Major histocompatibility complex associations with primary antiphospholipid syndrome.
Explore the source record for details and available documents.
Antiphospholipid Syndrome↗
Biomedical subjects
D Vergani
Publications and source records attributed to D Vergani.
Major histocompatibility complex genes and susceptibility to systemic lupus erythematosus in southern Chinese.
OBJECTIVE: To investigate the predisposing role of major histocompatibility complex (MHC) genes to systemic lupus erythematosus (SLE) in a Chinese population. METHODS: Polymorphism in the HLA-DRB, DQB, complement component C4, and 21-hydroxylase genes was analyzed by restriction fragment length polymorphism analysis and oligonucleotide probing of in vitro-amplified DNA from 88 Chinese patients with SLE and 69 matched control subjects. RESULTS: HLA-DRw15 and DQw1 were significantly more frequent in patients (corrected P less than 0.006, relative risk 5.2), but none of the 9 sequence variants of DQw1 were increased. The C4A gene deletion usually associated with SLE in Caucasoid and black patients was absent from all Chinese subjects, but possession of other C4 deletions and of DRw15 conferred the greatest risk (relative risk = 8.3). CONCLUSION: Different MHC haplotypes predispose to lupus in Chinese than in other ethnic groups. Our data suggest that the susceptibility lies at, or telomeric to, the DR locus, and that DRw15 and C4 deletions may act synergistically in conferring disease susceptibility.
China↗
Naturally occurring soluble CD4 in patients with human immunodeficiency virus infection.
To investigate its use as a marker of disease severity, serum soluble CD4 (sCD4) was measured by ELISA in patients with human immunodeficiency virus (HIV) infection. Levels of sCD4 were higher in patients than in controls (P less than .001) but did not increase with disease severity. sCD4 release per CD4 lymphocyte showed a linear increase with disease severity and performed as well as beta 2-microglobulin, a widely used marker. To study the role of sCD4 in the pathogenesis of HIV infection, an ELISA to detect sCD4 complexed with glycoprotein 120 (gp120) HIV envelope protein was developed. Preformed sCD4-gp120 complexes were not detectable in patient serum, but addition of recombinant gp120 showed that circulating sCD4 is capable of binding HIV envelope proteins. This study indicates that the sCD4-to-CD4 lymphocyte ratio increases linearly with disease severity and may be a useful marker of CD4 lymphocyte damage. In addition, serum sCD4 can bind viral particles, which may have implications for the use of recombinant sCD4 as a therapy in HIV infection.
AIDS-Related Complex↗
Elevation of activated gamma delta T cell receptor bearing T lymphocytes in patients with autoimmune chronic liver disease.
To study the possible role of T cells bearing the gamma delta T cell receptor (TCR) heterodimer in the pathogenesis of autoimmune chronic active hepatitis (AI-CAH) and primary sclerosing cholangitis (PSC) in children, we measured levels of gamma delta+ T cells in the peripheral blood, assessed the proportion of cells bearing the disulphide-linked (BB3+) and non-disulphide-linked (A13+) subtypes of the receptor, and studied the co-expression of TCR-gamma delta and the activation markers HLA-DR and IL-2 receptor (IL-2R), and the memory cell marker CD45RO. Percentage levels and absolute numbers of gamma delta +T cells were higher in both groups of patients than in controls (P less than 0.01), mainly as a result of an increase in both percentage levels and absolute numbers of the A13+ subtype (P less than 0.001). Co-expression of IL-2R and TCR-gamma delta was not found in controls but was present in some patients with AI-CAH (four out of 17) and PSC (six out of 12) at low levels (median 2.3%, range 1.7-5.0%). Expression of HLA-DR on gamma delta+ T cells was similar in both groups of patients and controls. The majority of gamma delta+ T cells in children with AI-CAH and PSC also expressed CD45RO (74.7 +/- 18.4% and 79.8 +/- 24.3%, respectively) at levels significantly higher than in controls (53.3 +/- 17.2%, P less than 0.01). These results suggest that autoimmune liver diseases in children are associated with an expansion and activation of gamma delta+ T cells in the peripheral blood, which may be important in the pathogenesis of these disorders.
Adolescent↗
Analysis of lymphocyte phenotypes in cord blood from early gestation fetuses.
Using cord blood samples obtained from fetuses between 16 and 40 weeks gestation, we have used a lysed whole blood flow cytometric technique to study the natural history of lymphocyte phenotypes known to be highly represented in cord blood at birth. The majority (51.0 +/- 14.7%) of lymphocytes expressed CD45RA, a marker of 'virgin' cells and there was a correlation between increasing percentages of CD45RA+lymphocytes and gestational age (r = 0.44, P < 0.01). Few cells (8.5 +/- 4.2%) expressed the CD45RO marker of primed lymphocytes and very few (1.0 +/- 0.7%) co-expressed CD45RA and RO, indicating little traffic between the two maturation markers. The percentage of B lymphocytes co-expressing CD5 was high in the fetal circulation (55.5 +/- 10.5%) compared with healthy adults (23.2 +/- 14.3%; P < 0.00001) and the level of CD5+ B cells declined with gestational age in an exponential manner (r = -0.45, P < 0.05). Similarly, levels of T lymphocytes expressing the gamma delta T cell receptor (TCR) declined exponentially (r = -0.59, P < 0.005). These results demonstrate that lymphocytes remain almost entirely unprimed before birth. In addition, CD5+ B lymphocytes and TCR-gamma delta+ T lymphocytes decline exponentially towards birth, in a manner suggesting that they may be seeding peripheral sites such as the spleen, skin and mucosae.
Antigens, CD↗
Radionuclide assessment of left ventricular function in patients with myocardial infarction and diabetes mellitus.
The aim of this study was to compare left ventricular function, assessed by radionuclide angiocardiography, in 54 diabetics and 194 non-diabetics with acute myocardial infarction (AMI). The most meaningful results concern the inferior AMI group, whose left ventricular ejection fraction (LVEF) and regional wall motion were significantly lower in diabetics than in non-diabetics (LVEF was 44.2 +/- 11 vs. 51.6 +/- 9%, P less than 0.005; the regional wall motion score was 0.46 +/- 1 vs. 1.56 +/- 1, P less than 0.01, respectively), while no significant difference was observed in the anterior AMI group. However, in the group as a whole, the LVEF was 41 +/- 13% in diabetics and 47 +/- 13% in non-diabetics (P less than 0.01), the number of abnormally contracting segments was 2.0 +/- 0.9 and 1.5 +/- 1, respectively, and the wall motion score was 0.2 +/- 1.1 and 1.0 +/- 1.4, respectively (P less than 0.01). These data could be explained by an underlying cardiac dysfunction in diabetes, in addition to AMI. The more marked difference between diabetics and non-diabetics in inferior AMI might be related to the smaller infarct size in this group.
Adult↗
Immunohistochemical features of the portal tract mononuclear cell infiltrate in chronic aggressive hepatitis.
The portal tract mononuclear cell infiltrate has been characterised in 28 liver biopsy samples showing features of chronic aggressive hepatitis from 12 patients with autoimmune chronic active hepatitis, 12 with primary sclerosing cholangitis, and four with other chronic liver diseases (two with alpha 1-antitrypsin deficiency, one with Wilson's disease, and one with chronic hepatitis B infection). In all patients liver disease had started in childhood. The mononuclear cell infiltrate was investigated by a two step immunoperoxidase technique using monoclonal antibodies to: total, alpha/beta T cell receptor positive, helper/inducer, suppressor/cytotoxic T lymphocytes; B lymphocytes; killer/natural killer cells; monocyte/macrophages; and to the activation markers HLA-DR antigens, interleukin 2 receptor (IL-2R), transferrin receptor, and 4F2Ag. In all samples the infiltrate consisted of mainly alpha/beta T cell receptor T lymphocytes. Although T helper/inducer cells predominated in patients with autoimmune chronic active hepatitis, T suppressor/cytotoxic lymphocytes were preponderant in patients with primary sclerosing cholangitis and the other chronic liver diseases. Killer/natural killer cells accounted for up to 25% of the mononuclear cell infiltrate in patients with autoimmune chronic active hepatitis, being rare or absent in the other diseases. Monocytes/macrophages were always found, but they were more numerous in primary sclerosing cholangitis than in the other chronic liver diseases. B lymphocytes were rare or absent in all subjects. Activated mononuclear cells were present in all subjects, but although in patients with autoimmune chronic active hepatitis and primary sclerosing cholangitis most cells of the infiltrate expressed HLA-DR antigens and up to 75% IL-2R, in other forms of chronic liver diseases HLA-DR positive cells were less common and IL-2R positive cells ere rare or absent. These results show that the cells responsible for the histological characteristics of chronic aggressive hepatitis vary in their functional phenotype and state of activation according to the type of underlying liver disorder, confirming the involvement of different pathogenetic mechanisms.
Adolescent↗
Complement activation in neonatal infection.
To investigate the usefulness of indices of complement activation in the diagnosis of infections in the neonatal period, activation products C4d, Ba, and C3d were measured in 42 babies with a putative diagnosis of infection based on clinical/laboratory criteria, and compared with conventional clinical and haematological criteria of infection and with C reactive protein. The diagnosis of sepsis was confirmed by culture and identification of organisms in 17. Fourteen babies in whom infection was not suspected formed the control group. In babies with proved infection, concentrations of the fragments C4d, Ba, and C3d were higher than in babies with suspected infection in whom microbiological tests were negative, and concentrations of Ba and C3d were higher than in controls. C reactive protein and the platelet count were not significantly different in babies with proved infection and those with negative microbiological tests, but in the latter, C reactive protein concentrations were higher than in controls. Of the indices studied, high concentrations of Ba predicted microbiologically proved infection with the highest sensitivity (47.1%) and specificity (92.0%). Ba thus seems to be useful as an early indicator of infection in the neonatal period.
Analysis of Variance↗
Activation of the classical complement pathway in spontaneous bacterial peritonitis.
To investigate the possibility that low complement concentrations in the plasma and ascites of patients with severe liver disease could be secondary to complement consumption, complement activation was studied in 32 patients with severe liver disease, 11 of whom had spontaneous bacterial peritonitis (SBP). In patients with SBP, plasma C3 and C4 were significantly lower than in uninfected patients (mean values 0.74 v 1.13 g/l, p less than 0.01 and 0.20 v 0.28 g/l, p less than 0.05 respectively). Plasma complement activation via the classical pathway, as shown by C4d/C4, was significantly increased in patients with SBP compared with uninfected patients (37.3 v 22.2, p less than 0.01) as was C3d/C3 (14.0 v 8.11, p less than 0.01), but there was no significant difference in Ba/B between SBP and uninfected patients. Ascitic C3 concentrations were higher in patients without SBP than in infected patients (0.37 v 0.08 g/l, p less than 0.05), as were factor B values (0.11 v 0.03 g/l, p less than 0.05). There was no significant difference in ascitic C4 concentrations in patients with SBP compared with uninfected patients (0.03 v 0.07 g/l). Although consumption of C3, as shown by C3d/C3 in ascites, was increased in infected patients compared with uninfected patients (79.1 v 36.1, p less than 0.05), there was no difference in ascitic complement activation between the groups for either the classical or alternative pathways. In SBP, decreased plasma C3 and C4 are primarily caused by increased activation of the classical pathway and not impaired hepatic synthesis. Activation and consumption of C3 is one factor causing the low ascitic C3 concentrations observed in SBP.
Adult↗
Complement and lupus: old concepts and new directions.
In this review it is our intention to outline briefly the relevance of the complement system in systemic lupus erythematosus. Three main issues will be addressed: the role of complement in handling immune complexes (ICs), the association between complement deficiencies and IC diseases, and the value of measuring complement components and their conversion products in monitoring disease activity.
Complement Activation↗
A new ELISA measuring antibodies to islet cell membranes: levels are increased in type 1 diabetes.
Using purified rat islet cell membranes as the solid phase antigen we have established an ELISA to detect anti-islet cell membrane antibodies. Levels were increased in Type 1 diabetics compared to controls (p < 0.02). There was no relationship between the level of antibodies to the membrane and the presence of islet cell cytoplasmic antibody (ICA), suggesting that they are not the same. The assay offers the opportunity to study antibodies to human beta cell membranes, the target of the immune attack in type 1 diabetes.
Antibodies↗
Glutamic acid decarboxylase expression in islets and brain.
Explore the source record for details and available documents.
Brain Chemistry↗
Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity.
To resolve conflicting reports about the occurrence of antibodies against hepatitis C virus (HCV) in patients with autoimmune chronic active hepatitis (AI-CAH), sera from UK and Italian patients were tested with the original anti-HCV assay (Ortho) and a novel anti-HCV assay (UBI) based entirely on synthetic HCV peptides. 28 (60%) of 47 Italian patients with type-1 AI-CAH were anti-HCV-positive by Ortho ELISA, 25 of whom were also strongly positive by the UBI assay. 15 (60%) of 25 UK patients with type-1 AI-CAH were HCV-positive by Ortho ELISA but only 2 were positive by the UBI assay. Similarly, 29 (88%) of 33 Italian patients with type-2 AI-CAH, but 0 of 10 UK patients, were very strongly anti-HCV-positive with the UBI assay. Italian patients with AI-CAH appear to have a high frequency of genuine exposure to HCV, whereas seropositivity by the Ortho HCV ELISA in UK patients is likely to represent a false-positive result. These findings indicate important geographical and/or genetic influences in autoimmune liver disease among different populations.
Adult↗
Complement activation during bypass in acquired C1 esterase inhibitor deficiency.
Serial complement estimations during cardiopulmonary bypass are reported in a patient with acquired C1 esterase inhibitor deficiency. Although the extent of classic and alternative pathway activation appeared appropriate, exaggerated common pathway activation with massive increase in the C3d:C3 ratio occurred. A fatal hemostatic disorder, pulmonary edema, and circulatory collapse ensued despite prophylaxis and therapy.
Aged↗
Anticardiolipin antibodies in patients from Malaysia with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is highly prevalent in Malaysia, which has a mixed population of Malays, Chinese, and Indians. A quantitative enzyme linked immunosorbent assay (ELISA) was used to determine anticardiolipin antibody (aCL) levels (total immunoglobulin, IgG, and IgM) in 200 patients with SLE (164 Chinese, 26 Malay, and 10 Indian) attending the University Hospital of Kuala Lumpur, Malaysia, and 103 matched controls. Only 33 (16.5%) of the patients had raised aCL levels; 26 had raised IgG aCL, five IgM aCL, and two both IgG and IgM aCL. There was a low prevalence of raised levels of aCL in the population studied, which was seen in conjunction with a rare occurrence of thrombosis. The classical association of high aCL levels with thrombocytopenia and recurrent abortions was noted, though not with cerebral disease. The low prevalence of aCL in this study population of mixed racial origin contrasts with findings in European patients with SLE and lends support to the influence of local factors, be they genetic or environmental, on the clinical manifestations of this disease.
Abortion, Habitual↗
Influence of C4 null alleles on C4 activation in systemic lupus erythematosus.
Deficiencies of early components of the classical complement pathway are known to be associated with systemic lupus erythematosus (SLE). C4 null alleles, C4A Q0 and C4B Q0, are prime candidates for the major histocompatibility complex associated factor which determines susceptibility to SLE. There is poor correlation, however, between the presence of low concentrations of C4 and possession of C4 null alleles, and thus the basis of the association between C4A Q0, C4B Q0 and SLE remains obscure. The possibility that activation of C4 may be related to the possession of C4 null alleles was examined. C4 phenotypes were investigated, and C4 concentration and activation were estimated in patients with SLE. C4 activation was determined by measuring the concentration of C4d--a split product of C4. Twenty five of 35 patients had C4 phenotypes which include null alleles. No association between low C4 concentrations and C4 null alleles was found, but a significant association between low C4d concentrations and C4 phenotypes including null alleles, particularly those with C4A Q0, was noted. No correlation between concentrations of C4 and C4d was found. These results show an influence of C4 null alleles on the activation of the C4 molecule, which is independent of the concentration of C4. The possession of silent genes coding for C4 null alleles might predispose to SLE by conditioning poor C4 activation, a critical event for the clearance of immune complexes mediated by the classical complement pathway.
Alleles↗
Autoimmune chronic active hepatitis in a family.
A positive family history of autoimmune disease is common among patients with autoimmune chronic active hepatitis, but usually autoimmunity is directed at organs other than the liver. We document for the first time the multiple occurrence of autoimmune chronic active hepatitis in a family. Out of a sibship of seven, three sisters developed this, one sister developed coeliac and autoimmune thyroid disease, one sister showed serological signs of autoimmunity, while the two brothers were well with no signs of autoimmunity. HLA typing showed that in association with the female sex DR3 seems to be more important than B8 in conferring susceptibility to autoimmune chronic active hepatitis, at least in this family.
Adolescent↗
Alpha 1-antitrypsin deficiency, complement activation, and chronic liver disease.
Activation of the complement system, the main humoral mediator of inflammation, is restrained by the action of enzyme inhibitors including alpha 1-antitrypsin. Deficiency leads to chronic liver disease in about one in five children with this genetic defect. Complement activation was investigated in 34 children with alpha 1 AT deficiency (12 with minimal, 10 with moderate, and 12 with severe liver disease) and in 38 sex and age matched normal children by measuring the complement parent molecules C3, C4, the C3d fragment and by calculating the C3d:C3 ratio. C3 and C4 were lower in children with severe liver disease compared with controls, indicating impairment of hepatic protein synthesis or complement consumption. The C3d activation fragment was higher in all the patient groups when compared with controls while the C3d:C3 ratio, a measure of activation independent of the concentrations of the parent molecule, was higher in patients than in controls and increased with the degree of disease severity. These results suggest that complement may have a role in the pathogenesis of the chronic liver disease associated with alpha 1AT deficiency.
Adolescent↗