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J I Bell

Publications and source records attributed to J I Bell.

At least 109 records · Page 6Linked to original sources
PubMed1992

Does the locus on chromosome 11 implicated in susceptibility to HLA-DR4 dependent type I diabetes mellitus also affect susceptibility to rheumatoid arthritis?

There is a polygenic component to rheumatoid arthritis (RA) in addition to the known association with HLA-DR4. It has previously been shown in another autoimmune disease (type I diabetes mellitus) that a gene on chromosome 11p can act with HLA-DR4 to enhance susceptibility (relative risk 5-6). It is therefore possible that this locus may also affect the development of RA. Genotype frequencies at this locus, defined by a dimorphic Fok 1 restriction site, were compared in 139 healthy controls and 213 patients with classical/definite RA. In contrast with diabetes there was no increase in genotypes lacking the Fok 1 site, either in the rheumatoid group overall (125/211 compared with 86/139 controls) or in the DR4 positive rheumatoid group (76/140 compared with controls). These results indicate that the interaction between DR4 and a locus on chromosome 11p is not common to all DR4 associated autoimmune diseases.

Amino Acid Sequence↗
PubMed1992

The human T cell receptor in health and disease.

The T cell antigen receptor (TCR) recognizes antigen in the form of short peptides bound to a major histocompatibility (MHC) molecule. This review provides a synopsis of the current state of knowledge of the structure and function of the receptor and its possible role in human disease. Analysis of the T cell receptor usage of T-cell lines and clones recognizing the same peptide-MHC complex is beginning to shed light onto the structural basis of the TCR-peptide-MHC complex. Also, it is now apparent that there are two mechanisms by which the TCR can interact with the MHC molecule, either through classical peptide interactions or through super-antigens. Finally, we review the role of specific TCRs in human disease. Current evidence in this area is difficult to interpret; however, it is likely that TCR-mediated disease susceptibility exists, and its basis at either a germline or somatic level will soon be clarified.

Autoimmune Diseases↗
PubMed1992

Molecular aspects of autoimmunity: a review.

Molecular genetic techniques are being widely applied to the study of autoimmune diseases. Major advances have been made in diabetes, rheumatoid arthritis and coeliac disease. Work on experimental models of autoimmune uveitis suggests that similar advances will follow in this field. The application of molecular genetics to the study of immunology has lead to great advances in our understanding of the anatomy of antigen recognition. This work has lead to the identification of some of the structural determinants of antigen binding by MHC molecules and is helping to explain some MHC-disease associations. More recently, molecular studies of the T cell receptor have characterized patterns of T cell receptor expression in humans and have lead to the identification of regions of the T cell receptor critical for antigen recognition. These techniques will hopefully provide insights into the nature of autoimmunity and permit the identification of targets for disease specific immunotherapies. This review describes attempts to corelate MHC structure and function in the context of autoimmunity and discusses some of the strategies for analyzing T cell receptor usage in autoimmune disease.

Animals↗
PubMed1992

HLA heterozygosity contributes to susceptibility to rheumatoid arthritis.

We have investigated the role of HLA-DR genotypes in 184 patients with severe rheumatoid arthritis (RA) and in 46 patients with Felty syndrome, to establish the relative contribution of the RA-associated subtypes of DR4 (Dw4, Dw14, and Dw15). There was an excess of DR4 homozygotes, particularly Dw4/Dw14 compound heterozygotes (relative risk [RR] 49). The risk associated with Dw4 depended on the other allele present--Dw4/DR1 (RR 21), Dw4/Dw4 (RR 15), and Dw4/DRX (RR 6). There was a significant risk from Dw4/Dw14 compared with Dw4/Dw4, both in those with severe RA (RR 2.9; P less than .02) and in those with Felty syndrome (RR 4.2; P less than .02). In contrast, in a further 63 known DR4 homozygotes with RA, not selected for severe disease, the excess of Dw4/Dw14 was much less striking (RR 1.4; not significant), suggesting that this genotype may be particularly associated with more severe disease. We also found four cases with the rare Dw4/Dw15 genotype (expected less than or equal to 0.5; P less than or equal to .02). Since the Dw4, Dw14, Dw15, and DR1 molecules have similar antigen-binding sites and since combinations of these alleles particularly predispose to severe RA, we suggest that synergistic mechanisms are involved. These could include an effect on T-cell repertoire selection.

Alleles↗
PubMed1991

Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide.

The major histocompatibility complex class I molecule HLA-A2.1 presents the influenza A virus matrix peptide 57-68 to cytotoxic T lymphocytes in all individuals with this common HLA type and is among the most thoroughly studied immune responses in humans. We have studied the T-cell receptor (TCR) heterogeneity of T cells specific for HLA-A2 and influenza A matrix peptide using the polymerase chain reaction. The usage of V alpha and V beta sequences seen on these T cells is remarkably conserved as are certain junctional sequences associated with alpha and beta chains. Furthermore, two unrelated HLA-A2 individuals have a similar pattern of TCR usage, implying that this is a predominant response in HLA-A2 populations. Analysis in one individual showed that the conserved TCR V alpha and V beta genes are minor members of the peripheral blood TCR repertoire. The sequences provide important information on the TCR necessary for the final structural analysis of this ternary complex.

Amino Acid Sequence↗
PubMed1991

Critical role for the Val/Gly86 HLA-DR beta dimorphism in autoantigen presentation to human T cells.

Helper T lymphocytes recognize fragments of foreign (or self) antigens in the peptide-binding clefts of major histocompatibility complex class II molecules; their activation is a crucial step in the induction of many immune and autoimmune responses. While studying the latter, we raised a T-cell line from the thymus of a myasthenia gravis patient against recombinant alpha subunit of the human acetylcholine receptor, the target of this autoimmune disease. The line responds to the 144-156 region of the human sequence and not to the same region of the electric fish homolog, which differs by only three residues. These CD4+ T cells recognize this epitope only in the context of HLA-DR4 class II molecules, of which the variants with Gly86 are absolutely required. Thus the naturally occurring alternatives Dw14.2 (Gly86) and Dw14.1 (Val86)--which differ only at this one position in the entire antigen-binding region--show an all-or-nothing difference in presenting activity. This dimorphism at position 86 is widespread, occurring in subtypes of DR1, DR2, DR3, DR5, and DR6 alleles as well as DR4. Since other DR4 subtypes with substitutions at positions 70-74 also fail to present this peptide, and glycine residues can be uniquely flexible, we suggest that this replacement at position 86 acts locally or at a distance by altering the conformation of the peptide-binding cleft. Such profound functional consequences for T-cell recognition as we report here may explain this example of conserved major histocompatibility complex diversity.

Adolescent↗
PubMed1991

Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome.

Felty's syndrome (FS) is a rare complication of rheumatoid arthritis (RA) previously shown to be strongly associated with HLA-DR4 and less significantly with HLA-DQw7. To map more precisely the HLA locus responsible for susceptibility to FS, we have examined HLA-DR4 and DQ beta-chain polymorphisms in FS patients and controls using restriction fragment length polymorphism analysis and polymerase chain reaction amplification in conjunction with oligonucleotide probing. The increased frequency of DR4 in FS (93% vs. 32% controls) was due almost entirely to enrichment for the Dw4 subtype (88% vs. 20% controls) with a secondary increase of the Dw14 subtype. Dw10 and Dw13 subtypes of DR4 were absent from the patient group. Increase in DQw7 frequency among DR4 FS patients could be accounted for by linkage disequilibrium between Dw4 and DQw7 alleles. Whereas susceptibility to RA is strongly associated with a conserved HLA-DR beta epitope associated with several DRB1 alleles, it is primarily the Dw4 allele which is associated with progression to Felty's syndrome. The finding that amino acid sequence variation at the DR4B1 locus rather than DQB1 is associated with development of FS will have important implications for the development of novel immunotherapies which are major histocompatibility complex allele-dependent.

Amino Acids↗
PubMed1991

Limited heterogeneity of the HLA class II contribution to susceptibility to rheumatoid arthritis is suggested by positive associations with HLA-DR4, DR1 and DRw10.

Most patients with rheumatoid arthritis (RA) exhibit an HLA class II epitope found on most DR4 and DR1 molecules. We have investigated the possibility of other associations being present in the minority of patients lacking these antigens. One hundred and eighty patients with classical or definite RA and 100 controls were assigned HLA-DR, DQ and DP types by a DNA-based system using sequence-specific oligonucleotides to probe amplified class II alleles amplified by the polymerase chain reaction. The expected associations with DR4 (relative risk 10, P less than 0.0001) and DR1 (relative risk 2.3, P less than 0.001) were observed and only 13% of individuals lacked both of these alleles compared with 54% of age- and race-matched controls. A significant association with DRw10 (P = 0.02) was also observed in the DR4/DR1-negative RA group (3/23 patients compared with 0/54 DR4/DR1-negative controls). No novel associations with other DR, DQ, or DP alleles were evident in contrast to some previous studies. The third allelic hypervariable region of the DR beta chain of DRw10 contains a similar amino acid sequence to that found in many DR4 and DR1 molecules. These results extend this correlation and suggest that this susceptibility determinant may account for the HLA-linked susceptibility in 89% of our cases of RA.

Amino Acid Sequence↗
PubMed1991

The genetic contribution to human T-cell receptor repertoire.

Recent studies in mice have highlighted the importance of polymorphic genetic loci such as the major histocompatibility complex (MHC) or minor lymphocyte-stimulating antigen (Mls) in determining the nature of the peripheral T-cell receptor (TcR) population. As our knowledge of the equivalent process in humans is incomplete, we have utilized a modification of the polymerase chain reaction (PCR) to determine the overall genetic contribution to the normal human TcR variable V beta gene repertoire. These data demonstrate that the normal human T-cell population contains members of all the major TcR V beta families and that there is considerable variation in the relative amounts of specific TcR V beta transcripts between individuals. We have established that the normal peripheral TcR V beta repertoire is more concordant in identical twins than in unrelated individuals. The relative importance of genetic factors in determining the peripheral TcR repertoire is emphasized by these results and suggests that, in humans, the genetic control of immune responsiveness is mediated in part by the peripheral TcR repertoire.

Adult↗
PubMed1990

Oxygen-dependent modulation of erythropoietin mRNA levels in isolated rat kidneys studied by RNase protection.

Using oligonucleotide primers complementary to conserved regions in the mouse erythropoietin (Epo) gene, a portion of the rat Epo gene was amplified by the polymerase chain reaction to produce a probe suitable for assay of rat Epo mRNA by RNAse protection. The assay, which has sufficient sensitivity to measure to Epo mRNA in unstimulated rat kidneys, was used to demonstrate high amplitude in vitro modulation of Epo mRNA levels in response to changes in perfusate flow rate and oxygen tension in isolated kidneys, thus providing clear evidence that all the necessary events linking changes in oxygen delivery to the modulation of Epo mRNA levels can occur intrarenally.

Animals↗
PubMed1990

Isolation of a cDNA encoding the human CD38 (T10) molecule, a cell surface glycoprotein with an unusual discontinuous pattern of expression during lymphocyte differentiation.

A cDNA clone encoding the human lymphocyte differentiation Ag CD38 was isolated from a mixture of four different lymphocyte CDNA libraries expressed transiently in COS cells and screened by panning with mAb. Transfected COS cells expressed a surface protein of Mr 46,000 that was similar to the native CD38 molecule expressed on the B cell line Daudi and the T cell leukemia HPB-ALL and which was recognized by each of the CD38 specific mAb HIT-2, T16, T168, HB7, 5D2, ICO-18, and ICO-20. The CD38 cDNA sequence predicts an unusual 30-kDa polypeptide with a short N-terminal cytoplasmic tail, and a carboxyl-terminal extracellular domain carrying the four potential N-linked glycosylation sites. The absence of significant homology with other known surface Ag including members of the Ig superfamily ruled out the possibility that CD38 was the human homologue of the murine Qa2 molecule as has been suggested previously. PvuII digests of human genomic DNA revealed a polymorphism linked to the CD38 gene.

ADP-ribosyl Cyclase↗
PubMed1990

HLA-DR typing using DNA amplification by the polymerase chain reaction and sequential hybridization to sequence-specific oligonucleotide probes.

A series of sequence-specific oligonucleotides (SSOs) have been used to type alleles at the HLA-DRB1 locus. Genomic DNA was amplified to high copy number by the polymerase chain reaction (PCR) and hybridizations of the dot-blotted, amplified DNA to a series of 14 SSOs enabled the identification of the major specificities DR1-DRw14. Certain alleles (DR3 and DR4) could be rapidly and accurately identified by running the products of allele-specific amplification of genomic DNA on agarose gels. This approach facilitated the typing of serological specificities such as subtypes of DR3 (DRw17 and DRw18) as well as alleles previously detected by the mixed lymphocyte reaction including subtypes of DR4 (Dw4, Dw10, Dw13, Dw14, and Dw15). The HLA-DR types obtained by SSO probing conformed to rules of Mendelian inheritance when they were applied to a series of 75 families. A full DR type could be obtained from many individuals simultaneously without needing to separate or store viable lymphocytes. Thus, this technique may have considerable implications for the analysis of disease associations with HLA class II alleles, particularly in circumstances where facilities for the initial preparation and storage of the samples may be limited.

Alleles↗
PubMed1990

Chlamydial DNA is absent from the joints of patients with sexually acquired reactive arthritis.

The polymerase chain reaction was used to detect the presence of a plasmid essential for the growth of Chlamydia trachomatis. As few as 10 copies of the plasmid in the initial reaction mix were detectable using this technique. In contrast, chlamydial DNA was not detectable in the knee joints of nine patients with definite sexually acquired reactive arthritis (SARA) or nine patients with suspected SARA. Five patients with an undifferentiated seronegative lower limb oligoarthropathy, one with Crohn's disease and another with post-enteric reactive arthritis had evidence of intra-articular chlamydial antigens as judged by fluorescein-labelled monoclonal antibody staining of joint material but, again, no chlamydia plasmid DNA was detected. The nature of the immunofluorescent staining seen in some of these samples remains to be elucidated. It could be due to the presence of chlamydial outer membrane protein or lipopolysaccharide antigens in the joints, either free or in immune complexes, or it may be artefactual. Our results indicate that viable C. trachomatis is not present in the joints of the patients in this study even in the presence of chlamydial antigen detected by fluorescence antibody testing.

Arthritis, Infectious↗
PubMed1989

HLA-DR4 subtype frequencies in rheumatoid arthritis indicate that DRB1 is the major susceptibility locus within the HLA class II region.

Susceptibility to rheumatoid arthritis (RA) may be due to the presence of shared functional epitopes common to the HLA-DR beta chains of several RA-associated haplotypes. We have obtained direct evidence for this hypothesis by using the polymerase chain reaction and sequencing the DRB1 and DQB1 genes from RA patients. A highly conserved epitope present on DR beta chains of DR4 and DR1 haplotypes was found in 83% of 149 patients with classical or definite RA but was found in only 46% of 100 control individuals (P less than 0.0001). Two Dw subtypes of DR4 (Dw4 and Dw14) were associated with disease susceptibility but two other subtypes (Dw10 and Dw13) were not. Sequence differences between these subtypes implicate those residues around the putative antigen binding site of the DR beta molecule in the pathogenesis of RA. These data provide a basis for understanding host susceptibility to RA at a molecular level.

Alleles↗