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

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 & 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

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

Towards a comprehensive characterization of durum wheat landraces in Moroccan traditional agrosystems: analysing genetic diversity in the light of geography, farmers’ taxonomy and tetraploid wheat domestication history

Background: Crop diversity managed by smallholder farmers in traditional agrosystems is the outcome of historical and current processes interacting at various spatial scales, and influenced by factors such as farming practices and environmental pressures. Only recently have studies started to consider the complexity of these processes instead of simply describing diversity for breeding purposes. A first step in that aim is to add multiple references to the collection of genetic data, including the farmers' varietal taxonomy and practices and the historical background of the crop. Results: On the basis of interview data collected in a previous study, we sampled 166 populations of durum wheat varieties in two traditional Moroccan agrosystems, in the Pre-Rif and Atlas Mountains regions. Using a common garden experiment, we detected a high phenotypic variability on traits indicative of taxonomical position and breeding status, namely spike shape and plant height. Populations often combined modern (short) with traditional-like (tall) statures, and classical durum squared spike shape (5 flowers/spikelet) with flat spike shape (3 flowers/spikelet) representative of primitive domesticated tetraploid wheat (ssp. dicoccum). By contrast, the genetic diversity assessed using 14 microsatellite markers was relatively limited. When compared to the genetic diversity found in a large collection of tetraploid wheat, it corresponded to free-threshing tetraploid wheat. Within Morocco, the two studied regions differed for both genetic diversity and variety names. Within regions, neither geography nor variety names nor even breeding status constituted strong barriers to gene exchange despite a few significant patterns. Conclusions: This first assessment of morphological and genetic diversity allowed pointing out some important factors that may have influenced the structure and evolutionary dynamics of durum wheat in Morocco: the significance of variety names, the occurrence of mixtures within populations, the relative strength of seed exchange between farmers and local adaptation, as well as the fate of modern varieties once they have been introduced. Further, multidisciplinary studies at different spatial scales are needed to better understand these complex agrosystems of invaluable importance for food security

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

An autosomal dominant major gene confers predisposition to pulmonary tuberculosis in adults

The molecular basis of genetic predisposition to pulmonary tuberculosis in adults remains largely elusive. Few candidate genes have consistently been implicated in tuberculosis susceptibility, and no conclusive linkage was found in two previous genome-wide screens. We report here a genome-wide linkage study in a total sample of 96 Moroccan multiplex families, including 227 siblings with microbiologically and radiologically proven pulmonary tuberculosis. A genome-wide scan conducted in half the sample (48 families) identified five regions providing suggestive evidence (logarithm of the odds [LOD] score >1.17; P < 0.01) for linkage. These regions were then fine-mapped in the total sample of 96 families. A single region of chromosome 8q12-q13 was significantly linked to tuberculosis (LOD score = 3.49; P = 3 × 10−5), indicating the presence of a major tuberculosis susceptibility gene. Linkage was stronger (LOD score = 3.94; P = 10−5) in the subsample of 39 families in which one parent was also affected by tuberculosis, whereas it was much lower (LOD score = 0.79) in the 57 remaining families without affected parents, supporting a dominant mode of inheritance of the major susceptibility locus. These results provide direct molecular evidence that human pulmonary tuberculosis has a strong genetic basis, and indicate that the genetic component involves at least one major locus with a dominant susceptibility allele

Impact du relief et des circuits semenciers locaux sur la diversité agro-morphologique du blé dur (Triticum turgidum ssp. durum) dans la vallée d'Er Rich à Imilchil (Maroc)

Phenotypic diversity of 101 durum wheat landrace populations collected from the oasis of the Oriental Atlas Mountains (Morocco) was studied. Nine characters (morphological and agronomic) were measured on the 3030 lines (30 lines per population). The frequencies of each phenotypic class were used for the estimate and the analysis of diversity, by considering the geographical zones of origin and the gradients of altitude. The Shannon-Weaver diversity index (H’) showed a wide variability for all considered traits. This index varies from one area to another and from one altitudinal class to another. The mean H’ recorded for all areas was 0.62, indicating the presence of a high degree of polymorphism among the studied durum wheat landrace populations. The results of the multiple component analysis and the hierarchical clustering showed that the geographical proximity and altitude play a main function in the discrimination and the structure of the studied durum wheat populations. The information gathered from this study could be used in conventional breeding programs and in situ conservation of the diversity.&nbsp;La diversité phénotypique de 101 populations locales de blé dur issues des oasis de montagnes de l’Atlas oriental (Maroc) a été étudiée. Neuf caractères (morphologiques et agronomiques) ont été mesurés sur les 3030 lignées (30 lignées par population). Les fréquences de chaque classe phénotypique ont été utilisées pour l’estimation et l’analyse de la diversité, en considérant les zones géographiques d’origine et les gradients d’altitude. L’indice de diversité de Shannon-Weaver (H’) a montré une forte variabilité pour l’ensemble des caractères considérés. Cet indice varie d’une zone à une autre et d’une classe d’altitude à une autre. Le H’ moyen obtenu pour l’ensemble des zones est de 0,62, indiquant la présence d’un degré élevé de polymorphisme au sein des populations locales de blé dur collectées. Les résultats de l’analyse en composantes multiples ainsi que de la classification hiérarchique ont montré que la proximité géographique et l’altitude jouent un rôle majeur dans la discrimination ainsi que sur la structuration des populations de blé dur étudiées. Les informations recueillies à partir de ces résultats peuvent être exploitées dans des programmes de sélection conventionnels et de conservation in situ de la diversité. Mots clés: Populations locales, diversité phénotypique, structuration, conservation in situ, blé dur (Triticum turgidum ssp. durum)

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