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C Boitard

Publications and source records attributed to C Boitard.

At least 37 records · Page 2Linked to original sources
PubMed1998

Identification of mimicry peptides based on sequential motifs of epitopes derived from 65-kDa glutamic acid decarboxylase.

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease with a predominantly non-hereditary etiology that results in a destruction of pancreatic beta cells by autoaggressive T lymphocytes. Neither the mechanism of initial stimulation of these T cells nor the nature of the environmental factors implicated in the disease have so far been identified. However, both issues are taken into account by the hypothesis of initial T cell activation by viral or bacterial mimicry peptides with sequence similarities to pancreatic self antigens. We determined sequential epitope motifs to search for mimicry peptides stimulating T cell lines specific for two epitopes derived from the IDDM autoantigen 65-kDa glutamic acid decarboxylase (GAD65). These were GAD65 (88-99), presented by HLA-DRB1*0101, and GAD65 (248-257), presented by HLA-DRB5*0101. T cell stimulation by peptides with substitutions in HLA anchor or T cell contact positions was analyzed to establish degenerate epitope motifs for database searching. Out of 28 tested candidate mimicry peptides derived from bacterial, viral and human proteins, 3 stimulated T cell lines and a T cell clone specific for epitope GAD65 (248-257). Our results demonstrate that mono- and polyclonal GAD65-specific T cells from IDDM patients can be stimulated by viral and bacterial peptides with little apparent sequence homology with autoantigenic epitopes. Moreover, in a synopsis with related published studies, our findings suggest that simple degenerate search motifs comprising principal T cell contacts plus HLA class II binding motifs may suffice to identify most mimicry peptides.

Adult↗
PubMed1998

Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial.

The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10-15% lower at 9 months (p = 0.003) and 12 months (p < 0.05) in the linomide group. The insulin dose was 32-40% smaller in the linomide group at 3 (p < 0.03), 6 (p < 0.02), 9 (p < 0.001) and 12 months (p = 0.01). Insulin doses correlated negatively with C peptide values (p = 0.001-0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45-59% higher C peptide value at 6 months (p < 0.05), 9 months (p < 0.05) and 12 months (p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10% in the linomide and placebo groups), thrombocytopenia (24 vs 10%), and mild joint discomfort (45 vs 5%) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established.

Adjuvants, Immunologic↗
PubMed1998

Peptide specificity of high-titer anti-glutamic acid decarboxylase (GAD)65 autoantibodies.

To study systematically the linear epitope specificity of anti-glutamic acid decarboxylase (GAD) autoantibodies associated with insulin-dependent diabetes mellitus (IDDM), we produced 93 overlapping 12-residue synthetic peptides derived from the sequence of the human GAD65 protein and covering the entire length of the protein. These peptides were used as antigens in an enzyme immunoassay to screen the sera from 10 IDDM patients, all of which contained at high level autoantibodies directed against GAD65. Three out of ten (30%) IDDM patients had antibodies that reacted with one or more of the synthetic peptides. Two of the peptide-reactive IDDM sera, which also bound denatured recombinant GAD65 on western blots, had the highest titers of anti-GAD antibodies in ELISA assay. Moreover, the anti-GAD antibodies-GAD complexes formed with these sera were characterized by low dissociation rates, indicative of their good stability. A fine specificity analysis, using analogs of antigen peptide 1 (residues 1-12), allowed us to identify the residues at positions 5-9 (GSGFW) as critical for antibody recognition.

Antibody Specificity↗
PubMed1998

Major histocompatibility class II genes polymorphism in insulin dependent diabetes mellitus with or without associated thyroid autoimmunity.

Insulin dependent diabetes mellitus (IDDM) is sometimes associated with extrapancreatic organ-specific autoimmune diseases, but whether this phenotype results from a peculiar genetic profile is still unclear. The allelic distribution of the major histocompatibility complex (MHC) class II genes (HLA-DRB1, DQA1, DQB1 and TAP) was analysed in 143 patients with IDDM alone by comparison with 82 IDDM patients with autoimmune thyroid disease (IDDM/AITD). The frequency of the DQB1*0301 IDDM-protective phenotype seemed to be lower in IDDM than in IDDM/AITD patients (16.8% vs 30.5% respectively, p = 0.02). By contrast, the frequency of the DRB1*04-DQB1*0302 IDDM-predisposing phenotype was higher in IDDM than in IDDM/AITD patients (91.3% vs 76.1% of DR4-positive patients respectively, p = 0.007), but these differences were not significant after correcting the p values, except in the case of the DRB1*0405-DQB1*0302 combination (21.3% vs 2.4% of DR4-positive patients, Pc = 0.05). Furthermore, all differences disappeared when patients were matched for age at IDDM-onset. Our data do not long give support for a particular role of MHC class II genes in favouring the occurrence of thyroid autoimmunity in IDDM patients, but rather suggest that some class II alleles or residues might determine the rapidity of progression to IDDM in genetically susceptible individuals. The involvement of non-MHC genes and/or environmental factors remains to be determined.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

HLA class II-associated predisposition to insulin-dependent diabetes mellitus in a Polish population.

Susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM) are strongly associated with alleles of HLA class II DR and DQ genes. We have studied HLA DRB1, DQA1, DQB1 allele and haplotype distribution in 152 IDDM children and 103 unrelated healthy individuals from the region of Lodz in central Poland by the polymerase chain reaction and hybridisation with allele-specific oligonucleotide probes. The DRB1*04 allele showed the strongest association with IDDM in the Polish population (OR = 3.87). The DRB1*03 allele was also associated with predisposition to the disease (OR = 3.25), particularly in DR3/4 heterozygous individuals (OR = 14.47). Among DR4 subtypes, DRB1*0401 was the most frequent both in patients and controls, whereas DRB1*0403 was rarely observed in patients and conferred a significant protection from IDDM. The DRB1*04-DQA1*0301-DQB1*0302 haplotype conferred the highest risk to develop IDDM. The presence of DRB1*0401 on this haplotype reinforced the disease risk whereas DRB1*0403 had a dominant protective effect even in the presence of the predisposing DQB1*0302 allele (OR = 0.24). The DRB1*1501-DQA1*0102-DQB1*0602 haplotype conferred a dominant protective effect (OR = 0.04). The different behaviour of the DRB1*04-DQB1*0302 haplotypes in conferring IDDM risk confirms that DRB1 by itself is strongly associated with IDDM independently from DQB1, with DRB1*0401 being a high frequency/moderate risk allele, and DRB1*0403 a high frequency/low risk allele in the Polish population.

Adolescent↗
PubMed1998

HLA class II allele and haplotype distribution in a population from central Poland.

We have studied the distribution of HLA DRB1, DQA1, DQB1 alleles and haplotypes in a sample of 103 unrelated healthy individuals from the region of Lodz in central Poland by the polymerase chain reaction and hybridization with allele-specific oligonucleotide probes (PCR-SSO). DRB1*0101, DRB1*07, DRB1*1501, DRB1*03 and DRB1*11 were the most frequent alleles at the DRB1 locus. The DRB1*04 group was observed at a high frequency, but only five out of the 19 DR4 subtypes tested were observed. The most frequent was DRB1*0401, followed by DRB1*0403, DRB1*0402, DRB1*0407 and DRB1*0417. Eight DQA1 alleles were found in this Polish population, among which DQA1*0501, DQA1*0101 and DQA1*0102 were the most frequent. At the DQB1 locus 13 alleles were found. Among them, four were present with frequencies above 10%: DQB1*0201, DQB1*0301, DQB1*0501 and DQB1*0602. Our results underline significant differences between the population of central Poland and populations of neighbouring countries such as Germany, Ukraine and the Czech Republic. This study will serve as a reference for further anthropological studies, as well as studies of associations between HLA and disease.

Alleles↗
PubMed1998

Evidence for the presence of insulin-dependent diabetes-associated alleles on the distal part of mouse chromosome 6.

Type 1 diabetes (IDDM) is a complex disorder with multifactorial and polygenic etiology. A genome-wide screen performed in a BC1 cohort of a cross between the nonobese diabetic (NOD) mouse with the diabetes-resistant feral strain PWK detected a major locus contributing to diabetes development on the distal part of chromosome 6. Unlike the majority of other Idd loci identified in intraspecific crosses, susceptibility is associated with the presence of the PWK allele. Genetic linkage analysis of congenic lines segregating PWK chromosome 6 segments in a NOD background confirmed the presence of the Idd locus within this region. The genetic interval defined by analysis of congenic animals showed a peak of significant linkage (P = 0.0005) centered on an approximately 9-cM region lying between D6Mit11 and D6Mit25 genetic markers within distal mouse chromosome 6. [Genetic markers polymorphic between the NOD and PWK strains are available as a supplement at http://www.genome.org]

Alleles↗
PubMed1998

Eating disorders and insulin-dependent diabetes mellitus (IDDM): relationships with glycaemic control and somatic complications.

This study was designed to assess (by means of a diagnostic interview based on DSM-III-R criteria) the prevalence of eating disorders in 69 insulin-dependent diabetic (IDDM) out-patients, and the relationship with somatic risks. We found no cases of anorexia nervosa or bulimia nervosa, current or lifetime, in male patients with IDDM. No female patients with IDDM had anorexia, and 4.8% had current and lifetime bulimia. Eating disorders not otherwise specified (bulimic type) were significantly more frequent in women than in men (lifetime incidence 43% vs. 21%; current incidence 33% vs. 5%), and generally occurred after the onset of IDDM. Self-reports of bulimic behaviours according to the Bulimic Investigatory Test of Edinburgh (BITE) were associated with high levels of glycosylated haemoglobin. There was no association between eating disorders (current or lifetime), with somatic complications being more likely to be explained by a long duration of illness and impaired glycaemic control.

Adult↗
PubMed1997

High affinity presentation of an autoantigenic peptide in type I diabetes by an HLA class II protein encoded in a haplotype protecting from disease.

Polymorphism of the genes coding for the human histocompatibility leukocyte antigen class II DR and DQ molecules makes the single largest genetic contribution to the risk of developing insulin-dependent diabetes mellitus (IDDM) and can be associated with highly elevated as well as decreased disease frequency. The mechanism of IDDM risk modification by HLA polymorphism is likely to involve differential presentation of autoantigenic peptides by HLA class II proteins. We have generated T cell lines (TCL) with specificity for the IDDM autoantigen 65 kDa glutamic acid decarboxylase (GAD65) from lymphocytes of two patients carrying HLA class II alleles associated with distinct risk of IDDM (DRB1*0101/0401 and 1302/1501). For both patients, TCL generated at various time points all recognized single epitopes mapped as GAD 88-99 and 248-257, respectively. These epitopes are presented by the DRB1*0101 and DRB5*0101, HLA class II molecules associated with a moderately elevated risk of IDDM, or carried in a strongly protective haplotype, respectively. In an HLA/peptide binding assay, epitope GAD 248-257 was shown to possess high affinity for DRB5*0101. This epitope overlaps with a central GAD peptide binding to the high risk allele DQB1*0302 and containing a Coxsackie P2C-identical mimicry sequence, raising the possibility of competition of DRB5*0101 and DQB1*0302 for binding of a central GAD65 fragment.

Adult↗