Decoding the relationship between cow’s milk proteins and development of type 1 diabetes mellitus

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ABSTRACT

Objective

To analyze in silico the evidence of molecular mimicry between human beta-cell autoantigens and cow’s milk proteins as a potential type 1 diabetes mellitus (T1DM) trigger.

Materials and methods

The in silico analysis was performed using bioinformatics tools to compare the amino acid sequences of cow’s milk proteins (bovine serum albumin [BSA] and beta-lactoglobulin [BLG]) and human beta-cell autoantigens (glutamic acid decarboxylase-65 [GAD-65], insulin, and zinc transporter 8 [ZnT8]). The structural and functional characteristics of the proteins were analyzed to identify potential molecular mimicry mechanisms.

Results

The results of the in silico analysis showed significant sequence similarity between BSA/BLG and GAD-65/human insulin/ZnT8, ranging from 19.64% to 27.27%. The cow’s milk proteins evaluated shared structural features with the beta-cell antigens selected for comparison, indicating a potential for molecular mimicry between these proteins.

Conclusion

The findings of this study provide further evidence for a potential role of cow’s milk proteins in triggering T1DM. The in silico analysis suggests that molecular mimicry mechanisms between cow’s milk proteins and human beta-cell antigens may contribute to the autoimmune response leading to T1DM.

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Most cited references 38

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NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

Morten Nielsen, Vanessa Jurtz, Sinu Paul … (2017)

Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes.

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The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Janet M Wenzlau, Kirstine Juhl, Liping Yu … (2007)

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic beta cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

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Molecular mimicry and autoimmunity

Manuel Andrés Rojas, Paula Restrepo-Jimenez, Diana M Monsalve … (2018)

Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual. However, molecular mimicry is unlikely to be the only underlying mechanism for autoimmune responses; other factors such as breach in central tolerance, non-specific bystander activation, or persistent antigenic stimuli (amongst others) may also contribute to the development of autoimmune diseases. Host genetics, exposure to microbiota and environmental chemicals are additional links to our understanding of molecular mimicry. Our current knowledge of the detailed mechanisms of molecular mimicry is limited by the issues of prolonged periods of latency before the appearance of disease, the lack of enough statistical power in epidemiological studies, the limitations of the potential role of genetics in human studies, the relevance of inbred murine models to the diverse human population and especially the limited technology to systematically dissect the human T-cell repertoire and B-cell responses. Nevertheless, studies on the role of autoreactive T-cells that are generated secondary to molecular mimicry, the diversity of the T-cell receptor repertoires of auto-reactive T-cells, the role of exposure to cryptic antigens, the generation of autoimmune B-cell responses, the interaction of microbiota and chemical adjuvants with the host immune systems all provide clues in advancing our understanding of the molecular mechanisms involved in the evolving concept of molecular mimicry and also may potentially aid in the prevention and treatment of autoimmune diseases.

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Author and article information

Journal

Journal ID (nlm-ta): Arch Endocrinol Metab

Journal ID (iso-abbrev): Arch Endocrinol Metab

Journal ID (publisher-id): aem

Title: Archives of Endocrinology and Metabolism

Publisher: Sociedade Brasileira de Endocrinologia e Metabologia

ISSN (Print): 2359-3997

ISSN (Electronic): 2359-4292

Publication date (Electronic): 13 August 2024

Publication date (Electronic, collection): 2024

Volume: 68

Electronic Location Identifier: e230248

Affiliations

[1 ] orgdiv1Departamento de Saúde orgnameUniversidade Estadual de Santa Cruz Ilhéus BA Brasil original Departamento de Saúde, Universidade Estadual de Santa Cruz, Ilhéus, BA, Brasil

[2 ] orgnamePrograma Saúde da Família Salvador BA Brasil originalPrograma Saúde da Família, Salvador, BA, Brasil

[3 ] orgnamePolytech Nancy France original Ecole Supériuere des Sciences et Technologies de I’Ingénie de Nancy – Polytech Nancy, France

[4 ] orgdiv1Faculdade de Medicina orgnameUniversidade Federal da Bahia Salvador BA Brasil originalFaculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brasil

[5 ] orgnameEscola Bahiana de Medicina e Saúde Pública Salvador BA Brasil originalEscola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brasil

Author notes

Correspondence to: Luis Jesuino de Oliveira Andrade. Universidade Estadual de Santa Cruz, Campus Soane Nazaré de Andrade. Rod. Jorge Amado, Km 16, Salobrinho. 45662-900 – Ilhéus, BA, Brasil. luis_jesuino@ 123456yahoo.com.br

Disclosure: no potential conflict of interest relevant to this article was reported.

Author information

Luís Jesuino de Oliveira Andrade https://orcid.org/0000-0002-7714-0330

Gabriela Correia Matos de Oliveira https://orcid.org/0000-0002-8042-0261

Luísa Correia Matos de Oliveira https://orcid.org/0000-0001-6128-4885

Alcina Maria Vinhaes Bittencourt https://orcid.org/0000-0003-0506-9210

Yvana Baumgarth https://orcid.org/0009-0003-2419-9077

Luís Matos de Oliveira https://orcid.org/0000-0003-4854-6910

Article

Other ID: 00352

DOI: 10.20945/2359-4292-2023-0248

PMC ID: 11460975

SO-VID: ab4e0aba-8b35-40c2-9bc8-3cabe1ab8986

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 14 June 2023

Date accepted : 8 February 2024

Page count

Figures: 12, Tables: 5, Equations: 0, References: 36

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Decoding the relationship between cow’s milk proteins and development of type 1 diabetes mellitus

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ABSTRACT

Objective

Materials and methods

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Most cited references 38

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

Molecular mimicry and autoimmunity

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