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Biomedical subjects

J F Bach

Publications and source records attributed to J F Bach.

At least 91 records · Page 5Linked to original sources
PubMed1997

Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy.

The GLC1A locus for autosomal dominant juvenile and middle age onset primary open angle glaucoma (OAG) has been mapped to chromosome 1q21-q31. OAG, however, is a heterogeneous disease. We tested linkage of OAG and ocular hypertension (OHT), a major risk factor for OAG, to GLC1A in eight French families with multiple cases of juvenile and middle age onset OAG. There was strong evidence of genetic heterogeneity, four families being linked to GLC1A and two or three others being unlinked, depending on whether the complete OAG phenotype was analysed alone or jointly with OHT. Peak intraocular pressure (IOP) did not differ significantly between the two groups of families, while linkage to GLC1A conferred a highly increased risk of developing OAG and of having severe glaucomatous optic neuropathy. Testing linkage of familial OAG to GLC1A may therefore have prognostic value too.

Adult↗
PubMed1997

The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn.

High anti-fetal/anti-adult muscle anti-acetylcholine receptor (AChR) antibody (Ab) titer ratio is predictive of the occurrence of neonatal myasthenia gravis in a first child. The aim of the present study was to determine whether the ratio between the levels of antibodies is an intrinsic property of the mother's sera or varies with physiologic status such as pregnancy. We performed a longitudinal study of the levels of Ab directed against both fetal and adult AChRs and the ratio between them in 11 mothers with myasthenia gravis (MG). Sera were taken during, before, and after pregnancy. Absolute levels of Ab varied considerably during the time of observation as indicated by analyzing the maximum change between any two sample times during the study (adult mean percentage change 45.9 +/- 26.4; fetal 42.51 +/- 22.05). In contrast to this, the anti-fetal/anti-adult muscle AChR Ab titer ratio was much less variable (mean percentage change 16.66 +/- 10.11; p < 0.0033). The levels of the two Ab types yielded a correlation of 0.918, consistent with the stability of the ratio between them. This stability of ratio has practical value in the management of pregnancy and infant care in mothers with MG because the ratio at any time, before or during pregnancy, will predict whether the child will contract neonatal MG. We determined this for the first child, but further studies are necessary to establish if this remains true for subsequent pregnancies.

Antibodies↗
PubMed1996

Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum.

A quantitative trait locus for increased IgG serum levels in the NOD mouse strain was mapped to distal chromosome 1, close to the fcgr2 locus encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII). Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gamma RIIb1) isoform was only slightly decreased and Fc gamma RIII was not altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr2 or by a closely linked locus, occurred at the mRNA level, and was associated with multiple mutations in the fcgr2 gene promoter. In relation with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsonized RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severely impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mice, indicating that Fc gamma RII plays a nondispensable role in binding of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 congenic mice. These findings indicate that macrophage Fc gamma RII may regulate serum IgG1 and IgG2b through their catabolism, and validate the NOD strain as a model to investigate the functions of Fc gamma RII isoforms.

Animals↗
PubMed1996

Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia.

Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.

Adult↗
PubMed1996

Distribution of HLA class II alleles and haplotypes in insulin-dependent Moroccan diabetics.

HLA class II polymorphism in Moroccan IDDM patients has not been investigated so far. In this study, HLA-DRB1, -DQA1, and -DQB1 allele and haplotype frequencies were analyzed in 125 unrelated Moroccan IDDM patients and 93 unrelated healthy controls, all originating from the Souss region and mostly of Berber origin. Some common features with other Caucasian groups were observed, in particular, a predisposing effect of the DRB1*03-DQA1*0501-DQB1*0201 and DRB1*04-DQA1*0301-DQB1*0302 alleles or allelic combinations. The Moroccan IDDM group also presented with more specific characteristics. Among DRB1*04 subtypes, DRB1*0405 was associated with susceptibility to and DRB1*0406 with protection from the disease. The haplotype and the relative predispositional effect (RPE) analyses indicated that the DRB1*08-DQA1*0401-DQB1*0402 haplotype was also associated with susceptibility to IDDM. Interestingly, the DRB1*09-DQA1*0301-DQB1*0201 haplotype, completely absent from the control group and very rare in North African populations, was observed in 7.2% of the Moroccan diabetics. Conversely, the DRB1*07-DQA1*0201-DQB1*0201 and DRB1*15-DQA1*0102-DQB1*0602 haplotypes were associated with protection from IDDM. Finally, we observed an age-dependent genetic heterogeneity of IDDM, the frequencies of predisposing alleles being higher and those of protective alleles lower in childhood- than in adult-onset diabetics. Our data on Moroccan diabetics, together with data on European and Northern Mediterranean patients, suggest a gradient of various HLA class II predisposing and protective markers that link these populations.

Adolescent↗
PubMed1996

TCR alpha beta gene usage for myelin basic protein recognition in healthy monozygous twins.

The pathogenic role of myelin basic protein (MBP)-specific T lymphocytes in multiple sclerosis (MS) has been suggested by the encephalitogenicity of MBP-specific T cells in experimental allergic encephalomyelitis (EAE). In humans, extensive analysis of TCRs involved in MBP recognition has led to conflicting results, varying from an intra- and/or interindividual restriction to high diversity in TCRAV/TCRBV gene usage. We previously established MBP-specific T cell lines (TCLs) from healthy monozygous twins and characterized their fine epitope specificity. In this study, we report on the TCR alpha beta gene usage of 52 of these MBP TCLs that are specific for epitopes recognized by both co-twins within the same pair. High overall diversity in the TCR alpha and TCR beta genes used for recognition of this self-Ag, MBP, was observed. Variable genes belonging to 19 different TCRAV and 16 different TCRBV subfamilies are expressed by the 52 TCLs herein studied. In co-twins, TCLs utilized genes belonging to common TCRAV and/or TCRBV gene subfamilies in 7 of 13 instances of shared epitope recognition. Statistical analysis of intrapair concordance for TCR gene usage for the recognition of a given peptide did not show any significant deviation from values that would be anticipated in the absence of genetic background effect.

Amino Acid Sequence↗
PubMed1996

Gene expression of pancreatic glutamic acid decarboxylase in the nonobese diabetic mouse.

The 65 kDa isoform of glutamic acid decarboxylase (GAD 65) is an autoantigen implicated in type I diabetes. We have developed a quantitative PCR method to measure GAD 65 mRNA in the pancreas of nonobese diabetic (NOD) mice. Two other nonautoimmune mouse strains were used as controls. In all mice, pancreatic GAD 65 expression declined with age. In 5-week-old NOD mice, a clear difference was detected between males and females. This sexual dimorphism may explain the absence of tolerance to GAD 65 in the NOD female which could contribute to autoimmune destruction of beta cells in the pancreas and subsequent development of diabetes.

Animals↗
PubMed1996

10-year educational programme aimed at rheumatic fever in two French Caribbean islands.

BACKGROUND: In less developed countries, rheumatic fever still occurs. We started a long-term educational programme in two French Caribbean islands that was directed at the public and at health-care workers to see whether we could reduce the incidence of rheumatic fever. METHODS: Our 10-year programme started in 1981 in Martinique and Guadeloupe, and was based in the community and in clinics and hospitals. The programme established a registry of all cases of primary and secondary rheumatic fever (diagnosed by Jones' modified criteria), with systematic hospital admission of children. We graded carditis as severe, mild, or subclinical, and acute glomerulonephritis was defined by oedema, proteinuria, and haematuria for less than 3 months. The educational part of the programme targeted the public and health-care workers, including doctors, with written information distributed in schools or via radio and television broadcasts or videotapes. For the public, the benign clinical presentation of the initial streptococcal infection was contrasted with the severity of later heart disease. FINDINGS: The first months of the programme led to a 10-20% increase in the number of rheumatic fever cases admitted to hospital, because of the renewed attention paid to the disease. Therefore we took 1982 as the baseline year. In 1982-83 the incidence of rheumatic fever was 19.6 per 100 000 inhabitants aged under 20 in Martinique, and 17.4 per 100 000 in Guadeloupe. In 100 Martinique children and 97 Guadeloupe children in 1982-83, 40 and 71% had carditis, respectively (severe in 10 and 32%). Rheumatic fever was preceded by symptomatic sore throat in 52 and 41% of cases, respectively. The disease was not seen in children with active streptococcal cutaneous infections. Disease frequency was highest in the poorest areas and families, a finding that persisted over time. The programme was associated with a progressive decline in the frequency of rheumatic fever: final reduction of 78% in Martinique and 74% in Guadeloupe. The frequency of carditis also fell. Apart from two outbreaks in one hospital, the frequency of acute glomerulonephritis also declined; 31% of cases had had sore throat, while 56% had skin infections. The cost of the programme during the 4 most intensive years was FFr 250 000 (US$ 44 500) in each island. The cost of childhood rheumatic fever, excluding late sequelae, was initially (in 1982) about FFr 7.8 million (US$ 1426 000). The cost fell to an average of Ffr 550 000 (US$ 100 000) per year in 1991-92. INTERPRETATION: A rapid decline in rheumatic fever incidence was achieved at modest cost. Such a programme needs to be continued because of the risk of disease resurgence.

Adolescent↗
PubMed1996

Binding of nucleosomes to a cell surface receptor: redistribution and endocytosis in the presence of lupus antibodies.

In the present study, we sought evidence for a surface nucleosome receptor in the fibroblastic cell line CV-1, and questioned whether anti-double-stranded (ds) DNA and/or anti-histone autoantibodies could recognize and influence the fate of cell surface-bound nucleosomes. 125I-labeled mononucleosomes were shown to bind to the cell layer in a specific, concentration-dependent and a saturable manner. Scatchard analysis revealed the presence of two binding sites: a high-affinity site with a Kd of approximately 7nM and a low-affinity site (Kd approximately 400 nM) with a high capacity of 9 x 10(7) sites. Visualization of bound mononucleosomes by fluorescence revealed staining on both the cell surface and the extracellular matrix (ECM). Purified mononucleosome-derived ds DNA (180-200 bp) was found to complete for binding of 125I-mononucleosomes on the low-affinity site, to stain exclusively the ECM in immunofluorescence, and to precipitate three specific proteins of 43, 180 and 240 kDa from 125-I-labeled cell lysates. Nucleosomes were found to precipitate not only the 180-kDa ds DNA-reactive component, but also a unique protein of 50 kDa, suggesting that this protein is a cell surface receptor for nucleosomes on these fibroblasts. Once bound on the cell surface, mononucleosomes were recognized and secondarily complexed by lupus anti-ds DNA or anti-histone antibodies (i.e. anti-nucleosome antibodies), thus forming immune complexes in situ. The presence of these complexing auto-antibodies was found dramatically to enhance the kinetics of mononucleosome internalization. Following the internalization of the nucleosome-anti-nucleosome complexes by immunofluorescence, we observed the formation of vesicles at the edge of the cells by 5-10 min which moved toward the perinuclear region by 20-30 min. By means of double-fluorescence labeling and proteolytic treatment, these fluorescent vesicles were shown to be in the cytoplasm, suggesting true endocytosis of nucleosome-anti-nucleosome immune complexes. As shown by confocal microscopy, at no stage of this endocytic process was there any indication that coated pits or coated vesicles participated. Co-distribution of the endocytic vesicles with regions rich in actin filaments and inhibition of endocytosis of nucleosome-anti-nucleosome complexes by disruption of the microfilament network with cytochalasin D suggest a mechanism mediated by the cytoskeleton. Taken together, our data provide evidence for the presence of a surface nucleosome receptor. We also show that anti-ds DNA and anti-histone antibodies can form nucleosome-anti-nucleosome immune complexes in situ at the cell surface, and thus dramatically enhance the kinetics of nucleosome endocytosis.

Animals↗
PubMed1996

Early quantitative and functional deficiency of NK1+-like thymocytes in the NOD mouse.

An immunoregulatory role has recently been attributed to the discrete subset of major histocompatibility complex class I-restricted NK1+ mature heat-stable antigen- (HSA-) thymocytes expressing an unusual Vbeta8-biased T cell receptor repertoire. NK1+ T cells are the main interleukin (IL)-4 producers upon priming. We have studied the size and the function of this subset in the nonobese diabetic (NOD) mouse, a model of spontaneous T cell-mediated autoimmune insulin-dependent diabetes. This study was complicated by the absence in this strain of the NK1.1 allele, the only one for which an antibody is available. To circumvent this difficulty, the cells, hereafter designated the NK1+-like T subset, were characterized by the use of monoclonal antibodies which showed the Vbeta8 bias in the CD44+ Ly-49+ MEL-14- 3G11- thymocyte subset of non-autoimmune strains and of its absence in class I-deficient (beta2-microglobulin-/-) mice. A clear deficit in the number of NK1+-like cells was evidenced at 3 weeks of age in NOD mice. It was still present at 8 weeks of age in the double-negative CD4-CD8- population. The functional anomaly was even more striking: NOD mouse NK1+-like thymocytes virtually lacked the ability to produce IL-4 at 3 weeks and still showed a very reduced capacity at 8 weeks. NK1+ T cell deficiency was also suggested in the periphery by the reduction of Ly-49A+ cells in the spleen of 3- and 8-week-old NOD mice and the absence of short-term production of IL-4 in vitro by NOD mouse spleen cells 90 min after the administration of anti-CD3 antibody, a response attributed to NK1+ T cells. Taken together, these data demonstrate a very early defect in NK1+-like T cells which could be involved in the genesis of autoimmunity in NOD mice through a deficiency in Th2 cell function.

Animals↗
PubMed1996

Contribution of DRB1*04 variants to predisposition to or protection from insulin dependent diabetes mellitus is independent of dq.

Certain DQ alpha/beta dimeric molecules have been shown to play a major role in determining susceptibility or resistance to IDDM. Whether or not predisposition associated with DR4 haplotypes is exclusively due to linkage to DQB1*0302 and DQA1*0301 alleles is still a controversial issue. A modifying effect of certain DRB1*04 subtypes on the susceptibility encoded by DQ alleles is possible, since not all DRB1*04-DQB1*0302 haplotypes are associated with the disease. The distribution of DRB1*04 subtypes was analysed in 240 DR4-positive Caucasian IDDM patients and 110 DR4-positive healthy controls using allele-specific hybridization after genomic amplification. Although an important contribution to IDDM predisposition was encoded by the DQB1*0302 allele which was found in the majority of patients (94.2% vs 64.7% in controls, Odd's ratio OR = 8.8, P < 0.0001), differences between DRB1*04 variants persisted after the effect of the DQB1 locus was removed by matching patients and controls for DQB1*0302. Thus, the DRB1*0402 allele conferred a strong IDDM-predisposing effect (OR = 3.1, P < 0.02) which was highly significant in the absence of DR3 on the second haplotype (OR = 5.6, P < 0.0001) but was not visible among DR3/4 heterozygote individuals. Conversely, the DRB1*0404 allele conferred a strong protective effect (OR = 0.26, P < 0.0001) which was dominant even in the presence of the associated high risk DR3 haplotype (OR = 0.21, P < 0.03). These data indicate that DQ molecules are not the sole contributors to the DR4-associated IDDM predisposition, and that peculiar DR4 subtypes play a significant role in susceptibility to or protection from the disease. DRB1*0402 differs from DRB1*0404 by only two acidic residues at positions 70 and 71 within the peptide binding groove, instead of amide and basic amino acids. This might induce changes of peptide binding specificity that correlate with the genetic linkage of IDDM predisposition.

Alleles↗
PubMed1996

Cyclosporine delays but does not prevent clinical onset in glucose intolerant pre-type 1 diabetic children.

We conducted a pilot study of immunosuppression with low dose cyclosporine in first degree relatives of diabetic patients with immunologic and metabolic criteria for preclinical diabetes: islet cell antibodies (ICA) > or = 20 Juvenile Diabetes Foundation (JDF) units, first phase insulin response < 10th percentile and impaired glucose tolerance. Cyclosporine was given at an initial dose of 7.5 mg/kg*d and tapered after the end of the first year. Six cyclosporine-treated relatives were compared to nine historical controls followed at the same or at different centres. All untreated patients developed diabetes within 12 months (5.9 +/- 1.1 months). Four of the cyclosporine-treated subjects developed diabetes at 5, 24, 24 and 47 months while the other two are non diabetic 47 and 57 months after entry into the trial (time to diabetes > 34 +/- 8 months, P < 0.001 vs the control group; Mann-Whitney test). First phase insulin response increased to normal values in two patients. These results suggest that reversible functional impairment, in association with beta-cell destruction, contributes to the failure of insulin secretion in preclinical type 1 diabetes.

Adolescent↗
PubMed1996

Interplay of four idiotypes and interaction with autoantibodies in lupus patients, their relatives and their spouses.

Our aim was to investigate links between systemic lupus erythematosus (SLE)-associated autoantibodies, idiotypes (Id) and genetic predisposition to their development. We studied four public Ids (16/6, WRI 176 beta, RT72 and RT84), identified the Km and Gm phenotypes and sought six selected autoantibodies in 32 SLE patients, 174 of their relatives and 15 spouses. Though anti-double-stranded DNA antibody was uncommon in the relatives (9%), the range of antinuclear reactivities was as broad in the relatives as in the probands. Antibodies to the synthetic peptide U1-RNP-A 35-38 were found in 56% of the patients, 28% of their relatives and 20% of the spouses, whereas antibodies to the Golgi apparatus was present in 7% of the patients, 26% of their relatives and 33% of the spouses. However, most of these family members were unaffected. RT84 Id was positively associated with antibodies to Sm-D peptide 1-20 and to Ro/SSA 60 kD peptide 304-324, but negatively associated with anti-dsDNA activity. The median of age was significantly lower in the RT84 Id-positive than in the RT84 Id-negative individuals. These data suggest that genetic as well as environmental factors are involved in the aetiology of SLE. In addition, RT84-carrying immunoglobulins (Ab2) might be directed to one of many cross-reactive Ids of dsDNA-binding antibodies (Ab1), perhaps down-regulating their production.

Adolescent↗