Identification of Hybrid Insulin Peptides (HIPs) in Mouse and Human Islets by Mass Spectrometry

Wiles, Timothy A.; Powell, Roger; Michel, Cole; Beard, K. Scott; Hohenstein, Anita C.; Bradley, Brenda J.; Reisdorph, Nichole; Haskins, Kathryn; Delong, Thomas

doi:10.1021/acs.jproteome.8b00875

Cited by 64 publications

(53 citation statements)

References 45 publications

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“…To establish the role of HIPs as naturally‐occurring T cell ligands, their presence in beta cell extracts had to be verified. Utilizing mass spectrometric analyses on islet cell extracts of both NOD mice and non‐autoimmune BALB/c mice, the presence of both peptides, 2.5HIP and 6·9HIP, was confirmed. More recently, it was also verified that HIPs are present in primary human islets from non‐diabetic organ donors .…”

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 94%

“…Utilizing mass spectrometric analyses on islet cell extracts of both NOD mice and non‐autoimmune BALB/c mice, the presence of both peptides, 2.5HIP and 6·9HIP, was confirmed. More recently, it was also verified that HIPs are present in primary human islets from non‐diabetic organ donors . In addition, Gonzales‐Duque et al reported on the identification of several putative hybrid peptides presented by human leucocyte antigen (HLA) class I on the surface of a human beta cell line .…”

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 94%

“…This need is highlighted by the highly disparate results reported in two of the works discussed here: Liepe et al estimated that cis‐spliced peptides constitute more than 30% of the peptide sequences displayed on the cell surface by MHC class I molecules , while Mylonas et al estimated that this value should be 2–6% . In the recent report by Wiles et al on the identification of HIPs in mouse and human islets , several strict criteria for validating mass spectrometry‐based HIP identifications were proposed, allowing a high degree of confidence in the identification of HIPs. More work in this area is needed in order to enable the confident identification of HIPs and spliced peptides by mass spectrometry.…”

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 99%

“…In an analysis by Wiles et al . , primary mouse and human islets were analysed by mass spectrometry to identify HIPs. This study was focused on establishing rigorous validation guidelines, thus a limited HIP database design was used in which only insulin C‐peptide fragments were considered as N‐terminal precursors and a limited number of potential protein cleavage products were considered as C‐terminal precursors.…”

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 99%

“…As pointed out in a recent review , validation in peptidomics studies, where identifications are often based on confidence in an interpretation of a single spectrum, is more critical than in traditional proteomics studies where identification of a protein is based on the detection of several spectra corresponding to different peptides of the same protein. Furthermore, because hybrid peptides often differ from genomically encoded sequences by only a few amino acid residues, a single spectrum can in some cases be matched with similar confidence to both a spliced and a non‐spliced sequence . Reliable, broadly implementable protocols for identifying spliced and hybrid peptides using tandem mass spectrometry data must be established.…”

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 99%

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HIPs and HIP-reactive T cells

Wiles

Delong

2019

Clinical and Experimental Immunology

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Mounting evidence implicates hybrid insulin peptides (HIPs) as important autoantigens in the development of type 1 diabetes (T1D). These fusion peptides formed between insulin and other pancreatic beta cell-derived peptides contain non-genomically encoded amino acid sequences, making them plausible targets for autoreactive T cells in T1D. HIPs are detectable by mass spectrometry in human and murine islets and are targeted by diabetes-inducing T cells in non-obese diabetic mice as well as by T cells isolated from the residual pancreatic islets of human organ donors with T1D. The discovery of HIPs comes with numerous new challenges, as well as opportunities to study the pathogenesis of T1D. Here we review the original discovery of HIPs and describe recent studies investigating the role of HIP-reactive T cells in the development of diabetes.We also discuss potential mechanisms that may be responsible for the generation of HIPs in beta cells and describe challenges that need to be addressed in the field of mass spectrometry to enable the discovery of new HIPs. The identification of these potentially disease-driving antigens in T1D is of key interest to the field as it may provide new tools to predict, prevent and potentially reverse the disease.

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Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 94%

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 94%

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 99%

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 99%

Section: Discovery Of Hips Utilizing Mass Spectrometrymentioning

confidence: 99%

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HIPs and HIP-reactive T cells

Wiles

Delong

2019

Clinical and Experimental Immunology

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Antigen Presentation to Lymphocytes

Muharemagic

Scott

Mishto

2019

Encyclopedia of Life Sciences

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Antigen presentation to T and B lymphocytes by antigen‐presenting cells plays a central role in the initiation and regulation of adaptive immune responses. T cells recognise peptides in the context of major histocompatibility complex (MHC) molecules via T cell receptors (TCRs). In contrast, B cells recognise and bind proteins via membrane‐bound immunoglobulins, known as B cell receptors (BCRs). Which epitopes are recognised by TCRs and BCRs has a major impact on the cell‐mediated immune response. Key Concepts T lymphocytes are key players in the adaptive immune response. T lymphocytes need professional antigen‐presenting cells (APCs) to be primed. Upon priming, T cell activation does not need professional APCs. CD8 + T cells mediate the cytotoxic response against infected cells. CD8 + T cells can mediate the cytotoxic response against cancer cells. T cell receptor αβ (TCR αβ) recognises complexes formed by major histocompatibility complex (MHC) molecules and antigenic peptides. After several steps of the antigen processing and presentation (APP) pathway, antigenic peptides are presented by MHC molecules to T cells. An antigenic peptide that triggers a T cell activation is defined as an ‘epitope’. Unconventional epitopes such as posttranslationally spliced epitopes can trigger a T cell response.

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Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

et al. 2021

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Objective. Type 1 diabetes (T1D) is an autoimmune disorder in which autoreactive T cells destroy insulin-producing β-cells. Interventions that preserve β-cell function represent a fundamental therapeutic goal in T1D and biomarkers that predict and monitor β-cell function, and changes in islet autoantigenic signatures are needed. As proinsulin and neoantigens derived from proinsulin peptides (hybrid insulin peptides, HIPs) are important T1D autoantigens, we analysed peripheral blood CD4 + T-cell autoantigen-specific proliferative responses and their relationship to estimated β-cell function. Methods. We recruited 72 people with and 42 without T1D, including 17 pre-diabetic islet antibody-positive and 9 antibody-negative first-degree relatives and 16 unrelated healthy controls with T1D-risk HLA types. We estimated C-peptide level at 3-month intervals for 2 years postdiagnosis and measured CD4 + T-cell proliferation to proinsulin epitopes and HIPs using an optimised bioassay. Results. We show that CD4 + T-cell proliferation to any islet peptide and to multiple epitopes were significantly more frequent in pre-diabetic islet antibody-positive siblings and participants with T1D ≤ 3 months of duration, than in participants with T1D > 3 months or healthy controls. Among participants with T1D and first-degree relatives, CD4 + T-cell proliferation occurred most frequently in response to proinsulin 33-63 (full-length C-peptide). Proinsulin 33-63 -specific responses were associated with HLA-DR3-DQ2 and/or HLA-DR4/ DQ8. In children with T1D, proinsulin 33-63 -specific T-cell proliferation positively associated with concurrent estimated Cpeptide and predicted survival in honeymoon. Conclusion. CD4 + Tcell proliferative responses to proinsulin-containing autoantigens are common before and immediately after diagnosis of T1D but decline thereafter. Proinsulin 33-63 -specific CD4 + T-cell response is a novel marker of estimated residual endogenous β-cell function and predicts a better 2-year disease outcome.

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Identification of Hybrid Insulin Peptides (HIPs) in Mouse and Human Islets by Mass Spectrometry

Cited by 64 publications

References 45 publications

HIPs and HIP-reactive T cells

HIPs and HIP-reactive T cells

Antigen Presentation to Lymphocytes

Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

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