Identification of HLA-DR–bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis

Wahlström, Jan; Dengjel, Jörn; Persson, Bengt; Duyar, Hüseyin; Rammensee, Hans‐Georg; Stevanović, Stefan; Eklúnd, Anders; Weissert, Robert; Grünewald, Johan

doi:10.1172/jci32401

Cited by 115 publications

(92 citation statements)

References 42 publications

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“…Literature search yielded a number of T-cell autoantigens that were also detectable in our samples ( Table 2). The table only includes T-cell autoantigens for which reactivity has been experimentally verified in humans, such as vimentin (rheumatoid arthritis, sarcoidosis) 34,35 , ATP synthase (sarcoidosis) 35 , enolase 2 (multiple sclerosis) 36 and heat shock protein 70 (type 1 diabetes mellitus) 37 . For those autoantigens where reactivity against specific epitopes (rather than whole protein) was reported, the epitopes were identical to, or contained within the peptide sequences that we identified in our samples, mostly on DCs.…”

Section: Resultsmentioning

confidence: 99%

Exploring the MHC-peptide matrix of central tolerance in the human thymus

et al. 2013

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Ever since it was discovered that central tolerance to self is imposed on developing T cells in the thymus through their interaction with self-peptide major histocompatibility complexes on thymic antigen-presenting cells, immunologists have speculated about the nature of these peptides, particularly in humans. Here, to shed light on the so-far unknown human thymic peptide repertoire, we analyse peptides eluted from isolated thymic dendritic cells, dendritic cell-depleted antigen-presenting cells and whole thymus. Bioinformatic analysis of the 842 identified natural major histocompatibility complex I and II ligands reveals significant crosstalk between major histocompatibility complex-class I and II pathways and differences in source protein representation between individuals as well as different antigen-presenting cells. Furthermore, several autoimmune-and tumour-related peptides, from enolase and vimentin for example, are presented in the healthy thymus. 302 peptides are directly derived from negatively selecting dendritic cells, thus providing the first global view of the peptide matrix in the human thymus that imposes self-tolerance in vivo.

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Section: Resultsmentioning

confidence: 99%

Exploring the MHC-peptide matrix of central tolerance in the human thymus

et al. 2013

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“…Two of the peptides (K15 and K20) were matched to HLA class II epitopes reported to be eluted from HLA-DRβ*0404 (K15-C and K20-C) and HLA-DRβ*0301 (K15-D and K20-D; Table 4; Kirschmann et al 1995;Wahlstrom et al 2007). The peptides with either an intensity lower than the double average value of the negative control spots, or did not reach an intensity higher than a twofold increase over the corresponding control, were assessed as none binding (0).…”

Section: Resultsmentioning

confidence: 99%

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Stocki

Morris

Preisinger

et al. 2010

Cell Stress and Chaperones

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Heat shock protein 70 (HSPA) is a molecular chaperone which has been suggested to shuttle human leukocyte antigen (HLA) epitope precursors from the proteasome to the transporter associated with antigen processing. Despite the reported observations that peptides chaperoned by HSPA are an effective source of antigens for cross-priming, little is known about the peptides involved in the process. In this study, we investigated the possible involvement of HSPA in HLA class I or class II antigen presentation and analysed the antigenic potential of the associated peptides. HSPA was purified from CCRF-CEM and K562 cell lines, and using mass spectrometry techniques, we identified 44 different peptides which were copurified with HSPA. The affinity of the identified peptides to two HSPA isoforms, HSPA1A and HSPA8, was confirmed using a peptide array. Four of the HSPAassociated peptides were matched with 13 previously reported HLA epitopes. Of these 13 peptides, nine were HLA class I and four were HLA class II epitopes. These results demonstrate the association of HSPA with HLA class I and class II epitopes, therefore providing further evidence for the involvement of HSPA in the antigen presentation process.

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“…Oshitani et al reported 55 HLA-DR peptides from human intestine samples of 4 controls and 18 patients affected by inflammatory bowel disease (13). More recently, 78 peptides have been reported from a pool of 16 bronchoalveolar lavage samples from patients with sarcoidosis, being the first such study in human autoimmunity, although the nature of the samples was very different (23). Using a different approach, a recent study has shown that most peptides bound to MHC-II from mouse insulinoma cells derive from proteins normally expressed in ␤ cells from normal islets and that some of them are recognized by CD4 ϩ T cells from NOD mice (24).…”

Section: Discussionmentioning

confidence: 99%

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

Muixí

Carrascal

Álvarez

et al. 2008

The Journal of Immunology

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Endocrine epithelial cells, targets of the autoimmune response in thyroid and other organ-specific autoimmune diseases, express HLA class II (HLA-II) molecules that are presumably involved in the maintenance and regulation of the in situ autoimmune response. HLA-II molecules thus expressed by thyroid cells have the “compact” conformation and are therefore expected to stably bind autologous peptides. Using a new approach to study in situ T cell responses without the characterization of self-reactive T cells and their specificity, we have identified natural HLA-DR-associated peptides in autoimmune organs that will allow finding peptide-specific T cells in situ. This study reports a first analysis of HLA-DR natural ligands from ex vivo Graves’ disease-affected thyroid tissue. Using mass spectrometry, we identified 162 autologous peptides from HLA-DR-expressing cells, including thyroid follicular cells, with some corresponding to predominant molecules of the thyroid colloid. Most interestingly, eight of the peptides were derived from a major autoantigen, thyroglobulin. In vitro binding identified HLA-DR3 as the allele to which one of these peptides likely associates in vivo. Computer modeling and bioinformatics analysis suggested other HLA-DR alleles for binding of other thyroglobulin peptides. Our data demonstrate that although the HLA-DR-associated peptide pool in autoimmune tissue mostly belongs to abundant ubiquitous proteins, peptides from autoantigens are also associated to HLA-DR in vivo and therefore may well be involved in the maintenance and the regulation of the autoimmune response.

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Identification of HLA-DR–bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis

Cited by 115 publications

References 42 publications

Exploring the MHC-peptide matrix of central tolerance in the human thymus

Exploring the MHC-peptide matrix of central tolerance in the human thymus

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Thyroglobulin Peptides Associate In Vivo to HLA-DR in Autoimmune Thyroid Glands

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