Candidate T cell epitopes of the human La/SSB autoantigen

Davies, Margaret; Taylor, Eleanor; Gordon, Caroline; Young, Stephen P.; Welsh, Kenneth I.; Bunce, Mike; Wordsworth, B P; Davidson, Brian; Bowman, S

doi:10.1002/1529-0131(200201)46:1<209::aid-art10066>3.0.co;2-1

Cited by 27 publications

(19 citation statements)

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“…From this they identified 7 peptides that stimulated T cells. Five of these 7 T cell epitopes were within the regions that Davies et al had previously identified in their studies using La/SSB fusion protein antigen-induced stimulation of peripheral blood mononuclear cells from patients with SS and controls (1,15). Interestingly, 2 new T cell epitopes, hLa 211-228 and hLa [313][314][315][316][317][318][319][320][321][322][323][324][325][326][327][328][329][330] , which were the most stimulatory, were identified in HLA-transgenic mice.…”

Section: T Cells and The Loss Of Immunologic Tolerance In Sjögren's Smentioning

confidence: 97%

“…Four groups of investigators have conducted studies examining patients and healthy controls for the presence of La/SSB-reactive human T cells, using a variety of approaches (12)(13)(14)(15). Namekawa et al (14) observed oligoclonal TCR use by T cells isolated from the salivary glands of SS patients, supporting the possibility that T cell epitopes recognized on the autoantigen might be limited to select regions on the molecule.…”

Section: T Cells and The Loss Of Immunologic Tolerance In Sjögren's Smentioning

confidence: 99%

“…Namekawa et al (14) observed oligoclonal TCR use by T cells isolated from the salivary glands of SS patients, supporting the possibility that T cell epitopes recognized on the autoantigen might be limited to select regions on the molecule. Davies et al (15) directly identified La/SSB-reactive T cells in the peripheral blood of SS patients and healthy controls, and identified 5 putative T cell epitopes on the La/SSB protein. Thus, while La/SSB-reactive T cells have been identified in the peripheral blood of patients and healthy controls, the precise importance of these T cells in the pathogenesis of SS has not been clearly defined (11)(12)(13)(14)(15).…”

Section: T Cells and The Loss Of Immunologic Tolerance In Sjögren's Smentioning

confidence: 99%

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T cells and the loss of immunologic tolerance in Sjögren's syndrome and systemic lupus erythematosus

Hoffman

2007

Arthritis & Rheumatism

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Section: T Cells and The Loss Of Immunologic Tolerance In Sjögren's Smentioning

confidence: 97%

Section: T Cells and The Loss Of Immunologic Tolerance In Sjögren's Smentioning

confidence: 99%

Section: T Cells and The Loss Of Immunologic Tolerance In Sjögren's Smentioning

confidence: 99%

See 1 more Smart Citation

T cells and the loss of immunologic tolerance in Sjögren's syndrome and systemic lupus erythematosus

Hoffman

2007

Arthritis & Rheumatism

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“…Computer analysis was performed using the SYFPEITHI (34) and ProPred (35) programs to find similarities between the hLa epitope sequences and putative DR3 binding motifs. Probable DRB1*0301 binding registers for each of the DR3-restricted epitopes uncovered in this study were identified ( Figure 4A), indicating that the most conserved residue is the p4 position, consisting of an aspartic acid (hLa [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] , hLa 55-72 , hLa 151-168 , hLa 211-228 , hLa [241][242][243][244][245][246][247][248][249][250][251][252][253][254][255][256][257][258] , and hLa 313-330 ) or conservatively substituted glutamic acid (hLa [46][47][48][49][50][51][52][53][54] ), in 7 of 7 epitopes, followed by p1 (in 5 of 7 epitopes), p6 (in 4 of 7 epitopes), and p9 (in 3 of 7 epitopes).…”

Section: Enhancement Of the Reactivity Of A Weak Epitope In Dr3/dq2mentioning

confidence: 99%

“…Although DR3-restricted epitopes of Ro have been described using this approach (21), the fine specificity of the HLA-restricted anti-hLa response is largely unknown. In the only relevant study available, Davies et al identified determinants within 3 large regions of the hLa protein at hLa , hLa , and hLa 241-312 in patients with SLE and patients with SS (22). A single epitope within hLa was fine-mapped to hLa [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] by recalling T cells from SS patients and SLE patients against synthetic peptide pools.…”

mentioning

confidence: 99%

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB10301/DQB10201

Dudek¹,

Maier²,

Chen³

et al. 2007

Arthritis & Rheumatism

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Objective. T cells are implicated in the production of anti-La/SSB and anti-Ro/SSA autoantibodies commonly associated with the DR3/DQ2 haplotype in systemic lupus erythematosus and Sjögren's syndrome. This study was undertaken to investigate the DR3/DQ2-restricted T cell response to wild-type human La (hLa) and a truncated form of mutant La.Methods. Humanized transgenic mice expressing HLA-DRB1*0301/DQB1*0201 (DR3/DQ2) were immunized with recombinant antigen and examined for development of autoantibodies and T cell proliferation against overlapping peptides spanning the La autoantigen. HLA restriction and peptide binding of identified T cell epitopes to DR3 or DQ2 were determined using blocking monoclonal antibodies and a direct binding assay.Results. DR3/DQ2-transgenic mice generated an unusually rapid class-switched humoral response to hLa with characteristic spreading to Ro 52 and Ro 60 proteins following hLa protein immunization. Seven T cell determinants in hLa were restricted to the HLA-DR3/DQ2 haplotype. Six epitopes tested were restricted to HLA-DR and bound DR3 with semiconserved DR3 binding motifs. No DQ restriction of these epitopes was demonstrable despite efficient DQ binding activity in some cases. No neo-T cell epitopes were identified in mutant La; however, T cells primed with mutant La exhibited a striking increase in proliferation to the epitope hLa 151-168 compared with T cells primed with hLa.Conclusion. Multiple DR3-restricted epitopes of hLa have been identified. These findings suggest that truncation of La produced by somatic mutation or possibly granzyme B-mediated cleavage alters the immunodominance hierarchy of T cell responsiveness to hLa and may be a factor in the initiation or maintenance of anti-La autoimmunity.A striking feature of many rheumatic diseases is the development of antinuclear autoantibodies (ANAs) directed at selected nuclear components, including RNPs. These ANA specificities often occur as linked antibody sets recognizing different epitopes on the same macromolecular complex. La/SSB, a ubiquitous 49-kd RNP that binds several RNA polymerase IIItranscribed structural RNAs, exists in the nucleus as part of a complex with Ro/SSA and its associated yRNA molecules. Autoantibodies directed against La are a

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Importance of T cells in rheumatoid synovitis: Comment on the review by Firestein and Zvaifler

Edwards

2002

Arthritis & Rheumatism

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In the 2002 update of the American College of Rheumatology Guidelines for the Management of Rheumatoid Arthritis (1), the authors stress the need for antiplatelet therapy with low-dose aspirin for patients at risk for cardiovascular disease who are taking selective cyclooxygenase-2 (COX-2) agents, reasoning that, unlike nonselective nonsteroidal antiinflammatory drugs (NSAIDs), the selective COX-2 inhibitors have no effect on platelet adhesion or aggregation. This seems to imply that antiplatelet therapy with aspirin is required only when selective COX-2 inhibitors are used. I believe nonselective NSAIDs neither ensure appropriate antiplatelet prophylaxis, nor do they appear better than selective COX-2 inhibitors for patients at cardiovascular risk who are receiving concomitant aspirin antiplatelet therapy. Unlike the potent and irreversible inhibition of platelet COX-1 induced by aspirin, the antiplatelet effect of NSAIDs is highly variable and depends on two factors: their potency for inhibiting COX-1 at pharmacologic doses and their half-life (2). Thus, neither NSAIDs with a short half-life, such as ibuprofen, nor those with a relatively low COX-1 inhibitory effect, such as diclofenac, provide efficient and sustained antiplatelet therapy. Only drugs with a long half-life and a potent COX-1 inhibitory effect, such as indobufen, flurbiprofen, and naproxen, have been suggested to be potentially useful as antiplatelet agents (2). This may explain the observation of a higher rate of thrombotic events with rofecoxib than with naproxen in a large trial (3), something not observed when rofecoxib or celecoxib is compared with other nonselective NSAIDs (4,5). However, due to the reversibility of the antiplatelet effect of NSAIDs, the cardioprotective effect of these drugs as shown in clinical trials, where compliance with the dose and treatment schedule is usually better, does not necessarily apply to clinical practice, where intermittent use by patients is common. Accordingly, epidemiologic studies have failed to demonstrate cardioprotective effects of NSAIDs, in contrast with aspirin (6). Furthermore, recently published data demonstrate that in patients taking aspirin, ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin, whereas other drugs with lower COX-1 inhibitory effects, such as diclofenac or rofecoxib, do not interfere with aspirin's effects (7). An additional matter of concern when using aspirin with NSAIDs is their synergistic action in terms of gastrointestinal toxicity, something that has not been sufficiently evaluated for COX-2 selective drugs (8). In conclusion, neither relying on the antiplatelet effect of NSAIDs in patients at cardiovascular risk, nor using NSAIDs instead of selective COX-2 inhibitors when low-dose aspirin is needed, can be recommended based on available evidence.

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Candidate T cell epitopes of the human La/SSB autoantigen

Cited by 27 publications

References 14 publications

T cells and the loss of immunologic tolerance in Sjögren's syndrome and systemic lupus erythematosus

T cells and the loss of immunologic tolerance in Sjögren's syndrome and systemic lupus erythematosus

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB10301/DQB10201

Importance of T cells in rheumatoid synovitis: Comment on the review by Firestein and Zvaifler

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Candidate T cell epitopes of the human La/SSB autoantigen

Cited by 27 publications

References 14 publications

T cells and the loss of immunologic tolerance in Sjögren's syndrome and systemic lupus erythematosus

T cells and the loss of immunologic tolerance in Sjögren's syndrome and systemic lupus erythematosus

T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB1*0301/DQB1*0201

Importance of T cells in rheumatoid synovitis: Comment on the review by Firestein and Zvaifler

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T cell epitopes of the La/SSB autoantigen in humanized transgenic mice expressing the hLa class II haplotype DRB10301/DQB10201