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.

Mass Screening for Celiac Disease Among School-aged Children: Toward Exploring Celiac Iceberg in Saudi Arabia.

Objectives: We conducted this mass screening study to determine the prevalence of celiac disease (CD) and characterize the celiac iceberg among Saudi pediatric population in Riyadh, the capital city of Saudi Arabia.

Methods: During the study period (January 2014-June 2016), we have conducted a cross-sectional, mass screening, immunoglobulin A-tissue transglutaminase (TTG-IgA)-based study on 7930 Saudi students from primary and intermediate schools in Riyadh. Students with positive TTG-IgA (>20 U/L) were called in the hospital to undergo a repeat of TTG-IgA; in those with borderline positive TTG-IgA (20-60 U/L), IgA-endomyseal antibody (EMA-IgA) test was performed.

Current trends in negative immuno-synergy between two sexually transmitted infectious viruses: HIV-1 and HSV-1/2.

In the current era of effective anti-retroviral therapy, immuno-compromised patients with HIV-1 infection do live long enough to suffer diseases caused by many opportunistic infections, such as herpes simplex virus type 1 and/or type 2 (HSV-1/2). An estimated two-third of the 40 million individuals that have contracted HIV-1 worldwide are co-infected with HSV-1/2 viruses, the causative agents of ocular oro-facial and genital herpes. The highest prevalence of HIV and HSV-1/2 infections are confined to the same regions of Sub-Saharan Africa.

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.

Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88.

Targeting of the mucosal immune system of the genital tract with subunit vaccines has failed to induce potent and durable local CD8(+) T cell immunity, which is crucial for protection against many sexually transmitted viral pathogens, including HSV type 2 (HSV-2), which causes genital herpes. In this study, we aimed to investigate the potential of a novel lipopeptide/adenovirus type 5 (Lipo/rAdv5) prime/boost mucosal vaccine for induction of CD8(+) T cell immunity to protect the female genital tract from herpes. The lipopeptide vaccine and the rAdv5 vaccine express the immunodominant HSV-2 CD8(+) T cell epitope (gB(498-505)), and both were delivered intravaginally in the progesterone-induced B6 mouse model of genital herpes.

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.

The herpes simplex virus type 1 latency-associated transcript inhibits phenotypic and functional maturation of dendritic cells.

We recently found that the herpes simplex virus-1 (HSV-1) latency-associated transcript (LAT) results in exhaustion of virus-specific CD8⁺ T cells in latently-infected trigeminal ganglia (TG). In this study we sought to determine if this impairment may involve LAT directly and/or indirectly interfering with DC maturation. We found that a small number of HSV-1 antigen-positive DCs are present in the TG of latently-infected CD11c/eYFP mice; however, this does not imply that these DCs are acutely or latently infected.

Discovery of potential diagnostic and vaccine antigens in herpes simplex virus 1 and 2 by proteome-wide antibody profiling.

Routine serodiagnosis of herpes simplex virus (HSV) infections is currently performed using recombinant glycoprotein G (gG) antigens from herpes simplex virus 1 (HSV-1) and HSV-2. This is a single-antigen test and has only one diagnostic application. Relatively little is known about HSV antigenicity at the proteome-wide level, and the full potential of mining the antibody repertoire to identify antigens with other useful diagnostic properties and candidate vaccine antigens is yet to be realized.

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.

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.

HIV-1 infection impairs HSV-specific CD4(+) and CD8(+) T-cell response by reducing Th1 cytokines and CCR5 ligand secretion.

Background: The concept of HIV-1/HSV-negative immunosynergy has recently come to light, which leads us to explore the impact of HIV-1 infection on HSV-specific T-cell immunity.

Methods: : A combination of interferon (IFN)-γ ELISpot and Luminex-based multicytokine profiling assays was used to compare, in a cross-sectional study, the HSV-specific CD4 and CD8 T-cell responses between 20 HIV-1/HSV-coinfected and 12 HIV-1-uninfected/HSV-infected individuals after in vitro restimulation with HSV glycoprotein D (gD) peptide epitopes.

Results: In response to CD4 and CD8 gD peptide epitopes, mean value (±standard errors of the mean) of the different IFN-γ-secreting T cells (ISC) means was significantly reduced in HIV-1/HSV-coinfected individuals (70 ISC ± 10 and 60 ISC ± 8/10 cells) compared with HIV-1-uninfected/HSV-infected individuals (280 ISC ± 25 and 234 ISC ± 23/10 cells, both P < 0.

Engagement of TLR2 reverses the suppressor function of conjunctiva CD4+CD25+ regulatory T cells and promotes herpes simplex virus epitope-specific CD4+CD25- effector T cell responses.

PURPOSE. The authors recently reported that Foxp3(+)CD4(+) CD25(+(Bright)) "natural" regulatory T cells (nT(reg) cells) are abundant in rabbit conjunctiva and suppress herpes simplex virus (HSV)-1-specific CD4(+) and CD8(+) effector T cells (T(eff) cells). However, little is known about the overall regulatory mechanisms of these nT(reg) cells.

The herpes simplex virus type 1 latency-associated transcript can protect neuron-derived C1300 and Neuro2A cells from granzyme B-induced apoptosis and CD8 T-cell killing.

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is the only HSV-1 gene transcript abundantly expressed throughout latency. LAT null mutants have a significantly reduced reactivation phenotype. LAT's antiapoptosis activity is the major LAT factor involved in supporting the wild-type reactivation phenotype.

Nasolacrimal duct closure modulates ocular mucosal and systemic CD4(+) T-cell responses induced following topical ocular or intranasal immunization.

Both topical ocular and topical intranasal immunizations have been reported to stimulate the ocular mucosal immune system (OMIS) and the systemic immune system. Nasolacrimal ducts (NLDs) are the connecting bridges between the OMIS and nasal cavity-associated lymphoid tissue (NALT). These ducts drain topical ocularly administrated solutions into the inferior meatus of the nose to reach the NALT.

Recent advances in multivalent self adjuvanting glycolipopeptide vaccine strategies against breast cancer.

Breast cancer (BrCa) is the second leading cause of cancer-related deaths for women worldwide. Evidence from both patients and mouse cancer models suggests that the simultaneous induction of BrCa-specific CD4(+) T cells, CD8(+) cytotoxic T cells, and antibodies is crucial for providing immune resistance. However, almost all current vaccines address only a single arm of the immune system, which may explain their lack of efficacy.

Asymptomatic human CD4+ cytotoxic T-cell epitopes identified from herpes simplex virus glycoprotein B.

The identification of "asymptomatic" (i.e., protective) epitopes recognized by T cells from herpes simplex virus (HSV)-seropositive healthy individuals is a prerequisite for an effective vaccine.

Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell, CD4+ and CD8+ T cell epitopes.

Molecularly defined synthetic vaccines capable of inducing both antibodies and cellular anti-tumor immune responses, in a manner compatible with human delivery, are limited. Few molecules achieve this target without utilizing external immuno-adjuvants. In this study, we explored a self-adjuvanting glyco-lipopeptide (GLP) as a platform for cancer vaccines using as a model MO5, an OVA-expressing mouse B16 melanoma.

HLA-A*0201-restricted CD8+ cytotoxic T lymphocyte epitopes identified from herpes simplex virus glycoprotein D.

Evidence obtained from both animal models and humans suggests that T cells specific for HSV-1 and HSV-2 glycoprotein D (gD) contribute to protective immunity against herpes infection. However, knowledge of gD-specific human T cell responses is limited to CD4+ T cell epitopes, with no CD8+ T cell epitopes identified to date. In this study, we screened the HSV-1 gD amino acid sequence for HLA-A*0201-restricted epitopes using several predictive computational algorithms and identified 10 high probability CD8+ T cell epitopes.

Isolation and characterization of proinsulin-producing medullary thymic epithelial cell clones.

Proinsulin, like many tissue-specific antigens, is expressed by rare (1-3%) cells of the thymus medullary stroma, presumably for the purpose of self-tolerance. Levels of this expression are associated with type 1 diabetes susceptibility in humans and in the NOD mouse. To further understand the mechanism of central tolerance induction by these rare cells, we have isolated and cultured two proinsulin-producing epithelial cell clones from murine thymus.

Proinsulin expression by Hassall's corpuscles in the mouse thymus.

The thymus expresses proinsulin, among many other tissue-specific antigens, and the inheritance of genetically determined low thymic proinsulin expression has been associated with impaired proinsulin-specific autoreactive T-cell tolerance and type 1 diabetes susceptibility. The cellular and molecular biology of proinsulin expression in the thymus remains unknown, and contradictory reports exist regarding the identity of proinsulin-producing cells. Using knock-in mice expressing beta-galactosidase (beta-Gal) under the control of an endogenous insulin promoter, we found that thymic proinsulin and beta-Gal transcripts were detectable at high levels in purified thymic epithelial cells.

Insulin expression levels in the thymus modulate insulin-specific autoreactive T-cell tolerance: the mechanism by which the IDDM2 locus may predispose to diabetes.

Type 1 diabetes results from autoimmune destruction of the insulin-producing pancreatic beta-cells. Evidence from our laboratory and others has suggested that the IDDM2 locus determines diabetes susceptibility by modulating levels of insulin expression in the thymus: the diabetes-protective class III alleles at a repeat polymorphism upstream of the insulin gene are associated with higher levels than the predisposing class I. To directly demonstrate the effect of thymic insulin expression levels on insulin-specific autoreactive T-cell selection, we have established a mouse model in which there is graded thymic insulin deficiency in linear correlation with insulin gene copy numbers, while pancreatic insulin remains unaltered.