Post-translational modifications contribute to neoepitopes in Type-1 diabetes: Challenges for inducing antigen-specific tolerance

Balakrishnan, Sivasangari; Kumar, Prabhakaran; Prabhakar, Bellur S.

doi:10.1016/j.bbapap.2020.140478

Cited by 12 publications

(9 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Until 2015, the UniProt database has recorded 469 PTMs including 326 PTMs in eukaryotes and more than 100 different PTMs in Homo sapiens [147], suggesting a potential clinical research direction for human diseases. It has been proven that PTMs are closely related to the occurrence of human diseases, such as cancer, diabetes, and CVDs [148][149][150]. To this end, it is critical for researchers to carry out biomarker discovery through characterization and quantitation of PTMs.…”

Section: Clinical Perspective and Application Of Ptms In Cvds And Other Diseasesmentioning

confidence: 99%

[Retracted] The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

Liu

Zhong

Guo

2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Cardiovascular disease (CVD) is the leading cause of death in the world. The mechanism behind CVDs has been studied for decades; however, the pathogenesis is still controversial. Mitochondrial homeostasis plays an essential role in maintaining the normal function of the cardiovascular system. The alterations of any protein function in mitochondria may induce abnormal mitochondrial quality control and unexpected mitochondrial dysfunction, leading to CVDs. Posttranslational modifications (PTMs) affect protein function by reversibly changing their conformation. This review summarizes how common and novel PTMs influence the development of CVDs by regulating mitochondrial quality control. It provides not only ideas for future research on the mechanism of some types of CVDs but also ideas for CVD treatments with therapeutic potential.

show abstract

Section: Clinical Perspective and Application Of Ptms In Cvds And Other Diseasesmentioning

confidence: 99%

[Retracted] The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

Liu

Zhong

Guo

2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

show abstract

“…Interestingly, they can also be induced as part of the antigen processing pathways (3)(4)(5). Inflammation or stress-related processes such as viral or oncogenic transformation of cells induces PTMs and an altered repertoire of MHC-associated peptides and has implications for many autoimmune-mediated diseases (6)(7)(8)(9). Since the cellular stress associated with cancer cells can also lead to changes in PTMs (10).…”

Section: Introductionmentioning

confidence: 99%

Vaccine Can Induce CD4-Mediated Responses to Homocitrullinated Peptides via Multiple HLA-Types and Confer Anti-Tumor Immunity

et al. 2022

View full text Add to dashboard Cite

Homocitrullination is the post translation modification (PTM) of the amino acid lysine to homocitrulline also referred to as carbamylation. This PTM has mainly been studied in relation to autoimmune diseases including rheumatoid arthritis. Homocitrullination of lysines alters their charge which can lead to generation of neoepitopes that are differentially presented by MHC-II and induce modification-specific immune responses. Homocitrullination is often considered a process which triggers autoimmune disease by bypassing self-tolerance however, we suggest that homocitrullination may also have an alternative role in immune responses including protection against cancer. Here we demonstrate that immune responses to homocitrullinated peptides from three different proteins can be induced via multiple HLA-types. Immunization of Balb/c or HLA-transgenic DR4 and DR1 mice can induce modification-specific CD4 mediated IFNγ responses. Healthy human donors show a clear repertoire for the homocitrullinated Vimentin peptide (Vim116-135Hcit), with modification-specific and oligoclonal responses. Importantly, in vivo homocitrulline specific Vim116-135Hcit,Cyk8 371-388Hcit and Aldo 140-157Hcit responses are able to confer an anti-tumor effect in the murine B16 melanoma model. The Vim116-135Hcit anti-tumor response was dependent upon tumor expression of MHC-II suggesting the direct recognition of PTMs on tumor is an important anti-tumor mechanism. Cancer patients also have a CD4 repertoire for Vim116-135Hcit. Together these results suggest that homocitrulline-specific immune responses can be generated in healthy mice and detected in human donors through a variety of HLA-restrictions. Immunization can induce responses to Vim116-135Hcit,Aldolase 140-157Hcit and Cyk8 371-388Hcit which provide anti-tumor therapy across several HLA-types. Our results advance our understanding of homocitrulline-specific immune responses, with implications for a number of fields beyond autoimmunity, including tumor immune surveillance.

show abstract

“…Building new SABR-II libraries based on tissue-specific gene expression may benefit by casting a wider net in search of cognate epitopes. In addition, a hallmark of numerous autoreactive diseases is the reactivity to post-translationally modified epitopes 61,62 . While we were able to encode hybrid and deamidated epitopes in our SABR-II libraries, we are developing approaches to incorporate a wider range of chemical modifications.…”

Section: Discussionmentioning

confidence: 99%

De novo identification of CD4+ T cell epitopes

Zdinak

Grebinoski

Torrey

et al. 2022

Preprint

View full text Add to dashboard Cite

CD4+ T cells recognize peptide antigens presented on class II Major Histocompatibility Complex (MHC-II) molecules to carry out their function. The remarkable diversity of T cell receptor (TCR) sequences and lack of antigen discovery approaches for MHC-II make profiling the specificities of CD4+ T cells challenging. We have expanded our platform of Signaling and Antigen-presenting Bifunctional Receptors to encode MHC-II molecules presenting covalently linked peptides (SABR-IIs) for CD4+ cell antigen discovery. SABR-IIs can present epitopes to CD4+ T cells and induce signaling upon their recognition, allowing a readable output. Here, we demonstrate that SABR-IIs libraries presenting endogenous and post-translationally modified epitopes can be used for antigen discovery. Using SABR-II libraries in conjunction with single cell RNA sequencing, we de-convoluted multiple highly expanded TCRs from pancreatic islets of Non-Obese Diabetic (NOD) mice. We compounded antigen discovery by incorporating computational TCR similarity prediction metrics followed by experimental validation. Finally, we showed SABR-IIs presenting epitopes in class II HLA alleles can be used for antigen discovery for human CD4+ T cells. Taken together, we have developed a rapid, flexible, scalable, and versatile approach for the de novo identification of CD4+ T cell ligands from single cell RNA sequencing data using experimental and computational approaches.

show abstract

Post-translational modifications contribute to neoepitopes in Type-1 diabetes: Challenges for inducing antigen-specific tolerance

Cited by 12 publications

References 72 publications

[Retracted] The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

[Retracted] The Role of Posttranslational Modification and Mitochondrial Quality Control in Cardiovascular Diseases

Vaccine Can Induce CD4-Mediated Responses to Homocitrullinated Peptides via Multiple HLA-Types and Confer Anti-Tumor Immunity

De novo identification of CD4+ T cell epitopes

Contact Info

Product

Resources

About