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Article ; Online: Early-life microbiota-immune homeostasis.

Reynolds, Hayley M / Bettini, Matthew L

2023 Volume 14, Page(s) 1266876

Abstract: As the prevalence of allergy and autoimmune disease in industrialized societies continues to rise, improving our understanding of the mechanistic roles behind microbiota-immune homeostasis has become critical for informing therapeutic interventions in ... ...

Abstract	As the prevalence of allergy and autoimmune disease in industrialized societies continues to rise, improving our understanding of the mechanistic roles behind microbiota-immune homeostasis has become critical for informing therapeutic interventions in cases of dysbiosis. Of particular importance, are alterations to intestinal microbiota occurring within the critical neonatal window, during which the immune system is highly vulnerable to environmental exposures. This review will highlight recent literature concerning mechanisms of early-life microbiota-immune homeostasis as well as discuss the potential for therapeutics in restoring dysbiosis in early life.
MeSH term(s)	Infant, Newborn ; Humans ; Probiotics/therapeutic use ; Dysbiosis ; Microbiota ; Gastrointestinal Microbiome ; Homeostasis
Language	English
Publishing date	2023-10-23
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1266876
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Article ; Online: Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes.

Bettini, Maria / Bettini, Matthew L

Diabetes

2021 Volume 70, Issue 6, Page(s) 1211–1219

Abstract: Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell ( ... ...

Abstract	Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Treg-based therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.
MeSH term(s)	Animals ; Autoimmunity/physiology ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Diabetes Mellitus, Type 1/pathology ; Diabetes Mellitus, Type 1/therapy ; Endocrinology/methods ; Endocrinology/trends ; Humans ; Immune Tolerance/physiology ; Immunotherapy, Adoptive/methods ; Immunotherapy, Adoptive/trends ; Mice ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/trends ; Pancreas/immunology ; Pancreas/metabolism ; Pancreas/pathology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; T-Lymphocytes, Regulatory/physiology ; T-Lymphocytes, Regulatory/transplantation
Language	English
Publishing date	2021-05-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/dbi18-0058
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Article ; Online: The amphiregulin/EGFR axis has limited contribution in controlling autoimmune diabetes.

Raugh, Arielle / Jing, Yi / Bettini, Matthew L / Bettini, Maria

Scientific reports

2023 Volume 13, Issue 1, Page(s) 18653

Abstract: Conventional immunosuppressive functions of ... ...

Abstract	Conventional immunosuppressive functions of CD4
MeSH term(s)	Animals ; Mice ; Amphiregulin/genetics ; Amphiregulin/metabolism ; Diabetes Mellitus, Type 1/metabolism ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Islets of Langerhans/metabolism ; Mice, Inbred NOD ; T-Lymphocytes, Regulatory
Chemical Substances	Amphiregulin ; ErbB Receptors (EC 2.7.10.1) ; Areg protein, mouse ; EGFR protein, mouse (EC 2.7.10.1)
Language	English
Publishing date	2023-10-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-45738-4
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Article: The Amphiregulin/EGFR axis has limited contribution in controlling autoimmune diabetes.

Raugh, Arielle / Jing, Yi / Bettini, Matthew L / Bettini, Maria

Research square

2023

Abstract: Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in pancreatic ... ...

Abstract	Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in pancreatic islets is unknown. Within the last decade novel tissue repair functions have been ascribed to Tregs. One function is production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, which promotes tissue repair in response to inflammatory or mechanical tissue injury. Whether such pathways are engaged during autoimmune diabetes and promote tissue repair is undetermined. Previously, we observed upregulation of amphiregulin at the transcriptional level was associated with functional Treg populations in the non-obese diabetic (NOD) mouse model of T1D. We postulated that amphiregulin promoted islet tissue repair and slowed the progression of diabetes in NOD mice. Here, we report that islet-infiltrating Tregs have increased capacity to produce amphiregulin and both Tregs and beta cells express EGFR. Moreover, we show that amphiregulin can directly modulate mediators of endoplasmic reticulum (ER) stress in beta cells. Despite this, NOD amphiregulin deficient mice showed no acceleration of spontaneous autoimmune diabetes. Taken together, the data suggest that the ability for amphiregulin to affect the progression of autoimmune diabetes is limited.
Language	English
Publishing date	2023-08-03
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-3204139/v1
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Article ; Online: The amphiregulin/EGFR axis has limited contribution in controlling autoimmune diabetes

Arielle Raugh / Yi Jing / Matthew L. Bettini / Maria Bettini

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 10

Abstract: Abstract Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in ... ...

Abstract	Abstract Conventional immunosuppressive functions of CD4+Foxp3+ regulatory T cells (Tregs) in type 1 diabetes (T1D) pathogenesis have been well described, but whether Tregs have additional non-immunological functions supporting tissue homeostasis in pancreatic islets is unknown. Within the last decade novel tissue repair functions have been ascribed to Tregs. One function is production of the epidermal growth factor receptor (EGFR) ligand, amphiregulin, which promotes tissue repair in response to inflammatory or mechanical tissue injury. However, whether such pathways are engaged during autoimmune diabetes and promote tissue repair is undetermined. Previously, we observed that upregulation of amphiregulin at the transcriptional level was associated with functional Treg populations in the non-obese diabetic (NOD) mouse model of T1D. From this we postulated that amphiregulin promoted islet tissue repair and slowed the progression of diabetes in NOD mice. Here, we report that islet-infiltrating Tregs have increased capacity to produce amphiregulin, and that both Tregs and beta cells express EGFR. Moreover, we show that amphiregulin can directly modulate mediators of endoplasmic reticulum stress in beta cells. Despite this, NOD amphiregulin deficient mice showed no acceleration of spontaneous autoimmune diabetes. Taken together, the data suggest that the ability for amphiregulin to affect the progression of autoimmune diabetes is limited.
Keywords	Medicine ; R ; Science ; Q
Subject code	616 ; 571
Language	English
Publishing date	2023-10-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Host-microbiota interactions shaping T-cell response and tolerance in type 1 diabetes.

Majumdar, Shubhabrata / Lin, Yong / Bettini, Matthew L

Frontiers in immunology

2022 Volume 13, Page(s) 974178

Abstract: Type-1 Diabetes (T1D) is a complex polygenic autoimmune disorder involving T-cell driven beta-cell destruction leading to hyperglycemia. There is no cure for T1D and patients rely on exogenous insulin administration for disease management. T1D is ... ...

Abstract	Type-1 Diabetes (T1D) is a complex polygenic autoimmune disorder involving T-cell driven beta-cell destruction leading to hyperglycemia. There is no cure for T1D and patients rely on exogenous insulin administration for disease management. T1D is associated with specific disease susceptible alleles. However, the predisposition to disease development is not solely predicted by them. This is best exemplified by the observation that a monozygotic twin has just a 35% chance of developing T1D after their twin's diagnosis. This makes a strong case for environmental triggers playing an important role in T1D incidence. Multiple studies indicate that commensal gut microbiota and environmental factors that alter their composition might exacerbate or protect against T1D onset. In this review, we discuss recent literature highlighting microbial species associated with T1D. We explore mechanistic studies which propose how some of these microbial species can modulate adaptive immune responses in T1D, with an emphasis on T-cell responses. We cover topics ranging from gut-thymus and gut-pancreas communication, microbial regulation of peripheral tolerance, to molecular mimicry of islet antigens by microbial peptides. In light of the accumulating evidence on commensal influences in neonatal thymocyte development, we also speculate on the link between molecular mimicry and thymic selection in the context of T1D pathogenesis. Finally, we explore how these observations could inform future therapeutic approaches in this disease.
MeSH term(s)	Autoimmune Diseases/complications ; Diabetes Mellitus, Type 1 ; Gastrointestinal Microbiome ; Humans ; Immune Tolerance ; Infant, Newborn ; Insulin
Chemical Substances	Insulin
Language	English
Publishing date	2022-08-18
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.974178
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Article: Understanding Autoimmune Diabetes through the Prism of the Tri-Molecular Complex.

Bettini, Matthew L / Bettini, Maria

Frontiers in endocrinology

2017 Volume 8, Page(s) 351

Abstract: The strongest susceptibility allele for Type 1 Diabetes (T1D) is human leukocyte antigen (HLA), which supports a central role for T cells as the drivers of autoimmunity. However, the precise mechanisms that allow thymic escape and peripheral activation ... ...

Abstract	The strongest susceptibility allele for Type 1 Diabetes (T1D) is human leukocyte antigen (HLA), which supports a central role for T cells as the drivers of autoimmunity. However, the precise mechanisms that allow thymic escape and peripheral activation of beta cell antigen-specific T cells are still largely unknown. Studies performed with the non-obese diabetic (NOD) mouse have challenged several immunological dogmas, and have made the NOD mouse a key experimental system to study the steps of immunodysregulation that lead to autoimmune diabetes. The structural similarities between the NOD I-A
Language	English
Publishing date	2017-12-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2017.00351
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Article ; Online: A dormant T-cell population with autoimmune potential exhibits low self-reactivity and infiltrates islets in type 1 diabetes.

Kong, Yuelin / Jing, Yi / Allard, Denise / Scavuzzo, Marissa A / Sprouse, Maran L / Borowiak, Malgorzata / Bettini, Matthew L / Bettini, Maria

European journal of immunology

2022 Volume 52, Issue 7, Page(s) 1158–1170

Abstract: The contribution of low-affinity T cells to autoimmunity in the context of polyclonal T-cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a ... ...

Abstract	The contribution of low-affinity T cells to autoimmunity in the context of polyclonal T-cell responses is understudied due to the limitations in their capture by tetrameric reagents and low level of activation in response to antigenic stimulation. As a result, low-affinity T cells are often disregarded as nonantigen-specific cells irrelevant to the immune response. Our study aimed to assess how the level of self-antigen reactivity shapes T-cell lineage and effector responses in the context of spontaneous tissue-specific autoimmunity observed in NOD mice. Using multicolor flow cytometry in combination with Nur77
MeSH term(s)	Animals ; CD4-Positive T-Lymphocytes ; Diabetes Mellitus, Type 1 ; Mice ; Mice, Inbred NOD ; Mice, Transgenic ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-04-22
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149690
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Article ; Online: Antibody-Mediated Targeting of a Hybrid Insulin Peptide Toward Neonatal Thymic Langerin-Positive Cells Enhances T-Cell Central Tolerance and Delays Autoimmune Diabetes.

Lin, Yong / Perovanovic, Jelena / Kong, Yuelin / Igyarto, Botond Z / Zurawski, Sandra / Tantin, Dean / Zurawski, Gerard / Bettini, Maria / Bettini, Matthew L

Diabetes

2022 Volume 71, Issue 8, Page(s) 1735–1745

Abstract: Thymic presentation of self-antigens is critical for establishing a functional yet self-tolerant T-cell population. Hybrid peptides formed through transpeptidation within pancreatic β-cell lysosomes have been proposed as a new class of autoantigens in ... ...

Abstract	Thymic presentation of self-antigens is critical for establishing a functional yet self-tolerant T-cell population. Hybrid peptides formed through transpeptidation within pancreatic β-cell lysosomes have been proposed as a new class of autoantigens in type 1 diabetes (T1D). While the production of hybrid peptides in the thymus has not been explored, due to the nature of their generation, it is thought to be highly unlikely. Therefore, hybrid peptide-reactive thymocytes may preferentially escape thymic selection and contribute significantly to T1D progression. Using an antibody-peptide conjugation system, we targeted the hybrid insulin peptide (HIP) 2.5HIP toward thymic resident Langerin-positive dendritic cells to enhance thymic presentation during the early neonatal period. Our results indicated that anti-Langerin-2.5HIP delivery can enhance T-cell central tolerance toward cognate thymocytes in NOD.BDC2.5 mice. Strikingly, a single dose treatment with anti-Langerin-2.5HIP during the neonatal period delayed diabetes onset in NOD mice, indicating the potential of antibody-mediated delivery of autoimmune neoantigens during early stages of life as a therapeutic option in the prevention of autoimmune diseases.
MeSH term(s)	Animals ; Antibodies ; Autoantigens ; Central Tolerance ; Diabetes Mellitus, Type 1 ; Insulin ; Insulin, Regular, Human ; Mice ; Mice, Inbred NOD ; Peptides ; Thymus Gland
Chemical Substances	Antibodies ; Autoantigens ; Insulin ; Insulin, Regular, Human ; Peptides
Language	English
Publishing date	2022-07-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db21-1069
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Article ; Online: T-Cell Receptor/HLA Humanized Mice Reveal Reduced Tolerance and Increased Immunogenicity of Posttranslationally Modified GAD65 Epitope.

Jing, Yi / Kong, Yuelin / McGinty, John / Blahnik-Fagan, Gabriele / Lee, Thomas / Orozco-Figueroa, Stephanie / Bettini, Matthew L / James, Eddie A / Bettini, Maria

Diabetes

2022 Volume 71, Issue 5, Page(s) 1012–1022

Abstract: Accumulating evidence supports a critical role for posttranslationally modified (PTM) islet neoantigens in type 1 diabetes. However, our understanding regarding thymic development and peripheral activation of PTM autoantigen-reactive T cells is still ... ...

Abstract	Accumulating evidence supports a critical role for posttranslationally modified (PTM) islet neoantigens in type 1 diabetes. However, our understanding regarding thymic development and peripheral activation of PTM autoantigen-reactive T cells is still limited. Using HLA-DR4 humanized mice, we observed that deamidation of GAD65115-127 generates a more immunogenic epitope that recruits T cells with promiscuous recognition of both the deamidated and native epitopes and reduced frequency of regulatory T cells. Using humanized HLA/T-cell receptor (TCR) mice, we observed that TCRs reactive to the native or deamidated GAD65115-127 led to efficient development of CD4+ effector T cells; however, regulatory T-cell development was reduced in mice expressing the PTM-reactive TCR, which was partially restored with exogenous PTM peptide. Upon priming, both the native-specific and the deamidated-specific T cells accumulated in pancreatic islets, suggesting that both specificities can recognize endogenous GAD65 and contribute to anti-β-cell responses. Collectively, our observations in polyclonal and single TCR systems suggest that while effector T-cell responses can exhibit cross-reactivity between native and deamidated GAD65 epitopes, regulatory T-cell development is reduced in response to the deamidated epitope, pointing to regulatory T-cell development as a key mechanism for loss of tolerance to PTM antigenic targets.
MeSH term(s)	Animals ; Autoantigens ; Diabetes Mellitus, Type 1 ; Epitopes ; Epitopes, T-Lymphocyte ; HLA-DR4 Antigen ; Islets of Langerhans ; Mice ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Autoantigens ; Epitopes ; Epitopes, T-Lymphocyte ; HLA-DR4 Antigen ; Receptors, Antigen, T-Cell
Language	English
Publishing date	2022-02-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db21-0993
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