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Biomedicines
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GABA, GABA-Receptors, and GAD in Immune System Function and...
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GABA, GABA-Receptors, and GAD in Immune System Function and Their Modulation for Therapeutic Outcomes

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 12158

Special Issue Editor

Dr. Daniel Kaufman

E-Mail Website
Guest Editor
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA
Interests: GAD; GABA and GABA-receptors in the immune system; autoimmune disease; COVID-19

Special Issue Information

Dear Colleagues,

The GABA system, composed of the amino acid GABA, GABA receptors (GABA-Rs), and the GABA synthesizing enzymes glutamic acid decarboxylase (GAD65 and GAD67), plays key roles in neurodevelopment and neurotransmission. Many cells of the immune system also express GABA-Rs, and their activation can modulate immune cell activity and phenotype. Moreover, some cells of the immune system express GAD and secrete GABA, which has immunomodulatory actions. An increasing number of studies have shown that GABA, GABA-Rs, and GAD play roles in autoimmune diseases, type 2 diabetes, cancer, and parasitology. The modulation of the GABA system has been shown to provide treatments for autoimmune diseases, tumors, parasitic infections, type 2 diabetes, and coronavirus infection in preclinical models. The scope of the GABA system involvement in health and disease states is likely to be even broader given that the immune system plays many roles in physiological homeostasis and responses to stress, injury, repair, inflammation, and infection. A key goal is to better understand the roles of the GABA system in the immune system and how it can be modulated to help to achieve beneficial outcomes in preclinical models of disease states and to translate those findings to clinical applications.

This Special Issue of Biomedicines on “The GABA System in Immune System Function and Its Modulation for Therapeutic Outcomes” provides a venue for publishing original research that broadens or provides deeper insights into the role of the GABA system in immune system functions and how GABA-Rs, GABA, and GAD can be modulated to improve outcomes in preclinical disease models and in clinical applications. 

Dr. Daniel Kaufman
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • GABA
  • GABA receptors
  • GAD
  • immune system
  • immunotherapy

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Published Papers (2 papers)

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Research

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17 pages, 3013 KiB  
Article
GABA and Combined GABA with GAD65-Alum Treatment Alters Th1 Cytokine Responses of PBMCs from Children with Recent-Onset Type 1 Diabetes
by Katie E. Heath, Joseph M. Feduska, Jared P. Taylor, Julie A. Houp, Davide Botta, Frances E. Lund, Gail J. Mick, Gerald McGwin, Jr., Kenneth L. McCormick and Hubert M. Tse
Biomedicines 2023, 11(7), 1948; https://doi.org/10.3390/biomedicines11071948 - 10 Jul 2023
Cited by 4 | Viewed by 1898
Abstract
Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic cells. There is a need for the development of novel antigen-specific strategies to delay cell destruction, including combinatorial strategies that do not elicit systemic immunosuppression. Gamma-aminobutyric acid (GABA) [...] Read more.
Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic cells. There is a need for the development of novel antigen-specific strategies to delay cell destruction, including combinatorial strategies that do not elicit systemic immunosuppression. Gamma-aminobutyric acid (GABA) is expressed by immune cells, β-cells, and gut bacteria and is immunomodulatory. Glutamic-acid decarboxylase 65 (GAD65), which catalyzes GABA from glutamate, is a T1D autoantigen. To test the efficacy of combinatorial GABA treatment with or without GAD65-immunization to dampen autoimmune responses, we enrolled recent-onset children with T1D in a one-year clinical trial (ClinicalTrials.gov NCT02002130) and examined T cell responses. We isolated peripheral blood mononuclear cells and evaluated cytokine responses following polyclonal activation and GAD65 rechallenge. Both GABA alone and GABA/GAD65-alum treatment inhibited Th1 cytokine responses over the 12-month study with both polyclonal and GAD65 restimulation. We also investigated whether patients with HLA-DR3-DQ2 and HLA-DR4-DQ8, the two highest-risk human leukocyte antigen (HLA) haplotypes in T1D, exhibited differences in response to GABA alone and GABA/GAD65-alum. HLA-DR4-DQ8 patients possessed a Th1-skewed response compared to HLA-DR3-DQ2 patients. We show that GABA and GABA/GAD65-alum present an attractive immunomodulatory treatment for children with T1D and that HLA haplotypes should be considered. Full article
(This article belongs to the Special Issue GABA, GABA-Receptors, and GAD in Immune System Function and Their Modulation for Therapeutic Outcomes)
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Review

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15 pages, 658 KiB  
Review
The GABA and GABA-Receptor System in Inflammation, Anti-Tumor Immune Responses, and COVID-19
by Jide Tian and Daniel L. Kaufman
Biomedicines 2023, 11(2), 254; https://doi.org/10.3390/biomedicines11020254 - 18 Jan 2023
Cited by 26 | Viewed by 9053
Abstract
GABA and GABAA-receptors (GABAA-Rs) play major roles in neurodevelopment and neurotransmission in the central nervous system (CNS). There has been a growing appreciation that GABAA-Rs are also present on most immune cells. Studies in the fields of [...] Read more.
GABA and GABAA-receptors (GABAA-Rs) play major roles in neurodevelopment and neurotransmission in the central nervous system (CNS). There has been a growing appreciation that GABAA-Rs are also present on most immune cells. Studies in the fields of autoimmune disease, cancer, parasitology, and virology have observed that GABA-R ligands have anti-inflammatory actions on T cells and antigen-presenting cells (APCs), while also enhancing regulatory T cell (Treg) responses and shifting APCs toward anti-inflammatory phenotypes. These actions have enabled GABAA-R ligands to ameliorate autoimmune diseases, such as type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis, as well as type 2 diabetes (T2D)-associated inflammation in preclinical models. Conversely, antagonism of GABAA-R activity promotes the pro-inflammatory responses of T cells and APCs, enhancing anti-tumor responses and reducing tumor burden in models of solid tumors. Lung epithelial cells also express GABA-Rs, whose activation helps maintain fluid homeostasis and promote recovery from injury. The ability of GABAA-R agonists to limit both excessive immune responses and lung epithelial cell injury may underlie recent findings that GABAA-R agonists reduce the severity of disease in mice infected with highly lethal coronaviruses (SARS-CoV-2 and MHV-1). These observations suggest that GABAA-R agonists may provide off-the-shelf therapies for COVID-19 caused by new SARS-CoV-2 variants, as well as novel beta-coronaviruses, which evade vaccine-induced immune responses and antiviral medications. We review these findings and further advance the notions that (1) immune cells possess GABAA-Rs to limit inflammation in the CNS, and (2) this natural “braking system” on inflammatory responses may be pharmacologically engaged to slow the progression of autoimmune diseases, reduce the severity of COVID-19, and perhaps limit neuroinflammation associated with long COVID. Full article
(This article belongs to the Special Issue GABA, GABA-Receptors, and GAD in Immune System Function and Their Modulation for Therapeutic Outcomes)
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