Promiscuous binding of proinsulin peptides to Type 1 diabetes-permissive and -protective HLA class II molecules

Astill, Thomas P.; Ellis, Richard J.; Arif, Sefina; Tree, Timothy; Peakman, Mark

doi:10.1007/s00125-003-1070-3

Cited by 21 publications

(18 citation statements)

References 36 publications

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“…We emphasize these results because other studies, including an early one from our laboratory (34), claimed the contrary, that there was a noticeable lack of specificity of I-A g7 or DQ8 molecules for peptides (24,30,31). These data were obtained by examining synthetic peptides or phage display libraries thought to represent the antigenic epitopes and equivalent to the natural peptides.…”

Section: Discussionmentioning

confidence: 62%

“…Concerning the peptide binding motif for DQ8 and DQ2, some reports suggested the preference for an acidic P9 anchor, while others did not (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Moreover, recent reports examining binding with synthetic peptides indicated that the murine and human diabetogenic molecules bound epitopes of various specificity (24,30,31).…”

Section: Introductionmentioning

confidence: 99%

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Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

Suri

Walters

Gross

et al. 2005

Journal of Clinical Investigation

131

144

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In this study, a large number of naturally processed peptides was isolated and identified from the human diabetes-susceptible class II MHC molecules HLA-DQ8 (DQA1*0301,DQB1*0302) and from murine I-A g7 species, both of which are expressed in genetically identical APC lines. The peptides presented during the processing of autologous proteins were highly selective in showing sequence specificity, mainly consisting of 1 or more acidic residues at their C terminus. Testing for binding to the MHC molecules revealed that the position 9 (P9) acidic residues of the peptides contributed decisively to binding. For HLA-DQ8, the P1 residue, which was also an acidic amino acid, influenced binding positively. Both HLA-DQ8 and I-A g7 selected for common peptides that bound in the same register. There was no evidence for selection of peptides having nonspecific or promiscuous binding. Thus, diabetogenic class II MHC molecules are highly selective in terms of the peptides presented by their APCs, and this is governed by the features of their P9 anchor pocket. These results are in striking contrast to those from studies examining synthetic peptide or phage display libraries, in which many peptides were shown to bind.

show abstract

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

Suri

Walters

Gross

et al. 2005

Journal of Clinical Investigation

131

144

View full text Add to dashboard Cite

show abstract

“…Models of affinity, competition, and determinant capture are consistent with these mechanisms and have been proposed to explain the genetic protection from HLA molecules (41,42). For example, the heterodimer encoded by DQA1*01:02-DQB1*06:02 displays high stability and increased ability to bind diabetogenic self-epitopes compared with predisposing molecules (43–46). These mechanisms, and ultimately whether certain HLA molecules protect from T1D or increase risk, may also be linked to variation in the density of expression of HLA-DQ molecules on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

HLA-DRB115:01-DQA101:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Pugliese

Boulware

et al. 2016

Diabetes

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The HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype is linked to protection from the development of type 1 diabetes (T1D). However, it is not known at which stages in the natural history of T1D development this haplotype affords protection. We examined a cohort of 3,358 autoantibody-positive relatives of T1D patients in the Pathway to Prevention (PTP) Study of the Type 1 Diabetes TrialNet. The PTP study examines risk factors for T1D and disease progression in relatives. HLA typing revealed that 155 relatives carried this protective haplotype. A comparison with 60 autoantibody-negative relatives suggested protection from autoantibody development. Moreover, the relatives with DRB1*15:01-DQA1*01:02-DQB1*06:02 less frequently expressed autoantibodies associated with higher T1D risk, were less likely to have multiple autoantibodies at baseline, and rarely converted from single to multiple autoantibody positivity on follow-up. These relatives also had lower frequencies of metabolic abnormalities at baseline and exhibited no overall metabolic worsening on follow-up. Ultimately, they had a very low 5-year cumulative incidence of T1D. In conclusion, the protective influence of DRB1*15:01-DQA1*01:02-DQB1*06:02 spans from autoantibody development through all stages of progression, and relatives with this allele only rarely develop T1D.

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“…Steiner, University of Chicago, Chicago, Illinois, USA) was cloned into a pET-12a vector (Novagen Inc., Madison, Wisconsin, USA) modified to include a 6-histidine purification tag and biotinylation sequence at the 5′ end. It was then transformed into BLR(DE3)pLysS-competent cells (Novagen Inc.) for expression and purification under denaturing conditions, followed by refolding using a glutathione redox reaction (17) and confirmation of correct folding by analysis of V8 protease-digestion products (18 (19). Binding affinity was expressed as IC 50 , determined as that required to inhibit binding of 2.5 µM biotinylated indicator peptide 50%.…”

Section: Methodsmentioning

confidence: 99%

Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

Arif¹,

Tree²,

Astill³

et al. 2004

J. Clin. Invest.

238

309

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Promiscuous binding of proinsulin peptides to Type 1 diabetes-permissive and -protective HLA class II molecules

Cited by 21 publications

References 36 publications

Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

HLA-DRB115:01-DQA101:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

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Promiscuous binding of proinsulin peptides to Type 1 diabetes-permissive and -protective HLA class II molecules

Cited by 21 publications

References 36 publications

Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

Natural peptides selected by diabetogenic DQ8 and murine I-Ag7 molecules show common sequence specificity

HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression

Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

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HLA-DRB115:01-DQA101:02-DQB1*06:02 Haplotype Protects Autoantibody-Positive Relatives From Type 1 Diabetes Throughout the Stages of Disease Progression