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Article ; Online: Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes.

Bettini, Maria / Bettini, Matthew L

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
Database	MEDical Literature Analysis and Retrieval System OnLINE

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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
Database	MEDical Literature Analysis and Retrieval System OnLINE

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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
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Agrobacterium rhizogenes rolB oncogene: An intriguing player for many roles.

Mauro, Maria Luisa / Bettini, Priscilla P

Plant physiology and biochemistry : PPB

2021 Volume 165, Page(s) 10–18

Abstract: The rolB oncogene is one of the so-called rol genes found in the T-DNA region of the Agrobacterium rhizogenes Ri plasmid and involved in the hairy root syndrome, a tumour characterized by adventitious root overgrowth on plant stem. rolB produces in ... ...

Abstract	The rolB oncogene is one of the so-called rol genes found in the T-DNA region of the Agrobacterium rhizogenes Ri plasmid and involved in the hairy root syndrome, a tumour characterized by adventitious root overgrowth on plant stem. rolB produces in plants a peculiar phenotype that, together with its root-inducing capacity, has been connected to auxin sensitivity. The gene is able to modify the plant genetic programme to induce meristem cells and direct them to differentiate not only roots, but also other cells, tissues or organs. Besides its essential function in hairy root pathogenesis, the rolB role has been progressively extended to cover several physiological aspects in the transgenic plants: from secondary metabolites production and ROS inhibition, to abiotic and biotic stress tolerance and photosynthesis improvement. Some of the observed effects could be determined, at least in part, through microRNAs molecules, suggesting an epigenetic control rolB-mediated. These multifaceted capacities could allow plants to withstand adverse environmental conditions, enhancing fitness. In spite of this expanding knowledge, functional analyses did not detect yet any definitive rolB-derived biochemical product, even if more than one enzymatic activity has been ascribed to it. Moreover, phylogenetic and evolutionary studies evidenced no homology with any plant sequences but, otherwise, it belongs to the Plast family, a group of rolB-homologous bacterial genes. Finally, the finding of sequences similar to rolB in plants not infected by A. rhizogenes suggests a hypothetical plant origin for this gene, implying different possibilities about its evolution.
MeSH term(s)	Agrobacterium/genetics ; Oncogenes ; Phylogeny ; Plants, Genetically Modified ; Rhizobium/genetics
Language	English
Publishing date	2021-05-14
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	742978-2
ISSN	1873-2690 ; 0981-9428
ISSN (online)	1873-2690
ISSN	0981-9428
DOI	10.1016/j.plaphy.2021.04.037
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Article ; Online: Nature vs. nurture: FOXP3, genetics, and tissue environment shape Treg function.

Raugh, Arielle / Allard, Denise / Bettini, Maria

Frontiers in immunology

2022 Volume 13, Page(s) 911151

Abstract: The importance of regulatory T cells (Tregs) in preventing autoimmunity has been well established; however, the precise alterations in Treg function in autoimmune individuals and how underlying genetic associations impact the development and function of ... ...

Abstract	The importance of regulatory T cells (Tregs) in preventing autoimmunity has been well established; however, the precise alterations in Treg function in autoimmune individuals and how underlying genetic associations impact the development and function of Tregs is still not well understood. Polygenetic susceptibly is a key driving factor in the development of autoimmunity, and many of the pathways implicated in genetic association studies point to a potential alteration or defect in regulatory T cell function. In this review transcriptomic control of Treg development and function is highlighted with a focus on how these pathways are altered during autoimmunity. In combination, observations from autoimmune mouse models and human patients now provide insights into epigenetic control of Treg function and stability. How tissue microenvironment influences Treg function, lineage stability, and functional plasticity is also explored. In conclusion, the current efficacy and future direction of Treg-based therapies for Type 1 Diabetes and other autoimmune diseases is discussed. In total, this review examines Treg function with focuses on genetic, epigenetic, and environmental mechanisms and how Treg functions are altered within the context of autoimmunity.
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Diabetes Mellitus, Type 1/immunology ; Forkhead Transcription Factors/genetics ; Humans ; Mice ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	FOXP3 protein, human ; Forkhead Transcription Factors ; Foxp3 protein, mouse
Language	English
Publishing date	2022-08-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.911151
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Article: Increased TCR signaling in regulatory T cells is disengaged from TCR affinity.

Jing, Yi / Kong, Yuelin / Allard, Denise / Liu, Baoyu / Kolawole, Elizabeth / Sprouse, Maran / Evavold, Brian / Bettini, Matthew / Bettini, Maria

bioRxiv : the preprint server for biology

2023

Abstract: Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, TCR affinity and specificities that support Treg function, and how these compare to autoimmune T cells remain unresolved. In this study, we used antigen ... ...

Abstract	Foxp3+ regulatory T cells (Tregs) are capable suppressors of aberrant self-reactivity. However, TCR affinity and specificities that support Treg function, and how these compare to autoimmune T cells remain unresolved. In this study, we used antigen agnostic and epitope-focused analyses to compare TCR repertoires of regulatory and effector T cells that spontaneously infiltrate pancreatic islets of non-obese diabetic mice. We show that effector and regulatory T cell-derived TCRs possess similar wide-ranging reactivity for self-antigen. Treg-derived TCRs varied in their capacity to confer optimal protective function, and Treg suppressive capacity was in part determined by effector TCR affinity. Interestingly, when expressing the same TCR, Tregs showed higher Nur77-GFP expression than Teffs, suggesting Treg-intrinsic ability to compete for antigen. Our findings provide a new insight into TCR-dependent and independent mechanisms that regulate Treg function and indicate a TCR-intrinsic insufficiency in tissue-specific Tregs that may contribute to the pathogenesis of type 1 diabetes.
Language	English
Publishing date	2023-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.17.523999
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Mutational Analysis of

Morini, Maria / Gentilini, Fabio / Turba, Maria Elena / Gobbo, Francesca / Mandrioli, Luciana / Bettini, Giuliano

Veterinary sciences

2022 Volume 9, Issue 7

Abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the canine gastrointestinal tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto- ... ...

Abstract	Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the canine gastrointestinal tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto-oncogenes
Language	English
Publishing date	2022-07-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2768971-2
ISSN	2306-7381 ; 2306-7381
ISSN (online)	2306-7381
ISSN	2306-7381
DOI	10.3390/vetsci9070376
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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: Immunohistochemical Analysis of Olfactory Sensory Neuron Populations in the Developing Olfactory Organ of the Guppy, Poecilia reticulata (Cyprinodontiformes, Poecilidae).

Bettini, Simone / Lazzari, Maurizio / Milani, Liliana / Maurizii, Maria Gabriella / Franceschini, Valeria

Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada

2023 Volume 29, Issue 5, Page(s) 1764–1773

Abstract: Olfaction is fundamental for sensing environmental chemicals and has obvious adaptive advantages. In fish, the peripheral olfactory organ is composed of lamellae in which the olfactory mucosa contains three main categories of olfactory sensory neurons ( ... ...

Abstract	Olfaction is fundamental for sensing environmental chemicals and has obvious adaptive advantages. In fish, the peripheral olfactory organ is composed of lamellae in which the olfactory mucosa contains three main categories of olfactory sensory neurons (OSNs) as follows: ciliated (cOSNs), microvillous (mOSNs), and crypt cells. We studied the appearance of these different OSNs during development of Poecilia reticulata, given its growing use as animal model system. We performed immunohistochemical detection of molecular markers specific for the different OSNs, carrying out image analyses for marked-cell counting and measuring optical density. The P. reticulata olfactory organ did not show change in size during the first weeks of life. The proliferative activity increased at the onset of secondary sexual characters, remaining high until sexual maturity. Then, it decreased in both sexes, but with a recovery in females, probably in relation to their almost double body growth, compared to males. The density of both cOSNs and mOSNs remained constant throughout development, probably due to conserved functions already active in the fry, independently of the sex. The density of calretinin-positive crypt cells decreased progressively until sexual maturity, whereas the increased density of calretinin-negative crypt cell fraction, prevailing in later developmental stages, indicated their probable involvement in reproductive activities.
MeSH term(s)	Animals ; Female ; Male ; Olfactory Receptor Neurons ; Poecilia ; Calbindin 2 ; Olfactory Mucosa
Chemical Substances	Calbindin 2
Language	English
Publishing date	2023-08-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1385710-1
ISSN	1435-8115 ; 1431-9276
ISSN (online)	1435-8115
ISSN	1431-9276
DOI	10.1093/micmic/ozad099
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