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The Immune Checkpoint HLA-G
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The Immune Checkpoint HLA-G

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (15 April 2022) | Viewed by 16189

Special Issue Editor

Dr. Philippe Moreau

grade E-Mail Website
Guest Editor
1. Commissariat à l'Energie Atomique et aux Energies Alternatives, Direction de la Recherche Fondamentale, Institut de Biologie François Jacob, Service de Recherches en Hémato-Immunologie, 75475 Paris, France
2. Institut de Recherche Saint-Louis, Université de Paris, UMR 976, 75475 Paris, France
3. Hôpital Saint-Louis, 1 Avenue Claude Vellefaux, CEDEX 10, 75475 Paris, France
Interests: immune checkpoints; gene regulation; immunogenetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The immune checkpoint HLA-G is a non-classical HLA-class I molecule primarily expressed in extravillous trophoblast cells; it was first described to play a critical role in protecting the fetus from destruction by the maternal immune system. While HLA-G expression in healthy tissues is restricted to immune-privileged sites, it is upregulated in several pathological situations and may be beneficial (allogenic transplantation, autoimmune diseases) or harmful (cancer, viral and parasitic infections) for patients. Unlike other checkpoints, the interaction of HLA-G with ILT-2 and ILT-4 receptors inhibits all actors and blocks all stages of an immune response, from APC activation and effector priming to the function of fully activated CTLs, NK cells or B cells.

The aim of this Special Issue is to present recent advances in HLA-G regulation and HLA-G function in the context of pregnancy, transplantation, cancer, infectious diseases, chronic inflammatory pathologies and autoimmunity. HLA-G can be considered on its own or in conjunction with other known immune checkpoints. In addition, research papers and review articles on the development of therapeutic and monitoring tools involving HLA-G and its receptors are also of interest.

Dr. Philippe Moreau
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • HLA-G regulation
  • HLA-G function
  • HLA-G/ILT-2/ILT-4 immune checkpoint
  • Pregnancy
  • Transplantation
  • Cancer
  • Infectious diseases
  • Inflammation and autoimmune diseases
  • Therapeutic and monitoring tools

Related Special Issues

Published Papers (5 papers)

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Research

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13 pages, 1237 KiB  
Article
Non-Classical HLA Determinants of the Clinical Response after Autologous Stem Cell Transplantation for Systemic Sclerosis
by Wahid Boukouaci, Pauline Lansiaux, Nathalie C. Lambert, Christophe Picard, Emmanuel Clave, Audrey Cras, Zora Marjanovic, Dominique Farge and Ryad Tamouza
Int. J. Mol. Sci. 2022, 23(13), 7223; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137223 - 29 Jun 2022
Cited by 2 | Viewed by 1646
Abstract
Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the [...] Read more.
Systemic Sclerosis (SSc) is a chronic autoimmune disease with high morbidity and mortality. Autologous Hematopoietic Stem Cell Transplantation (AHSCT) is the best therapeutic option for rapidly progressive SSc, allowing increased survival with regression of skin and lung fibrosis. The immune determinants of the clinical response after AHSCT have yet to be well characterized. In particular, the pivotal role of the Human Leukocyte Antigen (HLA) system is not well understood, including the role of non-classical immuno-modulatory HLA-E and HLA-G molecules in developing tolerance and the role of Natural Killer cells (NK) in the immunomodulation processes. We retrospectively tested whether the genetic and/or circulating expression of the non-classical HLA-E and HLA-G loci, as well as the imputed classical HLA determinants of HLA-E expression, influence the observed clinical response to AHSCT at 12- and 24-month follow-up. In a phenotypically well-defined sample of 46 SSc patients classified as clinical responders or non-responders, we performed HLA genotyping using next-generation sequencing and circulating levels of HLA-G and quantified HLA-E soluble isoforms by ELISA. The -21HLA-B leader peptide dimorphism and the differential expression level of HLA-A and HLA-C alleles were imputed. We observed a strong trend towards better clinical response in HLA-E*01:03 or HLA-G 14bp Del allele carriers, which are known to be associated with high expression of the corresponding molecules. At 12-month post-AHSCT follow-up, higher circulating levels of soluble HLA-E were associated with higher values of modified Rodnan Skin Score (mRSS) (p = 0.0275), a proxy of disease severity. In the non-responder group, the majority of patients carried a double dose of the HLA-B Threonine leader peptide, suggesting a non-efficient inhibitory effect of the HLA-E molecules. We did not find any correlation between the soluble HLA-G levels and the observed clinical response after AHSCT. High imputed expression levels of HLA-C alleles, reflecting more efficient NK cell inhibition, correlated with low values of the mRSS 3 months after AHSCT (p = 0.0087). This first pilot analysis of HLA-E and HLA-G immuno-modulatory molecules suggests that efficient inhibition of NK cells contributes to clinical response after AHSCT for SSc. Further studies are warranted in larger patient cohorts to confirm our results. Full article
(This article belongs to the Special Issue The Immune Checkpoint HLA-G)
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16 pages, 1665 KiB  
Article
HLA-G Is Widely Expressed by Mast Cells in Regions of Organ Fibrosis in the Liver, Lung and Kidney
by Nicolas Mouchet, Nicolas Vu, Bruno Turlin, Nathalie Rioux-Leclercq, Stéphane Jouneau, Michel Samson and Laurence Amiot
Int. J. Mol. Sci. 2021, 22(22), 12490; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212490 - 19 Nov 2021
Cited by 3 | Viewed by 1650
Abstract
We previously demonstrated that mast cells expressing HLA-G are associated with regions of hepatitis C virus-induced liver fibrosis. Here, we aimed to determine whether HLA-G expression in mast cells is specific to viral etiology, the liver, or to the general process of fibrosis. [...] Read more.
We previously demonstrated that mast cells expressing HLA-G are associated with regions of hepatitis C virus-induced liver fibrosis. Here, we aimed to determine whether HLA-G expression in mast cells is specific to viral etiology, the liver, or to the general process of fibrosis. We enumerated HLA-G+ cells and mast cells by the immunohistochemistry of (i) liver blocks from 41 cases of alcoholic cirrhosis, (ii) 10 of idiopathic pulmonary fibrosis (IPF), and (iii) 10 of renal fibrosis. The nature of the HLA-G+ cells was specified by multiplex immunofluorescence using software. More than half of all HLA-G+ cells were mast cells in fibrotic areas of alcoholic cirrhosis and IPF. In the kidneys, subjected to fibrosis, the HLA-G+ cells were indeed mast cells but could not be counted. Moreover, in certain cases of the liver and lung, we observed a number of cellular nodes, which were secondary or tertiary follicles, in which HLA-G was highly expressed by B lymphocytes. In conclusion, HLA-G+ mast cells could be observed in the fibrotic regions of all organs studied. Previous studies suggest a protective role for HLA-G+ mast cells against inflammation and fibrosis. The observed follicles with B lymphocytes that express HLA-G may also reinforce their antifibrotic role. Full article
(This article belongs to the Special Issue The Immune Checkpoint HLA-G)
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Review

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12 pages, 1105 KiB  
Review
Therapeutic Applications of Adeno-Associated Virus (AAV) Gene Transfer of HLA-G in the Eye
by Brian C. Gilger and Matthew L. Hirsch
Int. J. Mol. Sci. 2022, 23(7), 3465; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073465 - 23 Mar 2022
Cited by 8 | Viewed by 2815
Abstract
The purpose of this paper is to review human leukocyte antigen G (HLA-G) in the eye, its role in immune tolerance, and the potential therapeutic use of AAV gene transfer and expression of HLA-G in various ocular tissues. Several studies are reviewed that [...] Read more.
The purpose of this paper is to review human leukocyte antigen G (HLA-G) in the eye, its role in immune tolerance, and the potential therapeutic use of AAV gene transfer and expression of HLA-G in various ocular tissues. Several studies are reviewed that demonstrate efficacy in animal models of disease, including intracorneal delivery of AAV-HLA-G to treat corneal inflammation and prevent corneal graft rejection, subconjunctival injection of AAV-HLA-G for ocular graft vs. host disease and potentially dry eye disease, and intravitreal injection of AAV-HLA-G to inhibit uveitis. Furthermore, due to the anti-vascular function of HLA-G, AAV-HLA-G may be an effective therapy for posterior ocular diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and choroidal neovascularization. Therefore, AAV-mediated gene transfer of HLA-G may be an effective treatment for common immune-mediated, inflammatory, and neovascular diseases of the eye. Full article
(This article belongs to the Special Issue The Immune Checkpoint HLA-G)
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15 pages, 1001 KiB  
Review
HLA-G and Other Immune Checkpoint Molecules as Targets for Novel Combined Immunotherapies
by Fabio Morandi and Irma Airoldi
Int. J. Mol. Sci. 2022, 23(6), 2925; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23062925 - 08 Mar 2022
Cited by 18 | Viewed by 4710
Abstract
HLA-G is an HLA-class Ib molecule that is involved in the establishment of tolerance at the maternal/fetal interface during pregnancy. The expression of HLA-G is highly restricted in adults, but the de novo expression of this molecule may be observed in different hematological [...] Read more.
HLA-G is an HLA-class Ib molecule that is involved in the establishment of tolerance at the maternal/fetal interface during pregnancy. The expression of HLA-G is highly restricted in adults, but the de novo expression of this molecule may be observed in different hematological and solid tumors and is related to cancer progression. Indeed, tumor cells expressing high levels of HLA-G are able to suppress anti-tumor responses, thus escaping from the control of the immune system. HLA-G has been proposed as an immune checkpoint (IC) molecule due to its crucial role in tumor progression, immune escape, and metastatic spread. We here review data available in the literature in which the interaction between HLA-G and other IC molecules is reported, in particular PD-1, CTLA-4, and TIM-3, but also IDO and TIGIT. Clinical trials using monoclonal antibodies against HLA-G and other IC are currently ongoing with cancer patients where antibodies and inhibitors of PD-1 and CTLA-4 showed encouraging results. With this background, we may envisage that combined therapies using antibodies targeting HLA-G and another IC may be successful for clinical purposes. Indeed, such immunotherapeutic protocols may achieve a better rescue of effective anti-tumor immune response, thus improving the clinical outcome of patients. Full article
(This article belongs to the Special Issue The Immune Checkpoint HLA-G)
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28 pages, 648 KiB  
Review
A Critical Assessment of the Association between HLA-G Expression by Carcinomas and Clinical Outcome
by Ricky B. van de Water, Daniëlle Krijgsman, Ruben D. Houvast, Alexander L. Vahrmeijer and Peter J. K. Kuppen
Int. J. Mol. Sci. 2021, 22(15), 8265; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158265 - 31 Jul 2021
Cited by 12 | Viewed by 4476
Abstract
Human leukocyte antigen-G (HLA-G) conveys immunological tolerance at the maternal-foetal interface. HLA-G expression by tumour cells may also play such a role, resulting in tumour immune evasion, making HLA-G a potential target for immunotherapies. The aim of this review was to determine to [...] Read more.
Human leukocyte antigen-G (HLA-G) conveys immunological tolerance at the maternal-foetal interface. HLA-G expression by tumour cells may also play such a role, resulting in tumour immune evasion, making HLA-G a potential target for immunotherapies. The aim of this review was to determine to what extent it is justified that HLA-G expression is considered as a target for immune checkpoint inhibiting therapy by critically assessing the association between HLA-G expression by carcinomas and clinical outcome of patients. The used HLA-G-detecting mAb, HLA-G quantification methods and statistically significant HLA-G-associated clinicopathological parameters are discussed. Tumour HLA-G expression correlated with poor clinical outcome in breast, esophageal, gastric and hepatocellular carcinoma patients. Tumour HLA-G expression was not associated with clinical outcome in ovarian and oral carcinoma patients. Cervical, colorectal, lung, and pancreatic carcinoma patients presented discrepant and therefore inconclusive results regarding the association between tumour HLA-G expression and clinical outcome. These disparities might partly be the result of differences in the methodological approach to quantify HLA-G expression between studies. Therefore, implementation of universal methodological procedures is strongly advised. Overall, HLA-G expression did not univocally result in poor clinical outcome of carcinoma patients. This implies that tumour HLA-G expression is not necessarily part of an inhibited tumour-immune response and tumour progression. Consequently, it remains elusive whether HLA-G expression by carcinomas functions as an immune checkpoint molecule affecting a tumour-immune response. It may also reflect derailed control of gene expression in tumours, with no real functional consequences. Full article
(This article belongs to the Special Issue The Immune Checkpoint HLA-G)
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