First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Suri, Anish; Walters, Joseph; Rohrs, Henry W.; Gross, Michael L.; Unanue, Emil R.

doi:10.4049/jimmunol.180.6.3849

Cited by 53 publications

(36 citation statements)

References 46 publications

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“…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). In the present report, 162 peptides have been obtained from seven Graves' disease-affected thyroid tissue samples.…”

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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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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“…Two peptides of Atg8/LC3 (MAP1LC3B 93-109 and MAP1LC3B [93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109][110] ) have been found on HLA-DR4 and/or HLA-DR1 of an Epstein-Barr virus (EBV)-transformed B cell line (Dengjel et al 2005). In addition, H2-A g7 , a diabetogenic mouse MHC class II molecule, was found to present a peptide from another mammalian Atg8 member, GABARAP [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] , on the surface of a mouse B cell lymphoma cell line (Suri et al 2008). Interestingly, a potentially autoreactive CD4 + T cell clone against the latter peptide was isolated from pancreas-draining lymph nodes, identifying GABARAP as a potential autoantigen in type I diabetes in mice (Suri et al 2008).…”

Section: Source Proteins Of Peptide Ligands For Mhc Class II Moleculesmentioning

confidence: 99%

Autophagy in MHC Class II Presentation of Endogenous Antigens

Gannagé

Münz

2009

Current Topics in Microbiology and Immunology

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Macroautophagy is a catabolic process for the lysosomal turnover of cell organelles and protein aggregates. Lysosomal degradation products are displayed by major histocompatibility class II molecules to CD4(+) T cells in the steady state for tolerance induction and during infections to mount adaptive immune responses. It has recently been shown that macroautophagy substrates can also give rise to MHC class II ligands. We review here the breadth of antigens that may utilize this pathway and the possible implications of this alternate route to MHC class II antigen presentation for immunity and tolerance. Based on this discussion, it is apparent that the regulation of macroautophagy may be beneficial in various disease settings in order to enhance adaptive immune responses or to reduce autoimmunity.

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“…Thus, both BDC-2.5 and BDC-10.1 reacted similarly to b cell membrane extracts, weakly to the WE14 peptide but not to the vasostatin-1-derived peptide ChgA [29][30][31][32][33][34][35][36][37][38][39][40][41][42] or to the ChgA 410-423 , the only ChgA peptide eluted from I-A g7 molecules expressed on Nit-1 insulinoma ( Fig. 2A-D) (36). Both clones also responded strongly to the pS3 mimotope SRLGLWVRME, as previously reported (Fig.…”

Section: Tssp-deficient Bm-derived Apcs Induce the Deletion Of Chga-rmentioning

confidence: 80%

The T Cell Repertoire–Diversifying Enzyme TSSP Contributes to Thymic Selection of Diabetogenic CD4 T Cell Specificities Reactive to ChgA and IAPP Autoantigens

Viret

Mahiddine

Baker

et al. 2015

The Journal of Immunology

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Multiple studies highlighted the overtly self-reactive T cell repertoire in the diabetes-prone NOD mouse. This autoreactivity has primarily been linked to defects in apoptosis induction during central tolerance. Previous studies suggested that thymus-specific serine protease (TSSP), a putative serine protease expressed by cortical thymic epithelial cells and thymic dendritic cells, may edit the repertoire of self-peptides presented by MHC class II molecules and shapes the self-reactive CD4 T cell repertoire. To gain further insight into the role of TSSP in the selection of self-reactive CD4 T cells by endogenous self-Ags, we examined the development of thymocytes expressing distinct diabetogenic TCRs sharing common specificity in a thymic environment lacking TSSP. Using mixed bone marrow chimeras, we evaluated the effect of TSSP deficiency confined to different thymic stromal cells on the differentiation of thymocytes expressing the chromogranin A–reactive BDC-2.5 and BDC-10.1 TCRs or the islet amyloid polypeptide–reactive TCR BDC-6.9 and BDC-5.2.9. We found that TSSP deficiency resulted in deficient positive selection and induced deletion of the BDC-6.9 and BDC-10.1 TCRs, but it did not affect the differentiation of the BDC-2.5 and BDC-5.2.9 TCRs. Hence, TSSP has a subtle role in the generation of self-peptide ligands directing diabetogenic CD4 T cell development. These results provide additional evidence for TSSP activity as a novel mechanism promoting autoreactive CD4 T cell development/accumulation in the NOD mouse.

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First Signature of Islet β-Cell-Derived Naturally Processed Peptides Selected by Diabetogenic Class II MHC Molecules

Cited by 53 publications

References 46 publications

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

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

Autophagy in MHC Class II Presentation of Endogenous Antigens

The T Cell Repertoire–Diversifying Enzyme TSSP Contributes to Thymic Selection of Diabetogenic CD4 T Cell Specificities Reactive to ChgA and IAPP Autoantigens

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