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J F Bach

Publications and source records attributed to J F Bach.

At least 73 records · Page 4Linked to original sources
PubMed1997

Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients.

BACKGROUND: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy) is commonly overlooked or misdiagnosed owing to its recent identification and its variable mode of presentation. The defective gene in CADASIL is Notch3, which encodes a large transmembrane receptor. To set up a diagnostic test and to delineate the Notch3 domains involved in CADASIL., we undertook mutations analysis in this gene in a group of CADASIL patients. METHODS: 50 unrelated patients with CADASIL and 100 healthy controls were screened for mutations along the entire Notch3 sequence, by means of single-strand conformation polymorphism, heteroduplex, and sequence analysis. FINDINGS: Strongly stereotyped mis-sense mutations, located within the epidermal-growth-factor-like (EGF-like) repeats, in the extracellular domain of Notch3, were detected in 45 patients. Clustering of mutations within the two exons encoding the first five EGF-like repeats was observed (32 patients). All these mutations lead to loss or gain of a cysteine residue and therefore to an unpaired number of cysteine residues within a given EGF domain. None of these mutations was found in the 100 controls. INTERPRETATION: Because of the strong clustering and highly stereotyped nature of the pathogenetic mutations detected in CADASIL patients, and easy and reliable diagnostic test for CADASIL is feasible. The findings suggest that aberrant dimerisation of Notch3, due to abnormal disulphide bridging with another Notch3 molecule or with another protein, may be involved in the pathogenesis of this disorder.

Case-Control Studies↗
PubMed1997

Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

Adult↗
PubMed1997

Absence of functional relevance of human transporter associated with antigen processing polymorphism for peptide selection.

The polymorphic TAP (TAP1 and TAP2) genes code for a heteromeric complex that translocates cytosolic peptides across the membrane of the endoplasmic reticulum where they associate with MHC class I molecules. In the rat, extensive TAP2 polymorphism modifies the spectrum of peptides presented by MHC class I molecules on the cell surface. Although polymorphism of human TAP proteins is more limited, it has been proposed to be associated with susceptibility to autoimmune diseases. To analyze the peptide selectivity and transport efficiency of human TAP alleles, we have generated the most frequent TAP1 and TAP2 alleles using site-directed mutagenesis. Alleles were cloned in the baculovirus expression system and six TAP1/2 allelic combinations were overexpressed in Sf9 insect cells. Microsomes containing TAP1/2 dimers were isolated, and peptide binding assays were performed using random sequence peptide libraries of variable length (7-18 mer) and a 9-mer polyalanine peptide substituted with various amino acids in positions 1, 2, 3, 7, and 9. All studied allelic combinations selected peptides with identical substitutions and length. Furthermore, transport assays showed similar efficiency and kinetics of peptide translocation by the different TAP alleles. These data suggest that the major human TAP alleles transport identical peptide sets and are therefore unlikely to contribute to predisposition to autoimmune diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice.

Low doses of the CD3 mAb 145 2C11 restored self tolerance to beta cell Ags in adult overtly diabetic NOD mice. Within 2 to 4 wk after treatment, complete and permanent remission of diabetes was observed. Autoreactive T cells were not deleted in CD3 Ab-protected animals as evidenced first, by the persistence of peripheral insulitis and, second, by the capacity of spleen cells from CD3 Ab-treated mice to transfer diabetes to adult irradiated syngeneic recipients. Moreover, the conferred tolerance was reproducibly reversed by a single injection of cyclophosphamide. For 5 to 7 wk after treatment, IFN-gamma production by stimulated spleen cells was significantly decreased in treated animals. One unique feature was that the CD3 Ab-induced tolerance ensued only from treatment of overtly diabetic NOD mice. Durable protection was exclusively observed when treating mice with recent onset disease (14-20 wk old). At variance with this finding, treatment of 4- and 8-wk-old mice was without effect, and complete but transient protection followed the treatment of 12-wk-old NOD mice. The tolerogenic properties of 145 2C11 did not depend on its mitogenic capacity, since nonmitogenic F(ab')2 fragments also appeared potent at inducing durable remission in overtly diabetic NOD, although nonmitogenic CD3 F(ab')2 fragments could mediate T cell signaling, as evidenced by cytokine gene transcription (IL-2, IFN-gamma, IL-4, and IL-10) assessed by PCR on splenocytes from treated mice. A concomitant cyclosporine treatment abrogated the CD3 mAb-induced protection, further pointing to the crucial role of T cell signaling in the effect observed.

Adoptive Transfer↗
PubMed1997

Recombinational and physical mapping of the locus for primary open-angle glaucoma (GLC1A) on chromosome 1q23-q25.

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness in industrialized countries. A locus for juvenile-onset POAG, GLC1A, has been mapped to 1q21-q31 in a 9-cM interval. With recombinant haplotypes, we have now reduced the GLC1A interval to a maximum of 3 cM, between the D1S452/NGA1/D1S210 and NGA5 loci. These loci are 2.8 Mb apart on a 4.7-Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs. The new GLC1A interval itself is now covered by 25 YACs, 30 STSs, and 16 restriction enzyme site landmarks. The lack of a NotI site suggests that the region has few CpG islands and a low gene content. This is compatible with its predominant cytogenetic location on the 1q24 G-band. Finally, we have excluded important candidate genes, including genes coding for three ATPases (ATP1B1, ATP2B4, ATP1A2), an ion channel (VDAC4), antithrombine III (AT3), and prostaglandin synthase (PTGS2). Our results provide a basis to identify the GLC1A gene.

Chromosome Mapping↗
PubMed1997

Circulating plasma levels of nucleosomes in patients with systemic lupus erythematosus: correlation with serum antinucleosome antibody titers and absence of clear association with disease activity.

OBJECTIVE: To assess nucleosome plasma levels in patients with systemic lupus erythematosus (SLE) and to study the correlations with serum antinucleosome, anti-double-stranded DNA (anti-dsDNA), and antihistone antibody activities, as well as with disease activity (by the SLE Disease Activity Index [SLEDAI]). METHODS: In a cross-sectional study, we assessed 58 SLE patients for their plasma nucleosome levels. Plasma nucleosome levels as well as serum antinucleosome, anti-double-stranded DNA, and antihistone antibody activities were assessed by enzyme-linked immunosorbent assay. SLE activity was evaluated using the SLEDAI: RESULTS: The mean (+/-SD) plasma nucleosome concentration in SLE patients was 52 +/- 159 ng/ml (range 5-1,180), and was significantly higher than that of the controls (16 +/- 8.8 ng/ml, range 8-52; P = 0.03). Thirteen of the 58 lupus patients had levels over the range of normal (defined as the control mean + 3 SD, or 42 ng/ml). An inverse correlation was found between nucleosome plasma levels and serum antinucleosome antibody activity in the entire group of SLE patients, those with active disease, and those with inactive disease, respectively. No correlation was found between the SLEDAI and nucleosome plasma concentrations. CONCLUSION: Nucleosome plasma levels may be normal or increased in SLE, and found in patients with active or inactive SLE. Longitudinal studies are needed to further establish whether high levels of circulating nucleosomes may predict the occurrence of an SLE flare.

Adolescent↗
PubMed1997

Mechanisms of downmodulation and release of tumour necrosis factor receptor induced by human immunodeficiency virus type 1 in human monocytes.

Infection of human monocytes with human immunodeficiency virus type (HIV-1 LAI) triggers the release of both the cytokine tumour necrosis factor alpha (TNF-alpha) and its soluble receptor (TNFsr). In the present study, the authors have investigated the cellular events implicated in the modulation of expression and shedding of the monocyte TNF receptor induced by HIV-1 LAI. Release of TNFsr75 was triggered at an early step of interaction of the virus particles with the monocyte, involving the envelope glycoprotein gp120. HIV-1 LAI induced an upregulation of TNFr75 mRNA, whereas TNFr55 mRNA was not detectable. TNFsr75 release required exocytosis, proteolytic cleavage by serine protease(s), but was independent of prior endocytosis of the receptor. Early shedding of TNFr75 accounted for the almost total but transient disappearance of the membrane TNF receptor P75, observed 60 min after activation with HIV-1 LAI, whereas internalization was minimal. Endogenous TNF-alpha had no role in the disappearance of its own receptor. Complete and stable restoration of TNFr expression at the cell membrane, dependent on de novo protein synthesis, occurred after 5 h, followed by massive TNFsr75 release. These results demonstrate that interaction of human monocytes with HIV-1 LAI triggers at an early stage a cascade of cellular events that lead to profound remodeling of the cell TNFr pool. Understanding the mechanisms of these receptor movements is of importance to document the central role of the TNF system in HIV infection.

Cells, Cultured↗
PubMed1997

Association of the AChRalpha-subunit gene (CHRNA), DQA1*0101, and the DR3 haplotype in myasthenia gravis. Evidence for a three-gene disease model in a subgroup of patients.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction having multigene control. HLA-linked loci and the HB*14 micro-satellite marker located within the CHRNA gene which encodes the muscular acetylcholine receptor (AChR) alpha-subunit, the target self-antigen, were previously associated with MG. Combined analysis of these loci revealed a significant increase of DQA1*0101 alleles in HB*14+ vs. HB*14- patients and of DQA1*0501 alleles in HB*14/DQA1*0101 patients. Importantly, the effect of DQA1*0101 was independent of allelically associated DQB1 and DRB1 genes. In contrast, the effect of DQA1*0501 could not be dissociated from that of DRB1*03 and DQB1*0201 on the extended DR3 haplotype. These results indicate that a combination of three genes, of which two are linked to HLA, contributes to disease susceptibility in a subgroup of MG patients.

Adult↗
PubMed1997

No evidence for an association of AChR beta-subunit gene (CHRNB1) with myasthenia gravis.

Using a polymorphic dinucleotide repeat, we have investigated the contribution of the gene encoding the beta-subunit of the muscle acetylcholine receptor (CHRNB1), the target autoantigen, to the susceptibility to myasthenia gravis (MG). We have combined a case-control study (comparing 143 patients and 162 controls) and a transmission-disequilibrium test bearing on 35 simplex families with heterozygous parents. There was no evidence for an association of CHRNB1 with MG, even after subgrouping patients according to thymus histology, or other clinical criteria. Interestingly however, the shortest four variants of the CHRNB1 microsatellite were seen only in patients with thymus hyperplasia and in none of the control subjects (P < 0.0025).

Adult↗
PubMed1997

Interaction between certain major histocompatibility complex class II and T-cell receptor V beta alleles promotes the antibody production to extractable nuclear antigen-related peptides.

Our objective was to study the interaction between major histocompatibility complex (MHC) class II and T-cell receptor (TCR) alleles in the recognition of extractable nuclear antigen-derived peptides in 32 patients with systemic lupus erythematosus and 173 of their family members. MHC genes were analyzed using sequence specific oligonucleotides, and TCR beta-chain gene polymorphism using restriction fragment-length polymorphism. One dominant peptide (as defined by enzyme-linked immunosorbent assay autoantibody reactivity) was identified in each antigen studied: peptide 1-20 in Sm-D, peptide 35-58 in U1-RNP-A, and peptide 304-324 in the Ro/SSA 60 Kd protein. None of the MHC class II and TCR beta haplotypes was directly associated with any of the autoantibodies. Twenty-six subjects had antibodies to the peptide Sm-D1-20; nine of them were DRB1*0101/DQB1*0501. Among subjects with this haplotype, the number of responders was higher (p < 0.028, p corrected, pc = 0.336) in those with the 2-25-9 TCR beta haplotype than in the remainder. Conversely, the number of DRB1*04/DQB1*0302 responders was lower (p < 0.030, pc = 0.360) among subjects with the 23-20-9 TCR beta haplotype than in those without. The odds ratios (OR) were 4.23 and 0.21, respectively. Of the 54 subjects positive for anti-U1-RNP-A 35-38, 13 were DRB1*0101/DQB1*0501 and eight DRB1*04/DQB1*0302. The percentage of responders was higher (p < 0.041, pc = 0.492, OR = 3.48) in the former group of subjects with the 2-25-9 TCR beta haplotype, and lower (p < 0.02, pc = 0.024, OR = 0.09) in the latter with the 23-20-9 TCR beta haplotype. Three of the 12 anti Ro/SSA 60Kd 304-324-positive subjects were DRB1*0101/DQB1*0501. All had the 2-25-9 TCR beta haplotype (p < 0.046, pc = 0.552, OR = 6.29) and none the 23-20-9 (p < 0.031, pc = 0.372, OR = 0.10). The same combinations of genes were associated with high/low response toward the three peptides. These data provide evidence for an interplay of the MHC class II and TCR beta alleles in the control of specific autoantibody response to well-defined nuclear Ag peptides.

Adolescent↗
PubMed1997

The NOD mouse.

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Animals↗
PubMed1997

A new approach to cytochrome CYP2D6 antibody detection in autoimmune hepatitis type-2 (AIH-2) and chronic hepatitis C virus (HCV) infection: a sensitive and quantitative radioligand assay.

Antibodies specific for cytochrome CYP2D6, formally known as liver-kidney-microsome type-1 antibodies (LKM-1), are characteristically found in a subgroup of patients presenting autoimmune hepatitis. They are also found in some patients with chronic HCV infection. These autoantibodies are usually detected by indirect immunofluorescence, immunoblotting and ELISA tests. In an attempt to set up a more sensitive detection assay we developed a quantitative immunoprecipitation radioligand assay using a 35S-methionine-labelled CYP2D6 antigen obtained by in vitro transcription and translation synthesis. All 16 sera from AIH-2 patients strongly bound to this CYP2D6 antigen. Two of the nine sera (22%) from AIH-2 patients that presented only liver cytosol-1 antibodies also bound to CYP2D6. All 24 sera from HCV patients that were positive for LKM-1 antibodies by indirect immunofluorescence were also positive using this CYP2D6 radioligand assay. Lastly, all 15 sera from HCV patients negative for LKM-1 antibodies were negative by this test. The present results support the view that this quantitative radioligand assay is more sensitive than immunoblotting and ELISA CYP2D6 assays, and that it could be used in combination with indirect immunofluorescence assay.

Adolescent↗
PubMed1997

Recurrent mutations in a single exon encoding the evolutionarily conserved olfactomedin-homology domain of TIGR in familial open-angle glaucoma.

Primary open-angle glaucoma (POAG) is a highly prevalent cause of irreversible blindness which associates cupping of the optic disc and alteration of the visual field, elevation of intraocular pressure being a major risk factor. Provided diagnosis is made at an early stage, treatments are available to prevent visual impairment. A locus, GLC1A, has been mapped on chromosome 1q23-q25 in several families affected with juvenile-onset POAG (JOAG) and also in some families affected with juvenile and middle-age onset POAG. Recently, three mutations of the TIGR (Trabecular meshwork-Induced Glucocorticoid Response) gene were shown to be responsible for the disease in several American families and in unrelated POAG patients. We now describe five new mutations in eight French families. All mutations known to date appear to concentrate in the evolutionarily conserved C-terminal domain of TIGR which bears homology to frog olfactomedin, an extracellular matrix glycoprotein of the olfactory epithelium, to rat and human neuronal olfactomedin-related proteins and to F11C3.2, a protein from Caenorhabditis elegans . Moreover, this conserved domain of TIGR is encoded by a single exon to which mutation screening could be limited. Surprisingly, the TIGR message, which is abundantly transcribed in the trabecular meshwork and also in the ciliary body and the sclera, is not expressed in the optic nerve whose degeneration is, however, the primary lesion of POAG.

Adolescent↗
PubMed1997

Insulin-dependent diabetes mellitus (IDDM) is associated with CTLA4 polymorphisms in multiple ethnic groups.

Linkage disequilibrium (association) analysis was used to evaluate a candidate region near the CTLA4/CD28 genes using a multi-ethnic collection of families with one or more children affected by IDDM. In the data set unique to this study (Spanish, French, Mexican-American, Chinese and Korean), the transmission/disequilibrium test (TDT) revealed a highly significant deviation for transmission of alleles at the (AT)n microsatellite marker in the 3' untranslated region (P = 0.002) and the A/G polymorphism in the first exon (P = 0.00002) of the CTLA4 gene. The overall evidence for transmission deviation of the CTLA4 A/G alleles is also highly significant (P = 0.00005) in the combined data set (669 multiplex and 357 simplex families) from this study and a previous report on families from USA, Italy, UK, Spain and Sardinia. Significant heterogeneity was observed in these data sets. The British, Sardinian and Chinese data sets did not show any deviation for the A/G polymorphism, while the Caucasian-American data set showed a weak transmission deviation. Strong deviation for transmission was seen in the three Mediterranean-European populations (Italian, Spanish and French) (P = 10(-5)), the Mexican-American population (P = 0.002) and the Korean population (P = 0.03). These results suggest that a true IDDM susceptibility locus (designated IDDM12) is located near CTLA4.

Abatacept↗