Back pain in the older patient.
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Abscess↗
Biomedical subjects
A K So
Publications and source records attributed to A K So.
Genomic organization of the human T-cell receptor variable alpha (TCRAV) gene cluster.
A long-range physical map of the human T-cell receptor variable alpha (TCRAV) locus was produced using 23 V alpha subgroup-specific probes. Linkage disequilibrium across the locus was also studied using polymorphic TCRAV markers. Pulsed-field gel electrophoresis was used to map V alpha gene segments onto one SfiI fragment of 500 kb and two of 200 kb using DNA from peripheral blood neutrophils. PCR and conventional Southern techniques on Jurkat, CEM, and H9 T-cell lines were used to establish the 5' to 3' order of the gene segments and the relative positions of V alpha gene segments on the SfiI fragments. The linkage disequilibrium study used single-stranded conformation polymorphism analysis to genotype 100 normal caucasoid subjects for TCRAV5S1, V6S1, V8S1, V17S1, and V21S1 polymorphisms. Strong linkage disequilibrium was detected between V5S1 and V8S1, in concordance with the physical map. This new information will be useful for future studies of genetic variation at the TCRAV locus, its role in the shaping of the TCR repertoire, and its possible contribution to autoimmune diseases.
Base Sequence↗
A human monoclonal antiphospholipid antibody that is representative of serum antibodies and is germline encoded.
OBJECTIVE: To investigate the origins of antiphospholipid antibodies associated with thrombosis and other disorders that are found in patients with systemic lupus erythematosus and primary antiphospholipid syndrome (APS). METHODS: Characterization, idiotypic study, and nucleotide sequencing of a human monoclonal antiphospholipid antibody generated from a patient with primary APS. Identification of the germline genes from which the antibody is derived. RESULTS: A human monoclonal antibody, BH1, was generated. This antibody has ligand-binding properties that closely resemble those of the serum antiphospholipid antibodies found in our patient and in other individuals with APS: it recognizes negatively charged phospholipids, and has lupus anticoagulant activity; it does not bind to neutral phospholipids, or to single-stranded or double-stranded DNA. The relevance of BH1 to the patient's serum antibodies is supported by our idiotypic studies. BH1 is encoded by a new germline VH gene, and by a lambda light chain gene that displays > 99% homology with the V lambda III.1 germline gene. CONCLUSION: Serum antiphospholipid antibodies associated with thrombosis may be encoded by either germline or only slightly mutated variable-region genes.
Amino Acid Sequence↗
Physical mapping of the human T-cell receptor beta gene complex, using yeast artificial chromosomes.
Yeast artificial chromosomes (YACs) were used to construct a physical map of the germline human T-cell beta chain gene complex (TCRB). Variable region genes (BV) for the 25 known subfamilies were used as probes to screen the ICRF AM4x YAC library. Of the five positive YACs identified, one YAC designated B3, 820 kilobase pairs (kbp) in size, scored positive for all 25 TCRBV subfamilies plus the constant region genes (BC) when analyzed by pulse field gel electrophoresis. Restriction enzyme mapping of B3 located TCRBV and TCRBC gene regions to 4 Sfi I fragments of 280 110, 90, and 125 kbp and was in accordance with published data. In addition comparison of hybridization results of Sfi I-restricted B3 and genomic DNA from the parental cell line GM1416B revealed identical banding patterns. The data thus showed YAC B3 encoded a complete and unrearranged TCRB gene locus of some 600-620 kbp. The map was further resolved by locating restriction sites for Sal I and Bss HII on B3, giving more precise localization of the individual TCRBV gene families. Fluorescent in situ hybridization of B3 to spreads of human metaphase chromosomes localized B3 to 7q35. However, two additional signals were obtained; one attributable to the TCRBV orphon cluster on 9p21, the second to the long arm of chromosome 2. Polymerase chain reaction amplification of a chromosome 2 somatic cell hybrid, using primers for all 25 TCRBV gene families, revealed that the signal was not attributable to a second orphon cluster. It is suggested that B3 is a chimeric YAC with an intact TCRB locus flanked by chromosome 2 sequences.
Chromosomes, Artificial, Yeast↗
No association between HLA-DQ and -DR genotypes with nasopharyngeal carcinoma in southern Chinese.
The pathogenesis of nasopharyngeal carcinoma (NPC) is multifactorial. Associations have been reported between HLA and NPC. We studied the HLA-DR and -DQ regions on the molecular level in 136 persons (51 NPC patients and 85 healthy controls) from southern China, a particularly high-prevalence area for NPC. Restriction fragment-length polymorphism (RFLP) was used to genotype the MHC class II DR beta, DQ alpha, and DQ beta regions of the subjects. Polymerase chain reaction (PCR) using sequence-specific primer (SSP) for DQ beta genes was also performed. By RFLP, no significant difference was observed with respect to DRB, DQA, and DQB genes. By PCR SSP typing, we confirmed that there was no significant difference between NPC patients and controls with respect to DQ beta alleles. Our study suggests that HLA-DQ and -DR genes are not associated with NPC in southern Chinese and there may be other gene loci that predispose them to have such a high prevalence of the disease.
Adolescent↗
CD4 T cells in the rheumatoid joint are oligoclonally activated and change during the course of disease.
OBJECTIVE: To assess the nature of T cell receptor (TCR) utilisation by CD4 T cells in the rheumatoid joint. METHODS: Sequencing of the joining (NDJ) region of TCR beta chain mRNA isolated from synovial fluid CD4 T cells was performed in three patients in order to determine if oligoclonal expansion of particular sequences was present. Two patients were studied longitudinally to determine if these sequences changed over time. RESULTS: A number of dominant clonotypes were found within the TCR transcripts sequenced in each patient. In the two patients who were studied longitudinally, different dominant clonotypes were detected over time. No single clonotype was persistently dominant during the period of study. CONCLUSIONS: The pattern of TCR usage showed multiple oligoclonally expanded CD4 T cells within the rheumatoid joint. The change in clonotypes within the joint over time suggests that different antigens may be able to elicit synovial inflammation during the course of rheumatoid disease.
Arthritis, Rheumatoid↗
Lack of association of T cell receptor V beta 8 polymorphism with rheumatoid arthritis in United Kingdom and Italian white patients.
OBJECTIVES: To study if the reported association of a BamH I 2kb RFLP of the T cell receptor V beta 8 gene with DR4+ rheumatoid arthritis patients is found in non-American white populations. METHODS: The frequency of this RFLP in two different populations was analysed. Eighty one northern Italians were studied for HLA-DR genotypes and V beta 8 polymorphism, and 29 DR4+ British white patients were studied for V beta 8 polymorphism. RESULTS: No association between the V beta 8 RFLP and DR4 was found with rheumatoid arthritis in both groups. CONCLUSION: The reported V beta 8-DR4 association is not generally applicable. The lack of association in our populations may be due to genetic differences, or to differences in factors which shaped the T cell repertoire.
Arthritis, Rheumatoid↗
Homozygous hereditary C3 deficiency due to a partial gene deletion.
The molecular mechanism of C3 deficiency in an Afrikaans patient with recurrent pyogenic infections was studied. Restriction enzyme analysis showed a gene deletion of 800 base pairs (bp) mapping to the alpha chain of C3. Amplification of genomic DNA, using the PCR, demonstrated that the deletion included exons 22 and 23 of the C3 gene. Truncated mRNA was shown in an Epstein-Barr virus-transformed B-cell line by PCR amplification of first-strand cDNA. A consequence of this deletion was that the RNA transcribed 3' to the deletion was out of frame, resulting in formation of a stop codon 19 bp downstream from the deletion. The molecular basis of the deletion was compatible with homologous recombination between two Alu sequences located in introns 21 and 23. An unrelated nonconsanguineous relative and two of a sample of 174 Afrikaans-speaking individuals were heterozygous carriers of the same gene deletion. The wide prevalence of this null allele in this population is probably due to the effects of a small founder population. The presence of this deletion in the C3 gene is not compatible with production of any functional C3, supporting the idea that study of such patients offers a valid model for understanding physiological activities of C3 in vivo in humans.
Base Sequence↗
Linkage between rheumatoid arthritis susceptibility and the presence of HLA-DR4 and DR beta allelic third hypervariable region sequences in southern Chinese persons.
OBJECTIVE: To analyze HLA-DR and DQ associations with rheumatoid arthritis (RA) in patients from southern China. METHODS: In 66 patients and 45 controls, restriction fragment length polymorphism studies were performed using DRB, DQA, and DQB probes, and DRB allele-specific typing of polymerase chain reaction-amplified DRB DNA: RESULTS: The frequency of HLA-DR4 was significantly increased among RA patients (42.4% versus 17.8%). Increased frequencies of the DQA3 allele (77.8% versus 48.9%) and the DQB1*0302 allele (71.0% versus 46.3%), which are in linkage disequilibrium with DR4, were also found. Oligonucleotide typing showed that the amino acid sequence LLEQRRAA, spanning amino acid positions 67-74 of the DR beta molecule, was found in 19 of 49 patients and 5 of 32 controls. The main DR4 allelic subtypes found in the population were DRB1*0404 and DRB1*0405, both of which carried the sequence. There was no difference in subtype distribution between patients and controls. CONCLUSION: Chinese RA patients have an increased frequency of HLA-DR4 alleles which possess the same DRB third allelic hypervariable sequence shown to be associated with susceptibility in Caucasian RA patients.
Alleles↗
Identification of novel human T-cell receptor V beta gene segments by the anchored-polymerase chain reaction.
We have studied the diversity of the expressed human T-cell receptor (TCR) beta-chain repertoire by analysis of mRNA from unstimulated peripheral blood T-cells. The anchored-polymerase chain reaction (PCR) was used to isolate TCRB transcripts. Of 20 full or near full-length functional transcripts sequenced, two were novel TCRVB gene segments. They have strong sequence similarities to the known TCRBV5, and 8 subfamilies. Southern blot analysis and sequence-specific oligonucleotide hybridization confirmed: a) that these sequences are present in genomic DNA; b) their relationship to the known TCRBV families. A TCRBV sequence similar to a recently identified novel TCRBV24 subfamily was also found. We show by southern blotting that this sequence forms a single member subfamily, and by deletion analysis of T-cell lines, we have mapped this sequence to lie between the genes which encode the TCRBV8.1 and TCRBV5.3 gene segments. The results show that the anchored PCR is a powerful tool in the analysis of the TCR repertoire, which may contain more V gene segments than previously defined.
Amino Acid Sequence↗
Familial IgA nephropathy: a study of HLA class II allogenotypes in a Chinese kindred.
We have studied the restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) class II DQ, DR pattern of a Chinese family with IgA nephropathy (IgAN). The three affected and one apparently unaffected sibling shared the same DR and DQ pattern. The subjects were homozygous for DRw12, DQw7, DQ alpha 1b. The DQw7 allele was further confirmed by polymerase chain reaction (PCR) and allele-specific oligonucleotide (ASO) probing. This study confirms that IgAN can run in a family and is consistent with the possible immunopathogenetic effects of MHC class II antigens on IgAN.
Adult↗
Sulphasalazine induced autoimmune syndrome.
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Adult↗
T gamma delta cells and their subsets in blood and synovial fluid from patients with rheumatoid arthritis.
We have determined the distribution of T gamma delta cells in the peripheral blood of 44 patients with rheumatoid arthritis and in 36 healthy controls. In addition, paired blood and synovial fluid samples were obtained from seven patients with RA. The monoclonal antibodies A13, BB3 and Ti gamma A, which are specific for the V delta 1, V delta 2 and V gamma 9 gene products respectively, were used to define T gamma delta subsets. T gamma delta + cells expressed as a percentage of CD3+ lymphocytes were reduced in RA peripheral blood compared with the control group (3.9% +/- 0.5 versus 5.7% +/- 0.7; P less than 0.0001). There was a reduction in the V gamma 9/V delta 2+ subset (from 5.6% +/- 1.2 to 1.7% +/- 0.4) leading to a change in the mean ratio of V delta 2/V delta 1+ cells from 4.3 in normal subjects to 1.1 (P less than 0.002). No statistical difference was observed in T gamma delta cell numbers in synovial fluid compared with the paired blood samples (4.0% +/- 1.1 in blood and 4.4% +/- 1.4 in synovial fluid). Also the distribution of V delta 2+ and V delta 1+ cells was similar in the two compartments and a similar alteration in subset distribution was found in blood and synovial fluid. These findings do not indicate a selective accumulation of a specific T gamma delta subset in RA synovial effusions.
Antibodies, Monoclonal↗
The clinical and immunogenetic features of patients with autoantibodies to the nucleolar antigen PM-Scl.
The clinical and laboratory features of 32 patients with anti-PM-Scl were studied. Patients with this rare autoantibody suffered from a homogenous overlap connective tissue disease defined by Raynaud phenomenon (32/32), features of scleroderma (31/32), arthritis (31/32, erosive in 9/32), myositis (28/32), lung restriction (25/32), calcinosis (15/32), and sicca (11/32). Significant renal and neurologic involvement was uncommon. All patients examined (22/22) had HLA-DR3, and 50% of these patients were homozygous. Our patients responded favorably to moderate immunosuppression and, with therapy, the disease generally has a good prognosis; over 50% of our series (17/32) remained well on minimal or no immunosuppression after a median follow-up of 8 years.
Adolescent↗
An altered repertoire of T cell receptor V gene expression by rheumatoid synovial fluid T lymphocytes.
The pattern of T cell receptor V gene expression by lymphocytes from rheumatoid synovial fluid and paired peripheral blood samples was compared using a polymerase chain reaction (PCR)-based assay. Eight rheumatoid arthritis (RA) patients who had varying durations of disease (from 2 to 20 years) were studied. In all patients there was evidence of a different pattern of V gene expression between the two compartments. Significantly increased expression of at least one V alpha or V beta gene family by synovial fluid T cells was observed in all the patients studied. Three different V alpha (V alpha 10, 15 and 18) and three V beta (V beta 4, 5 and 13) families were commonly elevated. Sequencing of synovial V beta transcripts demonstrated that the basis of increased expression of selected V gene families in the synovial fluid was due to the presence of dominant clonotypes within those families, which constituted up to 53% of the sequences isolated from one particular synovial V gene family. There were considerable differences in the NDJ sequences found in synovial and peripheral blood T cell receptor (TCR) transcripts of the same V beta gene family. These data suggest that the TCR repertoire in the two compartments differs, and that antigen-driven expansion of particular synovial T cell populations is a component of rheumatoid synovitis, and is present in all stages of the disease.
Arthritis, Rheumatoid↗
The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians.
The frequencies of the MHC class II HLA-DR and DQ alleles in 36 Caucasian patients with IgA nephropathy (IgAN) were analyzed by RFLP analysis and allele specific oligonucleotide (ASO) probing of specifically amplified genomic DNA. The class II alleles HLA-DR4 (52.7%) and DR5 (30.5%) were increased in the patient group compared to 1103 UK Caucasoid controls, but these increases were not statistically significant. However, there was a significant increase in the HLA-DQw7 allele frequency (71%) (c = 27.8%, chi 2 = 29.2, P less than 0.001, Relative Risk = 6.17). This can be explained by linkage disequilibrium between the DQw7 allele at the DQB1 locus and DRB1 genes of some DR4 and all DR5 haplotypes. The polymorphic portion of the DQ alpha chains from DR4, DQw7 and DR5, DQw7 haplotypes differ but they have identical DQ beta chains. DNA encoding DQw7 allele at the DQB1 locus was sequenced in two patients and was identical to that previously published. We conclude that the DQw7 allele at the DQB1 locus is strongly associated with susceptibility to IgAN in Caucasians.
Alleles↗
Common variable immunodeficiency is associated with polymorphic markers in the human major histocompatibility complex.
Common variable immunodeficiency (CVI) is a heterogeneous condition characterized by arrest in B cell differentiation. A high frequency of null alleles of the C4 gene has been reported in patients with this disorder. We investigated the restriction fragment length polymorphisms (RFLP) of the MHC class II genes HLA-DRB, DQA, and DQB, the class III gene C4 and the tumour necrosis factor-alpha) (TNF-alpha) gene in 40 Caucasian patients. The results showed an increase in HLA-DR3 in patients (40% vs 30.5%), but, more significantly, there was a striking increase in the number of CVI patients who carried a deletion of the C4A gene (46% vs 25%). In both patients and controls there was strong allelic association between HLA-DR3 and C4A deletion, and HLA-DR3 and TNF-alpha. Our results suggest that genes present on an extended haplotype containing these three polymorphisms contribute to genetic susceptibility to CVI.
Adolescent↗
Reduction in T gamma delta cell numbers and alteration in subset distribution in systemic lupus erythematosus.
We have studied the distribution of T gamma delta cells in the peripheral blood of 35 patients with systemic lupus erythematosus (SLE) and 36 age-matched controls. The monoclonal antibodies A13, BB3 and Ti gamma A, which are specific for the V delta 1, V delta 2 and V delta 9 gene products respectively, were used to define T gamma delta cell subsets. A significantly lower frequency of T gamma delta cells was found in peripheral blood lymphocytes of SLE patients compared with normal subjects (3.2% versus 5.9%). There was a marked reduction in the V delta 2+ subset of T gamma delta cells, which resulted in a reversal of the ratio of V delta 2+/V delta 1+ cells from 4.34 to 0.56. No correlation was found with either clinical or laboratory measures of disease activity. These results suggest that the observed changed in T gamma delta subset distribution are related to the SLE itself, and not secondary to changes in disease activity.
Antigens, Differentiation, T-Lymphocyte↗