scholarly journals Definition of the DRB1*0901 peptide binding motif within novel DRB1*0901 restricted T cell epitopes by peptide binding and structural modeling

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Eddie A James ◽  
Antonis K Moustakas ◽  
George K Papadopoulos ◽  
Randi S Nouv ◽  
William W Kwok
2008 ◽  
Vol 45 (9) ◽  
pp. 2651-2659 ◽  
Author(s):  
Eddie A. James ◽  
Antonis K. Moustakas ◽  
DeAnna Berger ◽  
Laurie Huston ◽  
George K. Papadopoulos ◽  
...  

1997 ◽  
Vol 56 ◽  
pp. 239
Author(s):  
M.C. Grosfeld-Stulemeyer ◽  
I. Joosten ◽  
M. van der Kraan ◽  
M.H.M. Wauben

2019 ◽  
Author(s):  
Eleni Tiniakou ◽  
Andrea Fava ◽  
Zsuzsanna H. McMahan ◽  
Tara Guhr ◽  
Robert N. O’Meally ◽  
...  

AbstractDisease-associated HLA-DRB1 alleles are thought to confer risk of developing autoimmunity by favoring the presentation of select autoantigenic epitopes. However, identification of these epitopes and the principles governing their presentation has been hindered by the imprecision of currently available methods, which cannot fully recapitulate the complexity of human pathophysiology. We present a natural antigen processing assay (NAPA), which overcomes these limitations by studying the presentation of autoantigenic CD4+ T cell epitopes by monocyte-derived dendritic cells (mo-DCs) from patients. We applied this strategy to study the processing and presentation of topoisomerase-1 (TOP1), a prevalent autoantigen in scleroderma that is associated with lung fibrosis and high mortality. We found that a common set of 10 epitopes was presented by mo-DCs from patients with diverse HLA-DR variants, including those not previously associated with the disease. Sequence analysis revealed a shared peptide-binding motif within the HLA-DR peptide binding grooves of patients who developed anti-TOP1 autoantibodies. In addition, a subset of naturally presented TOP1 peptides were characterized by immunological promiscuity, as they could bind to diverse HLA-DR peptide binding grooves. NAPA epitopes were immunorelevant: they could stimulate autoreactive CD4+ T cells in patients, and the number of epitopes recognized correlated with lung disease severity. These findings mechanistically implicate presentation of a convergent set of TOP1 epitopes in the development of scleroderma lung disease. Precise identification of autoantigenic epitopes is key to understanding the primordial mechanisms for the loss of tolerance, studying disease-propagating autoreactive T cells, and developing antigen-specific immunotherapy.One Sentence SummaryUse of a novel natural antigen processing assay reveals a mechanism for the presentation of shared CD4+ T cell epitopes of topoisomerase-I in immunogenetically diverse patients with scleroderma.


PLoS ONE ◽  
2016 ◽  
Vol 11 (11) ◽  
pp. e0167017 ◽  
Author(s):  
Sharon M. Barth ◽  
Christian M. Schreitmüller ◽  
Franziska Proehl ◽  
Kathrin Oehl ◽  
Leonie M. Lumpp ◽  
...  

1997 ◽  
Vol 185 (6) ◽  
pp. 1013-1022 ◽  
Author(s):  
Leonard C. Harrison ◽  
Margo C. Honeyman ◽  
Sylvie Trembleau ◽  
Silvia Gregori ◽  
Fabio Gallazzi ◽  
...  

The class II major histocompatibility complex molecule I-Ag7 is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its β chain. To identify the requirements for peptide binding to I-Ag7 and thereby potentially pathogenic T cell epitopes, we analyzed a known I-Ag7-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9–27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-Ag7 M12-Y20/ K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-Ag7 deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-Ag7–restricted T cell epitopes or eluted from I-Ag7. Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.


1997 ◽  
Vol 10 (6) ◽  
pp. 569-578 ◽  
Author(s):  
A.Mieke H Boots ◽  
Gijs F.M Verheijden ◽  
Ron Schöningh ◽  
Catherina J van Staveren ◽  
Ebo Bos ◽  
...  

1992 ◽  
Vol 22 (6) ◽  
pp. 1405-1412 ◽  
Author(s):  
Ton N. M. Schumacher ◽  
Grada M. Van Bleek ◽  
Marie-ThéRèSe Heemels ◽  
Karl Deres ◽  
Ka Wan Li ◽  
...  

1996 ◽  
Vol 26 (11) ◽  
pp. 2764-2772 ◽  
Author(s):  
Frode Vartdal ◽  
Bente H. Johansen ◽  
Thomas Friede ◽  
Christopher J. Thorpe ◽  
Stefan Stevanović ◽  
...  

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