stoichiometric, covalent, and accompanied by the appearance of a thiol group. These data are consistent with the presence of an internal thiolester bond. Incubation of C4 with [14C] methylamine in the presence of activated thiol-Sepharose resulted in immobilization of the protein via its active-site thiol. Analysis of bound C4 indicated incorporation of 1.12 mol of [14C]methylamine per mol of protein. Digestion of the immobilized protein with porcine elastase resulted in the release of C4 beta- and gamma-chains and lower molecular weight fragments. The 14C label, however, was retained on the Sepharose beads. Subsequent release of bound material with L-cysteine indicated that the radiolabel was associated with two polypeptides of Mr 25,000 [C4d(ela25)]. The released material was dialyzed and the active-site thiol was radioalkylated with iodo[2-3H]acetic acid. C4d(ela25) was further purified by chromatography on Sephadex G-100 and, after reduction and alkylation, on Sepharose CL-6B in 0.2% NaDodSO4. The C4d(ela25) pool, containing 0.83 mol of [14C]methylamine per mol of iodo[2-3H]acetic acid, was subjected to automated sequence analysis. S-carboxy-[3H]methylcysteine was released at step 21 and gamma-glutamyl-[14C]methylamide was released at step 24. The recovery of radiolabel at positions 21 and 24 confirmed the originally calculated 14C/3H incorporation ratio and further indicated that the radiolabels were present at single sites in the C4 molecule. Comparison of the derived primary structure for the thiolester site in C4 with those for the corresponding regions in C3 and alpha 2-macroglobulin has shown sequence identity. Further comparisons among these three proteins have indicated additional homologies on both the NH2- and COOH-terminal sides of the thiolester site.

Amino Acid Sequence↗

PubMed2006

The immune response in autism: a new frontier for autism research.

Autism spectrum disorders (ASD) are part of a broad spectrum of neurodevelopmental disorders known as pervasive developmental disorders, which occur in childhood. They are characterized by impairments in social interaction, verbal and nonverbal communication and the presence of restricted and repetitive stereotyped behaviors. At the present time, the etiology of ASD is largely unknown, but genetic, environmental, immunological, and neurological factors are thought to play a role in the development of ASD. Recently, increasing research has focused on the connections between the immune system and the nervous system, including its possible role in the development of ASD. These neuroimmune interactions begin early during embryogenesis and persist throughout an individual's lifetime, with successful neurodevelopment contingent upon a normal balanced immune response. Immune aberrations consistent with a dysregulated immune response, which so far, have been reported in autistic children, include abnormal or skewed T helper cell type 1 (T(H)1)/T(H)2 cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen response, and the imbalance of serum immunoglobulin levels. In addition, autism has been linked with autoimmunity and an association with immune-based genes including human leukocyte antigen (HLA)-DRB1 and complement C4 alleles described. There is potential that such aberrant immune activity during vulnerable and critical periods of neurodevelopment could participate in the generation of neurological dysfunction characteristic of ASD. This review will examine the status of the research linking the immune response with ASD.

Animals↗

PubMed1993

Monitoring of serum proteinase--antiproteinase balance and systemic inflammatory response in prognostic evaluation of acute pancreatitis. Results of a prospective multicenter study.

With the aim of studying the clinical usefulness and applicability of circulating levels of protease inhibitors, complement factors, acute phase reactants, and leukocytic enzymes in the prognostic evaluation of acute pancreatitis (AP), the present prospective multicenter study has been carried out. A total of 182 patients with AP have been included, to whom an exhaustive evolutive protocol has been applied from the time of their hospital admission (2-12 hr from the onset of the disease) until the 15th day of evolution in order to clearly define them. The severe episodes exhibit a greater consumption of alpha 2-macroglobulin, and C3 and C4 complement factors, as well as a greater increase of alpha 1-protease inhibitor, C-reactive protein and polymorphonuclear elastase than mild events, with regards to the underlying pathophysiological condition. The determination of the plasma levels of leukocytic elastase in the first hours of evolution allows a prediction of the severity of the acute pancreatitis event with a high reliability (predictive values that become higher than 90%). The clinical value of the remaining parameters analyzed, in this aspect, is less, being applicable to the monitoring of the disease.

Acute Disease↗

PubMed1989

21-hydroxylase deficiency families with HLA identical affected and unaffected sibs.

During our investigations of polymorphisms at, and in the immediate chromosomal vicinity of, the 21-hydroxylase locus in families with 21-hydroxylase deficiency, three families were found to show marked discordance in clinical features of HLA identical subjects. In one family, there is discordance between a boy with the simple virilising form of 21-hydroxylase deficiency and his two younger sisters, who are both HLA identical to their brother, but who have additional salt wasting features. In the other two families, one subject is severely affected and has very high 17-hydroxyprogesterone levels, but has an HLA identical sib who is asymptomatic and shows only slightly raised 17-hydroxyprogesterone levels. In all cases, HLA identity, as indicated by protein polymorphism studies (HLA-A, B, DR, C4A, C4B, and Bf typing), has been verified at the gene organisation level using 21-hydroxylase and complement C4 DNA probes. An HLA-Bw47 bearing haplotype in one of the latter families has not been transmitted to the affected child and appears to carry a normal 21-OHB allele and two genes which specify C4A allotypes.

Adrenal Hyperplasia, Congenital↗

PubMed1985

Mice constitutive for sex-limited protein (SLP) expression contain multiple Slp gene sequences.

The murine fourth component of complement (C4) and sex-limited protein (Slp) are two closely related serum proteins whose structural genes map to the S region of H-2. Serum C4 levels vary as much as 20-fold between C4 high (C4H) and C4 low (C4L) strains, and Slp expression can be null (SlpO), limited to male mice of a subset of C4H strains (Slp+), or "constitutive" (SlpC), in which female as well as male mice express Slp. In this study, we compare, by genomic Southern blot analysis, the C4 and Slp genes from eight congenic inbred mouse strains representative of three distinct phenotypes: C4H, Slp+ (two strains), C4H, SlpO (two strains), C4H, SlpC (three strains), and C4L, SlpO (one strain). By using cDNA probes that recognize both C4 and Slp genes, and are derived from the extreme 5' and 3' ends of the mRNA as well as internal coding sequences, we find no evidence to suggest that strain-specific variations in the expression of C4 and Slp are due to gross deletions of major portions of the structural genes. In most cases, two distinct C4/Slp genes are detected; hybridization with C4- and Slp-specific probes indicate that one of these is C4 and the other is Slp. The three SlpC strains are exceptional: they carry at least four C4/Slp genes; one of these hybridizes to the C4-specific probe whereas the remaining genes hybridize to the Slp-specific probe. Hence, multiple duplication of a gene containing Slp sequences has occurred in certain strains of mice, and this is accompanied by constitutive expression of the Slp protein.

Animals↗

PubMed1987

Heterogeneity in the structural basis of the human complement C4A null allele (C4A Q0) as revealed by HindIII restriction fragment length polymorphism analysis.

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes. C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes, 21-OHA and 21-OHB, and is also remarkable in the high frequency of the 'null' alleles, C4A Q0 and C4B Q0. The molecular basis for the C4A Q0 allele was studied in 26 families through restriction fragment length polymorphism (RFLP) analysis with C4 and 21-OH cDNA probes after digestion of the DNA with the endonuclease HindIII. The individuals expressing the extended haplotype HLA-A1 (of A2) Cw7 B8 C2C BfS C4AQ0B1 DR3 have a large deletion taking off the C4A and 21-OHA genes.

Alleles↗

PubMed1992

Genetic control of nonresponsiveness to hepatitis B virus vaccine by an extended HLA haplotype.

We previously reported evidence for a statistical association between the serologically determined HLA-Bw54, DR4 and DRw53 alleles and the non-immune responsiveness to hepatitis B virus surface antigen (HBsAg) in the Japanese population. To identify the locus and allele within the HLA region associated with the nonresponsiveness to HBsAg, serological HLA typing, DNA typing of HLA-DQ and DP alleles using amplified HLA genes and sequence-specific oligonucleotide probes, and restriction fragment length polymorphism (RFLP) analysis of the fourth component of complement (C4) genes were performed in healthy unrelated Japanese vaccinees who were immunized subcutaneously three times with plasma-derived HBsAg vaccine. In nonresponders to HBsAg, the frequencies of HLA-Bw54 cross-reactive epitope group (CREG); (Bw54, Bw55, Bw56 and other Bw22), C4 RFLP (6.5 kb + 12.0 kb), DR4, DRw53 and DQw4 (DQA1*0301-DQB1*0401) were increased and the frequencies of HLA-DR1, DRw6 and DQw1 were decreased as compared with those in healthy unrelated controls. Further analysis revealed that the coexistence of HLA-Bw54CREG and DR4-DRw53-DQw4 (DQA1*0301-DQB1*0401) was associated with the nonresponder group, whereas, donors positive for exclusively either Bw54 CREG or DR4-DRw53-DQw4 (DQA1*0301-DQB1*0401) were not associated with the nonresponder group. Because there is a strong linkage disequilibrium between HLA-Bw54CREG, C4 RFLP (6.5 kb + 12.0 kb) and HLA-DR4-DRw53-DQw4 (DQA1*0301-DQB1*0401) in the Japanese population, the extended HLA-Bw54CREG-C4 RFLP (6.5 kb + 12.0 kb)-DR4-DR-w53-DQw4 (DQA1*0301-DQB1*0401) haplotype may well control nonimmune responsiveness to HBsAg. This extended HLA haplotype controls nonresponsiveness as a dominant genetic trait because all ten heterozygotes and two of three probable homozygotes of this extended HLA haplotype were nonresponders.

Adult↗

PubMed2003

Mannose-binding lectin engagement with late apoptotic and necrotic cells.

The serum opsonin mannose-binding lectin (MBL) has been shown to be involved in the handling of apoptotic cells. However, at what stage in the process this happens and whether this mediates activation of complement is unknown. Cells rendered apoptotic or necrotic were incubated with purified MBL/MBL-associated serine protease (MASP) complexes and assessed by flow cytometry and fluorescence microscopy. MBL bound specifically to late apoptotic cells, as well as to apoptotic blebs and to necrotic cells, but not to early apoptotic cells. Binding of MBL could be inhibited by EDTA as well as with an antibody against the CRD region. Addition of C1q, another serum opsonin involved in the handling of apoptotic cells, prior to MBL partly inhibited MBL binding to apoptotic cells and vice versa. MBL/MASP could initiate deposition of purified complement C4 on the target cells. However, addition of MBL/MASP to whole serum deficient for both C1q and MBL did not enhance deposition of C4, but MBL enhanced phagocytosis of apoptotic cells by macrophages. These results demonstrate that MBL interacts with structures exposed on cells rendered late apoptotic or necrotic and facilitates uptake by macrophages. Thus, MBL may promote non-inflammatory sequestration of dying host cells.

Apoptosis↗

PubMed2001

[Intravenous immunoglobulin and prednisolone treatment of cryoglobulinemic polyneuropathy].

A 71-year-old man with cryoglobulinemia associated with severe symmetrical sensorimotor polyneuropathy was successfully treated with intravenous immunoglobulin (IVIG) and a corticosteroid. Within 2-3 months, he developed distal motor and sensory deficits and burning feet deteriorating after cold exposure. On examination, symmetric hypesthesia and hypalgesia were found along with bilateral loss of vibration and position sense, loss of ankle jerks, and paralysis of the pretibial muscles with step-page gait. The laboratory exam revealed elevated cryoglobulin levels and reduced complement C4. Nerve conduction studies were consistent with a severe axonal sensorimotor polyneuropathy. Sural nerve biopsy showed chronic neuropathy with an acute component. The patient underwent a combined treatment with prednisolone (initially 100 mg) and intravenous immunoglobulin. His condition markedly improved after almost a year of treatment. Unfortunately, the treatment with intravenous immunoglobulin had to be interrupted due to an allergic reaction after the sixth application.

Aged↗

PubMedDate not supplied

The effects of daily stress and stressful life events on the clinical symptomatology of patients with lupus erythematosus.

OBJECTIVE: The purpose of this study was to verify whether stress worsens the clinical symptomatology perceived by patients with lupus erythematosus. Toward this end, we considered two types of stressors-daily stress and high-intensity stressful life events. METHODS: In 46 patients with systemic lupus erythematosus and 12 patients with chronic lupus discoid, we studied the stress they experienced daily for 6 months and their disease symptoms. During this period, we also analyzed the levels of C3 and C4 complements and anti-DNAn antibodies. The systemic lupus erythematosus activity (assessed by the Systemic Lupus Activity Measures) and cumulative organ damage (assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were also analyzed. RESULTS: We did not find that high-intensity stressful life events produced a worsening of the symptomatology of the disease. However, using a time-series analysis (Box-Jenkins), we found that a high percentage of lupus patients (74.1%) perceived a worsening in their clinical symptomatology due to the effects of daily stress. Of this 74.1%, 53.4% worsened the same day they suffered the perceived daily stress, and the remaining 20.7% experienced an increase in symptoms both the same day and the following day. Subsequent Mann-Whitney analyses showed that the patients who worsened for 2 days because of the effects of stress had greater lupus activity, as evaluated by their levels of C3, C4, and anti-DNAn. CONCLUSION: Daily stress, and not stressful life events, worsened the clinical symptomatology perceived by lupus erythematosus patients. This increase extended at times to 2 days, and was associated with greater lupic activity.

Adult↗

PubMed1990

C4B deficiency: a risk factor for bacteremia with encapsulated organisms.

The fourth component of complement (C4) is crucial to the activation of the classical complement pathway, a key defense against invading microorganisms. The two isotypes of C4, C4A and C4B, have very different in vitro activities. An increased incidence of total C4B deficiency was found in white patients with Streptococcus pneumoniae, Haemophilus influenzae, or Neisseria meningitidis infection (14% of bacteremic children vs. 2% of race-matched controls, P = .02). In black patients, however, there was no difference in incidence of C4B deficiency between bacteremic patients and race-matched controls (7% and 5%, respectively, P greater than .5). These data suggest that, at least in whites, total C4B deficiency is a risk factor for invasive disease with these three encapsulated organisms.

Adolescent↗

PubMed1982

Studies of phagocytic functions in rheumatoid arthritis. II. Effects of serum factors on phagocytic and metabolic activities of neutrophils.

A previous article has shown a diminished phagocytic and intracellular metabolic activity of the polymorphonuclear cells (PMN's) from patients with rheumatoid arthritis (RA). No correlation was found between PMN's functions with either clinical or laboratory expression of disease activity. In the present study the effects of rheumatoid sera on PMN's functions were investigated and the results revealed significant inhibition of phagocytic activity (PA) and nitroblue tetrazolium (NBT) dye reduction capacity of cells from RA as well as from a normal (N) control group. The number of PMN's showing aggregated latex particles on their surfaces was significantly higher in RA patient groups in the presence of rheumatoid sera. PMN's from N and RA groups were lysed in the presence of rheumatoid sera, with more significant destruction of RA-PMN's. No correlation was found between the PMN's function and the amount of circulating immune complexes (CIC's) or rheumatoid factor (RF). Significantly lower concentration of complement (C4) levels and higher IgA mean values were observed in the patient group compared to the standard values. The mechanism(s) underlying the impaired PA and NBT reduction may be due to defective intrinsic cell function as well as the extra cellular effects of blocking or lytic factors present in rheumatoid sera.

Antigen-Antibody Complex↗

PubMed1985

Adrenal 21-hydroxylase cytochrome P-450 genes within the MHC class III region.

Genes encoding several serum complement components and the gene(s) for steroid 21-hydroxylase (21-OH) have been located in the class III region of the major histocompatibility complex (MHC). All these genes are highly polymorphic in man, and these polymorphisms have been used to draw conclusions about the structure and function of these genes. For example, electrophoretic polymorphisms of the fourth component of complement (C4) have been shown to be controlled by two closely linked genes, which also control expression of the red cell antigens Rodgers and Chido. Steroid 21-OH deficiency (D) can occur in several forms which differ in severity, and because of genetic linkage disequilibrium with different HLA antigens the inheritance of these forms is consistent with the existence of several alleles at a single locus. When severe 21-OH D occurs in association with the HLA haplotype A3;Bw47;DR7, there is a simultaneous null allele at one of the C4 loci. This was hypothesized to result from a single deletion or rearrangement affecting the 21-OH and C4 loci and perhaps the HLA-B gene as well. To test this hypothesis and identify the 21-OH gene, a cDNA clone was isolated which encoded the cytochrome P450 specific for steroid 21-hydroxylation in the bovine adrenal gland. This clone hybridized to two genes in normal human DNA, but to only one gene in DNA from an individual homozygous for A3;Bw47;DR7. All individuals heterozygous for A3;Bw47;DR7 carry a heterozygous deletion of a gene. These experiments showed that at least one structural gene for the cytochrome P450 specific for 21-hydroxylation is located in the MHC, probably very near the C4 genes, and a mutation in this gene results in 21-OH D. Cosmid clones have been used to locate the 21-OH genes both in man and mouse. In both species, there are two 21-OH genes, each located immediately 3' of one of the two C4 genes, and oriented in the same direction as the C4 genes. In man, the gene located 3' of the C4B gene is deleted in 21-OH D on the Bw47 haplotype, but the gene 3' of the C4A gene is deleted in hormonally normal individuals on the A1;B8;C4AQO;C4B1;DR3 haplotype. Thus the 21-OH B gene is normally active in man, but the 21-OH A gene is not.

Adrenal Glands↗

PubMed1983

A newly defined murine alloantigen controlled by the S region of the H-2 complex: molecular association with the fourth component of complement.

A previous study has shown that prolonged immunization of strain A.TBR16 mice (H-2 haplotype at16) with lymphoid tissue derived from A.TBR13 (at13) donors results in an antiserum that defines a new H-2-associated allotype with a strain distribution antithetical to H-2.7. The present report describes a sensitive ELISA that demonstrated that this specificity represents an allotypic determinant(s) on the fourth component of complement (C4). Studies with Sephadex G-200 fractionated plasma and serum proteins suggest that, as is the case for H-2.7, the new specificity appears to reside on the C4d fragment after C activation. We therefore propose the tentative nomenclature C4d.2 for this specificity and suggest revision of the nomenclature for H-2.7 to C4d.1. Also described in this report is the formal mapping of the genetic control of the C4d.2 allotype to the H-2S region.

Animals↗