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L R Wedderburn

Publications and source records attributed to L R Wedderburn.

28 records · Page 2Linked to original sources
PubMed1999

Molecular fingerprinting reveals non-overlapping T cell oligoclonality between an inflamed site and peripheral blood.

We have demonstrated a stable expansion of CD8+ T cells in the peripheral blood of a child with chronic arthritis. The expanded TCRBV family (TCRBV14) was enriched for CD57hiCD28- T cells. Sequencing of the TCRBV14 amplification products showed a TCR sequence which contributed 32% of the total TCR in the CD8+TCRBV14 population. Using the modified heteroduplex technique, the CD8+TCRBV14 cells showed a clonal pattern and these bands were restricted to the CD28- population. This method also detected multiple other clones within the CD8+ population but few in the CD4+ cells. The dominant TCRBV14+ clone was not detectable in synovial fluid T cells from two inflamed joints by CDR3 length analysis or heteroduplex probing, suggesting that this long-lived clone is excluded from inflammatory sites. Synovial fluid T cells showed an unexpected discordance of the CD28 and CD57 phenotype compared to peripheral blood mononuclear cells. T cells from both inflamed joints both showed marked oligoclonality in all TCR families and had almost identical heteroduplex patterns. Taken together these data suggest that some clones are actively excluded from inflamed sites in juvenile chronic arthritis, yet the pattern of restricted T cell expansion is shared between sites of inflammation.

Arthritis, Juvenile↗
PubMed1998

A comparison of two techniques for the molecular tracking of specific T-cell responses; CD4+ human T-cell clones persist in a stable hierarchy but at a lower frequency than clones in the CD8+ population.

Oligoclonal or clonal T-cell expansions, presumed to be antigen driven, are frequently sought and followed for diagnostic and prognostic purposes, as well as to understand more about their natural history. Techniques based on conservation of T-cell receptor CDR3 length are increasingly widely used, often without assessment of sensitivity or specificity. We present a comparative evaluation of a novel modified heteroduplex technique and a CDR3-length-based assay. Dilution of a known clone in a mixed T-cell population shows that in our hands the heteroduplex technique is at least 10-fold more sensitive than the CDR3-length-based assay. However, even with this level of sensitivity, we do not detect clonal expansions in unstimulated CD4+ T cells. This contrasts with the frequent detection of CD8+ clones in fresh samples and suggests different mechanisms of clonal homeostasis in the two subsets. We show that both techniques detect functional expansions after in vitro stimulation with a recall antigen. The distinct molecular footprint seen with the heteroduplex technique allows reproducible follow up of specific clonal expansions. We have exploited this to demonstrate that the repertoire of clones expanded by in vitro tetanus toxoid stimulation shows stability within an individual, implying long-term maintenance of multiple CD4+ clones.

CD3 Complex↗
PubMed1995

Mapping T cell recognition: the identification of a T cell receptor residue critical to the specific interaction with an influenza hemagglutinin peptide.

The fine specificity of T cell receptor (TCR) interaction with the influenza hemagglutinin peptide HA 307-319 in the context of the DR1 (DRA, DRB1 0101) and DR4 (DRA, DRB1 0404) was studied in two human T cell clones (HA1.7 and Cl-1) derived from different individuals. Sequencing of amplified TCR transcripts revealed that these two clones express highly related TCR alpha chains, with a conserved junctional motif, but very different TCR beta chains. Modeling studies led to the prediction that the conserved glutamic acid residue in the TCR alpha chain could interact with the lysine at position 316 in the peptide, a known TCR contact residue. HA1.7 TCR-CD3 zeta chimeric constructs were expressed in the rat basophil line (RBL) and shown to confer specific antigen recognition. In two TCR alpha chain mutants, with the conserved glutamic acid residue altered to alanine and lysine, respectively, peptide recognition was lost. Specific recognition was not rescued by altered peptide ligands. Furthermore, Jurkat derivatives expressing the related Jurkat TCR alpha chain paired with the HA 1.7 TCR beta chain did not recognize the HA 307-319/DR1 complex. These data provide evidence for the critical interaction of a TCR residue with antigenic peptide.

Amino Acid Sequence↗
PubMed1993

In vivo clonal dominance and limited T-cell receptor usage in human CD4+ T-cell recognition of house dust mite allergens.

Sensitivity to house dust mite antigens in atopic individuals is a major cause of allergic diseases, ranging from asthma to rhinitis and dermatitis. We have studied the T-cell receptor (TCR) usage of house-dust-mite-specific CD4+ T-cell clones isolated from an atopic individual, by using the anchored polymerase chain reaction, and have analyzed the peripheral TCR repertoire of the same individual. Several T-cell clones had identified TCRs at the sequence level, despite the fact that they had been independently isolated, in some cases, in different years. These data suggest the presence in vivo of long-lived T-cell clones. We have also shown that junctional sequences identical to these clones are present in peripheral blood T cells taken 6 years after the isolation of the T-cell clones. The analysis of TCR genes used by the panel of clones reveals oligoclonality, with the variable (V) region gene segments V alpha 8 and V beta 3 being dominant, although there is minimal conservation of junctional sequences. The results have implications for understanding the TCR recognition of an environmental aeroallergen and the life span of T-cell clones in vivo during a chronic immune response.

Allergens↗
PubMed1992

Juvenile chronic arthritis and Wegener's granulomatosis.

We present a case of Wegener's granulomatosis in a teenage boy with systemic onset juvenile chronic arthritis. We discuss the implication of these two uncommon conditions coexisting in one patient. The recent characterization of the antineutrophil cytoplasmic antibody (ANCA) as a marker of small vessel vasculitis has helped in the differential diagnosis of pulmonary renal syndromes.

Adolescent↗
PubMedDate not supplied

Concurrence of sarcoidosis and systemic lupus erythematosus in three patients.

We present three cases of patients with systemic lupus erythematosus and sarcoidosis. Although both of these conditions are thought to involve autoimmune mechanisms they occur together only rarely. Our cases suggest that their concurrence may be more common than previously thought, and raise issues regarding the management of patients with SLE. We discuss the possibility that these two diseases are either causally or mechanistically related.

Adult↗