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Biomedical subjects

J Clot

Publications and source records attributed to J Clot.

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

Distribution of HLA-DRB1 alleles of patients with polymyalgia rheumatica and giant cell arteritis in a Mediterranean population.

OBJECTIVE: To evaluate HLA-DRB1 associations in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) compared to rheumatoid arthritis (RA). METHODS: One hundred twenty-one patients were included and oligotyped: 79 with PMR alone and 42 with GCA (14 also had PMR). We also genotyped 1609 healthy controls and 433 patients with RA. Statistical analysis included Fisher's exact test and calculation of the odds ratio (95% CI). RESULTS: Compared to controls, the DRB1*04 phenotype was increased in PMR (39.2%; OR = 2.4, p = 0.0005) and GCA (45.2%; OR = 3.1, p = 0.0005). This association was weaker than in RA (p = 0.01). DRB1*07 was more frequent in GCA (31.0%) than in PMR (13.4%; p = 0.03), but the difference was not significant in comparison to controls. The distribution of DRB1*04 subtypes was similar in PMR and GCA, but different from RA and controls. However, the frequency of 0402 and 0403 subtypes could not be distinguished from that in patients with RA. Double occurrence of RA associated alleles was less frequent in PMR and GCA (9.9%; p = 0.005) than in patients with RA (20.8%). There was no significant relationship between markers of disease activity/severity and HLA-DRB1 genes in PMR or GCA. CONCLUSION: PMR and GCA were associated with HLA-DRB1*04, but more weakly than RA. Nevertheless, these data suggest that HLA-DRB1* genes are closely related to susceptibility in PMR, GCA, and RA and do not support the hypothesis of a different linkage to the 3rd hypervariable region of DRB1 alleles. By contrast with RA, HLA-DRB1* genes do not appear to be indicators of disease severity in PMR and GCA.

Aged↗
PubMed1997

Synergistic effect of two HLA heterodimers in the susceptibility to celiac disease in Tunisia.

The DR and DQ HLA genotypes of 94 Tunisian children affected with celiac disease are analyzed so that we can gain a better understanding of the HLA component of this disease. All of them carry at least one of two specific heterodimers: a DQ heterodimer, encoded by DQA1*0501, DQB1*0201 and/or a DR heterodimer, encoded by the nonpolymorphic gene DRA and the DRB4 gene. Quantifying the relative penetrances of all susceptible genotypes gives evidence for a synergistic effect of these two heterodimers and for a dose effect of the alleles encoding the beta chains of these two heterodimers. The DR3DR7 individuals have the greatest risk. They present the two kinds of heterodimers and carry two DQB1*0201 alleles. Celiac disease is the first HLA-associated disease for which the at-risk genotypes are so well delineated.

Adolescent↗
PubMed1997

Polymorphism of the HLA-DMA and DMB genes in rheumatoid arthritis.

OBJECTIVE: To determine whether the HLA-DMA and DMB genes, whose encoded molecules are involved in HLA class II-restricted antigen presentation, contribute to the genetic susceptibility to rheumatoid arthritis (RA). METHODS: One hundred ninety-one RA patients, 147 control subjects, and 218 HLA-DRB1 genotype-matched control subjects were oligotyped for DMA and DMB genes. RESULTS: DMA*0103 and DMB*0104 were significantly increased in the RA patients compared with the randomly selected and the matched controls, thus indicating a direct influence of the DM genes. After stratification of the patients and matched controls according to DRB1 genotypes, only DMA*0103 was increased in the RA patients with DRB1*01, as well as in the patients negative for the RA-susceptibility DR alleles. CONCLUSION: Our results suggest that DMA*0103 could play an additional role in the genetic susceptibility to RA.

Alleles↗
PubMed1997

Autoantibodies predicting the outcome of rheumatoid arthritis: evaluation in two subsets of patients according to severity of radiographic damage.

OBJECTIVE: Autoantibodies such as rheumatoid factor (RF), antikeratin antibodies (AKA), antiperinuclear factor (APF), and anti-RA 33 antibodies are considered of value for the diagnosis of RA. The purpose of this study was to evaluate these autoantibodies as predictors of severe radiographic damage in rheumatoid arthritis (RA). PATIENTS AND METHODS: Eighty six patients with RA (70 women, 16 men) fulfilling 1987 ACR criteria were selected from a cohort of 469 patients followed up since the first year of RA onset because they could be divided in two groups according to the severity of the radiographic damage. These 86 patients had a mean (SD) disease duration of eight (four) years: 43 patients had severe radiographic damage (Larsen score > or = 2) and 43 had limited radiographic damage (Larsen score < 2). The two groups were matched by disease duration and sex. The following autoantibodies were looked for: RF, ANA, AKA, APF, and anti-RA 33 antibodies. In addition, HLA class II DR beta alleles and standard inflammatory parameters (erythrocyte sedimentation rate, C reactive protein) were determined. RESULTS: Patients with severe radiographic damage differed from those with limited radiographic damage in that they had higher RF (p = 0.01), APF (p < 0.02), and AKA (p = 0.001) titres. Stepwise regression analysis was done to calculate the odds ratios (OR) for each clinical and laboratory variable; only presence of cutaneous nodules (OR: 14.9; 95% CI: 7, 128), HLA DRB1*04 or DRB1*01 (OR: 7.53; 95% CI: 1.32, 42.9), AKA (OR: 3.11; 95%, CI: 0.58, 16.8), a high erythrocyte sedimentation rate (OR: 2.66; 95% CI: 0.60, 11.9), and a high C reactive protein value (OR: 7.4; 95% CI: 1.43, 38.1) were predictive of severe radiographic damage. CONCLUSION: These data suggest that the risk of severe radiographic damage in RA patients is higher when cutaneous nodules, HLA DRB1*04 or DRB1*01, and/or AKA are present. The other autoantibodies of diagnostic significance are of little help for predicting joint destruction.

Adolescent↗
PubMed1997

Pharmacology of ribosomal immunotherapy.

The use of immunostimulating drugs is one way to intervene in the immune system. Many of these agents are of bacterial origin and most are able to stimulate the nonspecific immune response by acting on polymorphonuclear cells (PMNs) and macrophages. Ribosomal immunotherapy ('Ribomunyl') contains both proteoglycans from Klebsiella pneumoniae and ribosomes from 4 different bacterial strains. It can stimulate not only macrophages but also specific antibody production. 'Ribomunyl' has been shown to stimulate many of the functions of PMNs, specifically the formation of oxygenated free radicals, chemotaxis and adhesion. The effect of 'Ribomunyl' immunostimulant on the properties of macrophages is of special interest, as these cells participate in both the nonspecific immune response (phagocytosis, proinflammatory cytokine production) and the specific immune response (antigen processing and presentation, lymphocyte proliferation). 'Ribomunyl' has been shown to increase the production of many cytokines [interleukin (IL)-1, IL-6, IL-8, tumour necrosis factor-alpha and colony-stimulating factor], leading to the activation of the cytokine network. 'Ribomunyl' was also able to stimulate natural killer cells involved in viral immunity. Because of the presence of ribosomes from 4 frequently encountered bacterial strains, 'Ribomunyl' has specific immunostimulant properties. This has been clearly demonstrated in animals and humans, where specific antibody-forming B cells were found in the tonsils after oral administration. However, specific T-cell response has not been reported, suggesting that 'Ribomunyl' could act directly on B cells such as T-cell-independent bacterial antigens.

Adjuvants, Immunologic↗
PubMed1997

Qualitative and quantitative analysis of HLA-DRB gene expression.

Determination of the molecular mechanisms influencing HLA-DRB gene expression would allow better understanding of the regulation of the immune response in normal as well as in pathological conditions. We started an extensive sequencing analysis of the proximal promoter regions of the DRB genes and observed a nucleotide polymorphism involving the classical regulatory regions of the DRB promoters. These nucleotide substitutions were observed to induce variations of the promoter activities as assessed by chloramphenicol acetyl transferase assays and the quantification of DRB transcripts. Similar analysis performed in patients with rheumatoid arthritis strongly suggests dysregulation of HLA-DRB gene expression.

Alleles↗
PubMed1996

Quantitative analysis of the expression of the HLA-DRB genes at the transcriptional level by competitive polymerase chain reaction.

In addition to polymorphism of the peptide-binding site, the density of the MHC class II molecules expressed on the membrane of APC could well play a significant role in the MHC-peptide-TCR interaction during the immune response. We therefore investigated the regulation of the expression of the HLA-DRB genes at the transcriptional level. A competitive PCR approach was used to estimate the quantities of the HLA-DRB transcripts in peripheral blood B cells. When comparing the amounts of steady-state mRNAs among the different DRB1 alleles, the DRB1 transcripts in the DR52 haplotype group were found to be 2.5 to 3.5 times more abundant than the DRB1*01 transcripts, 1.5 to 2 times more abundant than the DRB1*04 transcripts, and 7 times more abundant than the DRB1*08 transcripts. Within the DR52 haplotype group, the DRB1 and DRB3 transcripts had the same abundance. Taken together, these results are in good agreement with the previously reported transcriptional activities of the DRB promoters except for DRB1*04, thus suggesting a differential post-transcriptional regulation among the DRB1 mRNAs.

Alleles↗
PubMed1996

Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3.

Glutamic acid is the major excitatory amino acid of the central nervous system which interacts with two receptor families, the ionotropic and metabotropic glutamate receptors. The metabotropic glutamate receptors (mGluRs) are coupled to G proteins and can be divided into three subgroups based on their sequence homology, signal transduction pathway and pharmacology. In this study, we describe the cloning of the cDNA encoding the human metabotropic glutamate receptor type 3 (HmGluR3). It was obtained by reverse transcription-polymerase chain reaction (RT-PCR) with degenerate oligonucleotides corresponding to highly conserved sequences between rat mGluRs. The receptor shows 879 amino acids with 96% amino acid sequence identity with rat mGluR3. It is strongly expressed in fetal and adult whole brain, especially in caudate nucleus and corpus callosum. The gene was identified by fluorescence in situ hybridization on chromosome 7 band q22. Activation of the human mGluR3, permanently expressed in Baby Hamster Kidney (BHK) cells, by excitatory amino acid inhibits the forskolin-stimulated accumulation of intracellular cAMP. The rank order of potency is L-glutamic acid > or = (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R)-ACPD) >> ibotenic acid > quisqualic acid. (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG, 1 mM] is without effect on inhibition of forskolin-induced cAMP accumulation by L-glutamic acid.

Amino Acid Sequence↗
PubMed1995

Immunogenetic study of couples with recurrent spontaneous abortions.

OBJECTIVES: Clinical observations suggest that genetic and immunologic disparity could be a factor in fecundity. The HLA system (HLA) is polymorphic and TLX (Trophoblast Lymphocyte Cross-Reactive), which is also polymorphic, seems to be linked to it. The immunologic hypothesis follows that excessive HLA and TLX-sharing could explain the rejection of a semi-allogenic blastocyst. Study objectives are therefore twofold; To determine whether or not there is significant HLA-sharing between spouses with unexplained recurrent spontaneous abortions (RSA) and to determine whether or not there is an association between some HLA specificities and RSA. STUDY DESIGN: The study includes only Caucasian couples that have had three successive spontaneous abortions. These were distributed in two groups: Group E: 18 couples either with known aetiology or with secondary RSA; Group U: seven couples with unexplained primary RSA; Control group C: 21 couples with at least two children and no spontaneous abortions. Tissue typing for HLA-A and B molecules was performed using serotyping methodology based on lymphocytotoxicity reaction. The different DRB1 alleles (class II) were determined by oligotyping with a non-radioactive reverse dot-blot methodology. RESULTS: Statistical comparison shows that the number of couples without shared specificity is not significantly different between the three groups for each locus independently and for the set of three. Our results show also that the allelic frequencies are not significantly different between the three groups. CONCLUSIONS: There is no higher HLA-sharing in couples with RSA than in fertile couples. Similarly, no particular HLA specificity can be associated with the RSA.

Abortion, Habitual↗
PubMed1995

Prognostic factors in rheumatoid arthritis. Comparative study of two subsets of patients according to severity of articular damage.

Clinical and biological profiles at the onset of the disease, obtained retrospectively, and human leucocyte antigen typing were studied in 47 rheumatoid arthritis (RA) patients with severe articular damage (group 1) and in 47 patients with limited radiological abnormalities (group 2). The two groups were matched according to disease duration (mean: 8.1 yr). Systemic manifestations were more frequent in group 1. Erythrocyte sedimentation rate (ESR), platelet counts, C-reactive protein (CRP), rheumatoid factor and IgG titres were higher and haemoglobin level lower in group 1. HLA class II genotyping demonstrated that 95.7% of patients in group 1 were Dw4, Dw14 or DR1 as compared to 55.3% in group 2 and 37.1% in normal controls. Two RA-linked DRB1 genes were detected in 34.1% of patients in group 1, vs 8.5% in group 2 and 7.9% in controls. Multiple logistic regression analysis demonstrated that ESR, CRP and genetic markers were the most relevant independent variables and when combined could indicate the outcome in early RA. These data confirmed that different RA subtypes with different prognoses could be associated with particular clinical, biological and genetic profiles. Moreover, some of these factors could serve as predictive markers for outcome at the onset of RA.

Adult↗
PubMed1995

Molecular determinants of the species selectivity of neurokinin type 1 receptor antagonists.

Most nonpeptide neurokinin (NK)1 antagonists display a marked difference in affinity for rat versus human NK1 receptors. The molecular basis for the species selectivity of RP67580 and CP96,345 has been previously addressed [J. Biol. Chem. 267:25668-25671 (1992); J. Biol. Chem. 268:2319-2323 (1993)]. We are extending these previous results to additional NK1 antagonists, which are members of different chemical families. Included is a new perhydroisoindolol, RPR100893, which unlike its parent compound (RP67580) is human receptor selective. Chimeric rat/human NK1 receptors, as well as rat and human mutant NK1 receptors, were constructed and expressed in COS-1 cells, and affinities for substance P and the various antagonists were determined in binding studies. With human receptor-selective antagonists, the rat R290(S-->I) mutation was the most effective in increasing antagonist affinity (from 7- to 23-fold). Combination with the R116(L-->V) mutation led to an additional increase in affinity for trans-4-hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N- methyl-N-(phenylmethyl)-L-tyrosineamide (a derivative of FK888) and to nearly full human receptor affinity for RPR100893 and (+/-)-CP99,994. Based on the gains in affinities, these results confirm and extend the role of residues 116 and 290 of the NK1 receptor in the species selectivity of these three new human receptor-selective NK1 antagonists. In comparison, the affinity of RP67580, the least selective molecule, was most affected by changes at position 116, and combination with mutations at either position 97 (V-->E) or position 290 led to the human receptor phenotype. For the heterosteroid KAN610857, modifications of the rat receptor at positions 97 and 290, and to a lesser degree position 116, were the most effective in reducing affinity. Two double-mutants [R(97,290) and R(116,290)], although different from those identified for RP67580, also displayed human receptor-like affinity. Therefore, the molecular determinants of the species selectivity appear to be different, in part, between rat and human receptor-selective compounds, even between closely related chemical families.

Androstanes↗
PubMed1994

Differential transcriptional activities of HLA-DR genes in the various haplotypes.

The regulation of HLA class II genes is of particular interest with regard to the modulation of the immune response. The polymorphism of their coding regions is directly involved in the specificity of the Ag presentation, and their level of expression affects the extent of T cell activation. Previously, we have described an allelic polymorphism in the proximal promoter regions of HLA-DRB genes. The aim of this study was to compare the transcriptional activities of the promoters of the DRB genes and DRB1 alleles in a transient expression system. We have demonstrated a marked difference in their promoter strengths, as determined by their relative abilities to initiate transcription of the chloramphenicol acetyltransferase reporter gene in human B cell lines. The polymorphism of the promoter regions has been mapped to the regulatory boxes, and, by using gel retardation experiments, we found a differential ability of the nuclear proteins to bind to the partially conserved X box regions. Taken together, our results demonstrate the functional consequences of the allelic polymorphism of the proximal promoter regions of the DRB genes. These findings strongly suggest the existence, for the HLA-DR genes, of an interdependence between the polymorphism of the coding regions, which directly affects the capacity of peptide binding, and the polymorphism of the regulatory regions, which influences the transcriptional activities of the promoters.

Base Sequence↗
PubMed1994

Biclonal Sézary syndrome with capillary leak syndrome.

Sézary syndrome is a rare, usually monoclonal proliferation of T lymphoid cells. We report a case of this form of cutaneous T cell lymphoma with highly probable biclonality of neoplastic proliferation. Biclonality in malignant lymphoma is a rare feature, until now generally reported in B cell lymphoma. Its identification by accurate immunological studies could be of importance since one of the two populations can exhibit a less differentiated phenotype requiring a more aggressive therapeutic regimen than usual. The occurrence of anasarca in our patient was probably due to capillary leak syndrome, already discussed in another case of peripheral T cell lymphoma.

Aged↗
PubMed1994

Differential expression of HLA-DRB genes according to the polymorphism of their regulatory region.

The polymorphism of the HLA-class II molecules is directly involved in the specificity of the antigen presentation. We have previously described an allelic polymorphism in the proximal promoter region of the HLA-DRB genes. In this study, we demonstrate that this polymorphism has functional consequences on the transcriptional activity of the promoter of the different DRB genes. Indeed, transiently transfected DRB gene promoters into human B cell lines showed a marked difference in their ability to induce transcription of the chloramphenicol acetyl transferase (CAT) reporter gene. These findings suggest the presence of two interdependent effects of the HLA-class II molecules on the specificity of the immune response: one corresponding to the allelic polymorphism of the peptide-binding site and the second resulting from the polymorphism of the promoter regions inducing a variable expression of the DRB genes.

DNA↗