C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

Wang, Yang; Sosinowski, Tomasz; Novikov, Andrey; Crawford, Frances; Neau, David; Yang, Junbao; Kwok, William W.; Marrack, Philippa; Kappler, John W.; Dai, Shaodong

doi:10.1073/pnas.1716527115

Cited by 38 publications

(73 citation statements)

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“…In rodents and humans, certain MHCII alleles (IA g7 in mice, RT2 u in rats, and HLA-DQ8 or HLA-DQ2 in humans) pose a high risk for developing the disease (reviewed in Marrack and Kappler, 2012 ; Mullen, 2017 ). Over several decades, numerous CD4 T cell clones in mice and humans have been identified whose MHCII-presented pancreatic epitopes map to several pancreatic β cell granule proteins; however, as with other autoimmune diseases, natural peptides derived from these proteins were often either inactive or only weakly active in stimulating the clones ( Dallas-Pedretti et al, 1995 ; Stadinski et al, 2010a , b ; Wang et al, 2018 ). Recently, we and others have reported highly stimulatory versions of these peptides in which certain amino acids in the natural peptide have been replaced with other amino acids sometimes derived from the same or different pancreatic proteins ( Babon et al, 2016 ; Crawford et al, 2011 ; Delong et al, 2016 ; Jin et al, 2015 ; Stadinski et al, 2010a , b ; Wang et al, 2018 , 2019 ; Wiles et al, 2017 ; Yang et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…We have argued ( Jin et al, 2015 ; Wang et al, 2018 , 2019 ) that transpeptidation in the lysosome/endosome compartment is a likely mechanism for generating chimeric epitopes for MHCII, since these organelles contain many cysteine/serine proteases capable of mediating the reaction and, moreover, are the location where most peptides destined for presentation by MHCII are produced. Furthermore, in β cells and other neuroendocrine cells, secretory granules that contain high concentrations of the relevant protein precursors of potential autoantigen epitopes continuously turn over by the process of crinophagy, in which the granules fuse with lysosomes and their contents are degraded by these proteases ( Boudier and Picard, 1976 ; Sandberg and Borg, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

Reed

Crawford

Hill

et al. 2020

Journal of Experimental Medicine

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The identification of the peptide epitopes presented by major histocompatibility complex class II (MHCII) molecules that drive the CD4 T cell component of autoimmune diseases has presented a formidable challenge over several decades. In type 1 diabetes (T1D), recent insight into this problem has come from the realization that several of the important epitopes are not directly processed from a protein source, but rather pieced together by fusion of different peptide fragments of secretory granule proteins to create new chimeric epitopes. We have proposed that this fusion is performed by a reverse proteolysis reaction called transpeptidation, occurring during the catabolic turnover of pancreatic proteins when secretory granules fuse with lysosomes (crinophagy). Here, we demonstrate several highly antigenic chimeric epitopes for diabetogenic CD4 T cells that are produced by digestion of the appropriate inactive fragments of the granule proteins with the lysosomal protease cathepsin L (Cat-L). This pathway has implications for how self-tolerance can be broken peripherally in T1D and other autoimmune diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

Reed

Crawford

Hill

et al. 2020

Journal of Experimental Medicine

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“…Other modifications of (pro)insulin, such as deamidation of C‐peptide and covalent cross‐linking of proinsulin peptides to other peptides (insulin hybrid peptides), are targets of T cell responses. More recently, Wang et al showed that mutations at the C‐terminal end of the insulin epitope B9:23 dramatically improved presentation to pathogenic T cells, suggesting PTM‐like transpeptidation as another potential mechanism to create pathogenic epitopes in T1D …”

Section: Discussionmentioning

confidence: 99%

Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies

Strollo

Vinci

Napoli

et al. 2019

Diabetes Metabolism Res

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Background: Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INS-Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB). Methods: We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AABpositive (AAB + ) children from the general population (median follow-up 8.8 years). Results: oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INS-Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA-2A (P = 0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA + children. Risk for diabetes was higher (P = 0.03) among multiple AAB + who were also oxPTM-INS-Ab + compared with those who were oxPTM-INS-Ab -. Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab + in combination with GADA + and IA-2A + , compared with 84.37% in those with IAA + , GADA + , and IA-2A + (P = 0.04).Conclusions: Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB + children.

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“…Interestingly, in the context of T1D the identification of neoepitopes opened new perspectives in the field. The peptides characterized by improved MHC binding register, such as the insulin peptide InsB 9−23 with combined substitutions in positions 14, 21, and 22 ( 122 ), those generated by fusion of peptides, such as the Hybrid Insulin Peptides (HIPs) ( 123 ), or by aberrant translation, such as INS-DriP peptide ( 124 ), have been shown to trigger strong specific T cell responses. These highly immunogenic peptides presented by tolDC are promising tools for the reprogramming of pathogenic T cells and induction of tolerance in T1D.…”

Section: Cell-based Approachesmentioning

confidence: 99%

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

Passerini

Gregori

2020

Front. Immunol.

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The development of novel approaches to control unwanted immune responses represents an ambitious goal in the management of a number of clinical conditions, including autoimmunity, autoinflammatory diseases, allergies and replacement therapies, in which the T cell response to self or non-harmful antigens threatens the physiological function of tissues and organs. Current treatments for these conditions rely on the use of non-specific immunosuppressive agents and supportive therapies, which may efficiently dampen inflammation and compensate for organ dysfunction, but they require lifelong treatments not devoid of side effects. These limitations induced researchers to undertake the development of definitive and specific solutions to these disorders: the underlying principle of the novel approaches relies on the idea that empowering the tolerogenic arm of the immune system would restore the immune homeostasis and control the disease. Researchers effort resulted in the development of cell-free strategies, including gene vaccination, protein-based approaches and nanoparticles, and an increasing number of clinical trials tested the ability of adoptive transfer of regulatory cells, including T and myeloid cells. Here we will provide an overview of the most promising approaches currently under development, and we will discuss their potential advantages and limitations. The field is teaching us that the success of these strategies depends primarily on our ability to dampen antigen-specific responses without impairing protective immunity, and to manipulate directly or indirectly the immunomodulatory properties of antigen presenting cells, the ultimate in vivo mediators of tolerance.

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C-terminal modification of the insulin B:11–23 peptide creates superagonists in mouse and human type 1 diabetes

Cited by 38 publications

References 42 publications

Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

Lysosomal cathepsin creates chimeric epitopes for diabetogenic CD4 T cells via transpeptidation

Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

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