Thymic Self-Antigen Expression for the Design of a Negative/Tolerogenic Self-Vaccine against Type 1 Diabetes

Before being able to react against infectious non-self-antigens, the immune system has to be educated in the recognition and tolerance of neuroendocrine proteins, and this critical process essentially takes place in the thymus. The development of the autoimmune diabetogenic response results from a thymus dysfunction in programming central self-tolerance to pancreatic insulin-secreting islet β cells, leading to the breakdown of immune homeostasis with an enrichment of islet β cell reactive effector T cells and a deficiency of β cell-specific natural regulatory T cells (nTreg) in the peripheral T-lymphocyte repertoire. Insulin-like growth factor 2 (IGF-2) is the dominant member of the insulin family expressed during fetal life by the thymic epithelium under the control of the autoimmune regulator (AIRE) gene/protein. Based on the close homology and cross-tolerance between insulin, the primary T1D autoantigen, and IGF-2, the dominant self-antigen of the insulin family, a novel type of vaccination, so-called “negative/tolerogenic self-vaccination”, is currently developed for prevention and cure of T1D. If this approach were found to be effective for reprogramming immunological tolerance in T1D, it could pave the way for the design of negative self-vaccines against autoimmune endocrine diseases, as well as other organ-specific autoimmune diseases

Type 1 Diabetes Immunological Tolerance and Immunotherapy

Type 1 diabetes (T1D) is a chronic autoimmune disorder associated, in genetically susceptible individuals, with the generation and activation of autoreactive CD4+ and CD8+ T cells that infiltrate the pancreas and selectively destroy the insulin-producing β-cells in the islets. The impairment of T-cell tolerance in T1D has been reported at many levels including abnormal self-antigen presentation in the thymus and periphery, autoreactive T-cell resistance to apoptosis, unbalanced immunoregulatory T-cell function, and deregulation of Th1/Th2/Th17 axes. Despite the identification of type1 diabetes-associated autoantigens and their derived CD4+ and CD8+ T-cell epitopes, numerous antigen-specific immunoregulatory therapies have failed when evaluated for their utility in the prevention and treatment of T1D. In this special issue, we invite authors to submit original research and review articles highlighting the recent advances that have broadened our understanding of immunological tolerance and T1D vaccine strategies. Also, we welcome papers that seek to define immunoregulatory properties of T cells to provide new insights as to their potential for clinical use. We are interested in articles that explore salient aspects of T1D-associated tolerance and immunotherapy. Potential topics include, but are not limited to: * T1D-associated central and peripheral tolerance mechanisms * Elucidating the functional impairment in immunoregulatory T-cell function in T1D * New animal models to test and understand dysfunctional immunity in T1D * Identification of new beta islet-specific autoantigens * Development of antigen-based immunotherapeutic strategies to prevent or treat T1D * Clinical trials with novel antigen-specific immunoregulatory therapie

Type I Diabetes-Associated Tolerogenic Properties of Interleukin-2

Type 1 Diabetes (T1D) results from insulin-producing beta cells destruction by diabetogenic T lymphocytes in humans and nonobese diabetic (NOD) mice. The breakdown of tolerance has been associated with a defect in the number and the function of naturally occurring regulatory T cells (nTreg) that are the master player in peripheral tolerance. Gene knockout experiments in mouse models have shown a nonredundant activity of IL-2 related to its critical role in inducing nTreg and controlling peripheral T cell tolerance. Whereas strong evidence has suggested that IL-2 is critically required for nTreg-mediated T1D control, several fundamental questions remain to be addressed. In this paper, we highlight the recent findings and controversies regarding the tolerogenic properties of IL-2 mediated through nTreg. We further discuss a potential link between the immunomodulatory role of interleukin-2 and the pathogenesis of type 1 diabetes

Towards a Rational Design of an Asymptomatic Clinical Herpes Vaccine: The Old, the New, and the Unknown

The best hope of controlling the herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) pandemic is the development of an effective vaccine. However, in spite of several clinical trials, starting as early as 1920s, no vaccine has been proven sufficiently safe and efficient to warrant commercial development. In recent years, great strides in cellular and molecular immunology have stimulated creative efforts in controlling herpes infection and disease. However, before moving towards new vaccine strategy, it is necessary to answer two fundamental questions: (i) why past herpes vaccines have failed? (ii) Why the majority of HSV seropositive individuals (i.e., asymptomatic individuals) are naturally “protected” exhibiting few or no recurrent clinical disease, while other HSV seropositive individuals (i.e., symptomatic individuals) have frequent ocular, orofacial, and/or genital herpes clinical episodes? We recently discovered several discrete sets of HSV-1 symptomatic and asymptomatic epitopes recognized by CD4+ and CD8+ T cells from seropositive symptomatic versus asymptomatic individuals. These asymptomatic epitopes will provide a solid foundation for the development of novel herpes epitope-based vaccine strategy. Here we provide a brief overview of past clinical vaccine trials, outline current progress towards developing a new generation “asymptomatic” clinical herpes vaccines, and discuss future mucosal “asymptomatic” prime-boost vaccines that could optimize local protective immunity

Development of simple and effective PCR based assay to detect PCCA mutation (c.425G > A) among Saudi carriers and functional study of the homozygous PCCA mutations

The aim of this study is to develop a rapid and effective method to screen for Saudi carriers of one of the most common propionic acidemia mutations (c.425G > A) and to study the functional impact of this mutation. Using allele-specific primers, we have developed a qPCR assay that clearly distinguishes heterozygotes from mutated and wild type homozygotes that overcome the dependence on labor-intensive gene sequencing. We show here that (i) qPCR rapid test has strong accuracy in detecting (c.425G > A) mutation in heterozygotes and homozygotes individuals and that the Ct-value cut-offs were estimated to be and 23.37 ± 0.04 (CV-6 %, 95 %CI-7.25) for homozygote, 25.06 ± 0.02 (CV-3.5 %, 95 %CI-7.85) for heterozygote PCCA c.425G > A mutation and 29.55 ± 0.002 (CV-11 %, 95 %CI-1.41) for PCCA wild type; (ii) the incidence of PA heterozygotes/carriers in Saudi population is about 550/100,000; (iii) skin fibroblast assays show that homozygote c.425G > A mutation induced propionyl-CoA carboxylase activity abrogation, (iv) PA patients showed an increased level of propionyl carnitine C3 in blood and 3-hydroxy propionic acid and methyl citrate in urine. Conclusion: qPCR represent an effective strategy to assess for PCCA mutation carriers in the Saudi population and we believe that will help in preventing homozygosity in the population after been implemented in pre-marriage screening program.KFMC research grant.https://www.journals.elsevier.com/saudi-journal-of-biological-scienceshj2023Medical Microbiolog

HLA diversity in Saudi population : high frequency of homozygous HLA alleles and haplotypes

Human leukocyte antigens (HLA) diversity has a tremendous impact on shaping the transplantation practices, transfusion-associated graft versus host disease prevention strategies, and host–pathogen interactions. Here, we conducted a retrospective study of HLA class I and class II homozygosity at allelic and haplotype levels in unrelated individuals genotyped from 2012 to 2016 in a tertiary hospital in the capital of Saudi Arabia. Among 5,000 individuals, 2,773 individuals meet inclusion criteria and were retrospectively analyzed for HLA-A, -B, -C–DRB1, and -DQB1 homozygosity at allelic and haplotype levels. HLA molecular typing was performed using a commercial reverse sequencespecific oligonucleotide (rSSO) kit. We were able to identify 15 HLA-A, 20 HLA-B, 11 HLA-C, 13 HLA-DRB1, and five HLA-DQB1 homozygous alleles demonstrating a very low genetic diversity in the Saudi population. The highest homozygosity in HLA class I was found in locus C followed by A and B (20.3% > 16.1% > 15.5%; p < 0.001) where the most homozygote alleles were A*02 (9.2%), B*51 and B*50 (5.7% and 3.7%), and C*07, C*06, and C*15 (7.2%, 5.48%, and 3.3%) and in HLA class II, the highest homozygosity was found in locus DQB1 compared to DRB1 (31.71% > 19.2%; p < 0.001), with the most common homozygote alleles being DRB1*07 and DRB1*04 (5.33% and 4.2%) and DQB1*02, DQB1*06, and DQB1*03 (13.55%, 7.92%, and 7.64%). The frequency of finding an individual with one homozygote allele was (24.6%), two homozygote alleles (13.5%), three homozygote alleles (4.7%), four homozygote alleles (3.4%), and five alleles were (4.8%). The most frequent homozygote haplotypes are A*23~C*06~B*50~DRB1*07~DQB1*02 and A*02~C*06~B*50~DRB1*07~DQB1*02. This study shows low diversity of both class I and II alleles and haplotypes in the Saudi population, which would have a significant impact on shaping the transplantation practices, transfusion-associated graft versus host disease prevention strategies, and host–pathogen interactions.KFMChttps://www.frontiersin.org/journals/geneticsdm2022Medical Microbiolog

Induction d'une tolérance aux antigènes T-indépendants de type 2 chez la souris adulte à l'aide d'anticorps monoclonaux anti-Ig

Depuis quelques années, la xénotransplantation ou transplantation entre espèces phylogénétiquement distinctes suscite un regain d’intérêt au vu de la pénurie d’organes disponibles pour allogreffes. Cependant, ce type de greffes se heurte au problème du rejet hyperaigu dû aux anticorps préformés interespèces ou anticorps xénoréactifs naturels (XNA). Ces XNA sont généralement dirigés contre des épitopes xénogéniques de nature saccharidique, reconnus comme Ag TI-2 (T-indépendant de type 2), comme l’épitope α-gal exprimé chez tous les mammifères exceptés l’humain et les primates du Nouveau Monde. Différentes approches ont été tentées au sein de notre laboratoire et dans d’autres afin d’éliminer les XNA et leurs cellules productrices. Toutefois, celles-ci ne sont que partiellement efficaces. En effet, l’élimination des XNA est temporaire et liée exclusivement au traitement effectué. Dans ce travail, nous nous sommes particulièrement intéressés, non seulement à l’élimination des XNA, mais également de celle des cellules qui les produisent. Notre approche consiste à éliminer les lymphocytes B matures, identifiés grâce aux caractéristiques de leurs différences phénotypiques, et à bloquer la maturation des cellules immatures au niveau de la moelle osseuse à l’aide d’Ac monoclonaux anti-δ et anti-μ. Il serait donc possible « d’abuser » du système immunitaire en lui présentant un Ag TI-2 ou une xénogreffe au cours de son développement, l’Ag serait alors reconnu comme soi et toléré. Des injections répétées d’anticorps anti-μ chez la souris adulte ont montré, par appauvrissement des cellules IgMfort (cellules B de la zone marginale et B1), que celles-ci sont responsables de la production des IgM-TI2 et des XNA d’isotype IgM et que ce traitement stimule la production des IgG-XNA par les cellules IgDfort résistantes au traitement (cellules B conventionnelles , B2) A l’opposé du traitement avec les Ac anti-μ les injections d’anti-δ ont montré, par l’appauvrissent des celles IgDfort, que les cellules IgDfort sont responsables de la production des IgG-TI-2 et –XNA par les cellules IgMfort résistantes au traitement (cellules B de la zone marginale). Les injections séquentielles d’anticorps anti-δ et anti-μ ont montré un appauvrissement des différentes populations de lymphocytes B et une suppression des Ac IgM et IgG-TI-2 et –XNA sans effet sur la réponse TD. Ce modèle d’injections séquentielles représente donc une approche potentielle pour l’induction de tolérance aux xénogreffes discordantes. Le traitement séquentiel d’anticorps anti-δ et anti-μ a en outré permis l’identification d’une population de lymphocytes B IUgD+IgM- qui échappent à la sélection négative exercée par l’anti-µ et requièrent l’aide des cellules T pour se développer. L’absence d’expression des IgM à la surface de ces cellules est le résultat d’une régulation post-transcriptionelle. En conclusion au cours de cette thèse nous avons développé une méthode efficace d’appauvrissement des XNA et des cellules qui les produisent qui pourrait être utilisé pour inhiber le rejet hyperaigu des xénogreffes discordantes. Nous avons également identifié une nouvelle population de cellules B IgD+IgM- capable d’achpper à la sélection négative exercée par l’anti-µ sur les cellules B immatures IgM+, IgD-Thèse de doctorat en sciences biomédicales (immunologie) -- UCL, 199

Mucosal herpes immunity and immunopathology to ocular and genital herpes simplex virus infections.

Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 &amp; HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed

Mucosal Herpes Immunity and Immunopathology to Ocular and Genital Herpes Simplex Virus Infections

Herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) are amongst the most common human infectious viral pathogens capable of causing serious clinical diseases at every stage of life, from fatal disseminated disease in newborns to cold sores genital ulcerations and blinding eye disease. Primary mucocutaneous infection with HSV-1 &amp; HSV-2 is followed by a lifelong viral latency in the sensory ganglia. In the majority of cases, herpes infections are clinically asymptomatic. However, in symptomatic individuals, the latent HSV can spontaneously and frequently reactivate, reinfecting the muco-cutaneous surfaces and causing painful recurrent diseases. The innate and adaptive mucosal immunities to herpes infections and disease remain to be fully characterized. The understanding of innate and adaptive immune mechanisms operating at muco-cutaneous surfaces is fundamental to the design of next-generation herpes vaccines. In this paper, the phenotypic and functional properties of innate and adaptive mucosal immune cells, their role in antiherpes immunity, and immunopathology are reviewed. The progress and limitations in developing a safe and efficient mucosal herpes vaccine are discussed