Cluster Analysis of Dry Eye Disease Models Based on Immune Cell Parameters - New Insight Into Therapeutic Perspective

Dry eye disease (DED) can be represented as a display of disease in the mucosal part of the eye. It is quite distinct from the retinal side of the eye which connects with the neurons and thus represents the neuroimmunological disease. DED can occur either by the internal damage of the T cells inside the body or by microbial infections. Here we summarize the most common animal model systems used for DED relating to immune factors. We aimed to identify the most important immune cell/cytokine among the animal models of the disease. We also show the essential immune factors which are being tested for DED treatment. In our results, both the mechanism and the treatment of its animal models indicate the involvement of Th1 cells and the pro-inflammatory cytokine (IL-1 beta and TNF-alpha) related to the Th1-cells. The study is intended to increase the knowledge of the animal models in the field of the ocular surface along with the opening of a dimension of thoughts while designing a new animal model or treatment paradigm for ocular surface inflammatory disorders

Determination of a predictive cleavage motif for eluted major histocompatibility complex class II ligands

CD4+ T cells have a major role in regulating immune responses. They are activated by recognition of peptides mostly generated from exogenous antigens through the major histocompatibility complex (MHC) class II pathway. Identification of epitopes is important and computational prediction of epitopes is used widely to save time and resources. Although there are algorithms to predict binding affinity of peptides to MHC II molecules, no accurate methods exist to predict which ligands are generated as a result of natural antigen processing. We utilized a dataset of around 14,000 naturally processed ligands identified by mass spectrometry of peptides eluted from MHC class II expressing cells to investigate the existence of sequence signatures potentially related to the cleavage mechanisms that liberate the presented peptides from their source antigens. This analysis revealed preferred amino acids surrounding both N- and C-terminuses of ligands, indicating sequence-specific cleavage preferences. We used these cleavage motifs to develop a method for predicting naturally processed MHC II ligands, and validated that it had predictive power to identify ligands from independent studies. We further confirmed that prediction of ligands based on cleavage motifs could be combined with predictions of MHC binding, and that the combined prediction had superior performance. However, when attempting to predict CD4+ T cell epitopes, either alone or in combination with MHC binding predictions, predictions based on the cleavage motifs did not show predictive power. Given that peptides identified as epitopes based on CD4+ T cell reactivity typically do not have well-defined termini, it is possible that motifs are present but outside of the mapped epitope. Our attempts to take that into account computationally did not show any sign of an increased presence of cleavage motifs around well-characterized CD4+ T cell epitopes. While it is possible that our attempts to translate the cleavage motifs in MHC II ligand elution data into T cell epitope predictions were suboptimal, other possible explanations are that the cleavage signal is too diluted to be detected, or that elution data are enriched for ligands generated through an antigen processing and presentation pathway that is less frequently utilized for T cell epitopes.Fil: Paul, Sinu. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Karosiene, Edita. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Dhanda, Sandeep Kumar. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Jurtz, Vanessa. Technical University of Denmark; DinamarcaFil: Edwards, Lindy. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Nielsen, Morten. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Sette, Alessandro. University of California at San Diego; Estados Unidos. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Peters, Bjoern. La Jolla Institute for Allergy and Immunology; Estados Unidos. University of California at San Diego; Estados Unido

The Innate Immune Cell Profile of the Cornea Predicts the Onset of Ocular Surface Inflammatory Disorders

Ocular surface inflammatory disorder (OSID) is a spectrum of disorders that have features of several etiologies whilst displaying similar phenotypic signs of ocular inflammation. They are complicated disorders with underlying mechanisms related to several autoimmune disorders, such as rheumatoid arthritis (RA), Sjogren's syndrome, and systemic lupus erythematosus (SLE). Current literature shows the involvement of both innate and adaptive arms of the immune system in ocular surface inflammation. The ocular surface contains distinct components of the immune system in the conjunctiva and the cornea. The normal conjunctiva epithelium and sub-epithelial stroma contains resident immune cells, such as T cells, B cells (adaptive), dendritic cells, and macrophages (innate). The relative sterile environment of the cornea is achieved by the tolerogenic properties of dendritic cells in the conjunctiva, the presence of regulatory lymphocytes, and the existence of soluble immunosuppressive factors, such as the transforming growth factor (TGF)-beta and macrophage migration inhibitory factors. With the presence of both innate and adaptive immune system components, it is intriguing to investigate the most important leukocyte population in the ocular surface, which is involved in immune surveillance. Our meta-analysis investigates into this with a focus on both infectious (contact lens wear, corneal graft rejection, Cytomegalovirus, keratitis, scleritis, ocular surgery) and non-infectious (dry eye disease, glaucoma, graft-vs-host disease, Sjogren's syndrome) situations. We have found the predominance of dendritic cells in ocular surface diseases, along with the Th-related cytokines. Our goal is to improve the knowledge of immune cells in OSID and to open new dimensions in the field. The purpose of this study is not to limit ourselves in the ocular system, but to investigate the importance of dendritic cells in the disorders of other mucosal organs (e.g., lungs, gut, uterus). Holistically, we want to investigate if this is a common trend in the initiation of any disease related to the mucosal organs and find a unified therapeutic approach. In addition, we want to show the power of computational approaches to foster a collaboration between computational and biological science

Prediction of IL4 Inducing Peptides

The secretion of Interleukin-4 (IL4) is the characteristic of T-helper 2 responses. IL4 is a cytokine produced by CD4+ T cells in response to helminthes and other extracellular parasites. It has a critical role in guiding antibody class switching, hematopoiesis and inflammation, and the development of appropriate effector T-cell responses. In this study, it is the first time an attempt has been made to understand whether it is possible to predict IL4 inducing peptides. The data set used in this study comprises 904 experimentally validated IL4 inducing and 742 noninducing MHC class II binders. Our analysis revealed that certain types of residues are preferred at certain positions in IL4 inducing peptides. It was also observed that IL4 inducing and noninducing epitopes differ in compositional and motif pattern. Based on our analysis we developed classification models where the hybrid method of amino acid pairs and motif information performed the best with maximum accuracy of 75.76% and MCC of 0.51. These results indicate that it is possible to predict IL4 inducing peptides with reasonable precession. These models would be useful in designing the peptides that may induce desired Th2 response

IEDB-AR: immune epitope database - analysis resource in 2019

The Immune Epitope Database Analysis Resource (IEDB-AR, http://tools.iedb.org/) is a companion website to the IEDB that provides computational tools focused on the prediction and analysis of B and T cell epitopes. All of the tools are freely available through the public website and many are also available through a REST API and/or a downloadable command-line tool. A virtual machine image of the entire site is also freely available for non-commercial use and contains most of the tools on the public site. Here, we describe the tools and functionalities that are available in the IEDB-AR, focusing on the 10 new tools that have been added since the last report in the 2012 NAR webserver edition. In addition, many of the tools that were already hosted on the site in 2012 have received updates to newest versions, including NetMHC, NetMHCpan, BepiPred and DiscoTope. Overall, this IEDB-AR update provides a substantial set of updated and novel features for epitope prediction and analysis.Fil: Dhanda, Sandeep Kumar. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Mahajan, Swapnil. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Paul, Sinu. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Yan, Zhen. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Kim, Haeuk. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Jespersen, Martin Closter. Technical University of Denmark; DinamarcaFil: Jurtz, Vanessa. Technical University of Denmark; DinamarcaFil: Andreatta, Massimo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; Argentina. Technical University of Denmark; DinamarcaFil: Greenbaum, Jason A. La Jolla Institute for Allergy and Immunology; Estados UnidosFil: Marcatili, Paolo. Technical University of Denmark; DinamarcaFil: Sette, Alessandro. La Jolla Institute for Allergy and Immunology; Estados Unidos. University of California; Estados UnidosFil: Nielsen, Morten. Technical University of Denmark; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas; ArgentinaFil: Peters, Bjoern. University of California; Estados Unidos. La Jolla Institute for Allergy and Immunology; Estados Unido

A Review on T Cell Epitopes Identified Using Prediction and Cell-Mediated Immune Models for Mycobacterium tuberculosis and Bordetella pertussis

In the present review, we summarize work from our as well as other groups related to the characterization of bacterial T cell epitopes, with a specific focus on two important pathogens, namely, Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), and Bordetella pertussis (BP), the bacterium that causes whooping cough. Both bacteria and their associated diseases are of large societal significance. Although vaccines exist for both pathogens, their efficacy is incomplete. It is widely thought that defects and/or alteration in T cell compartments are associated with limited vaccine effectiveness. As discussed below, a full genome-wide map was performed in the case of Mtb. For BP, our focus has thus far been on the antigens contained in the acellular vaccine; a full genome-wide screen is in the planning stage. Nevertheless, the sum-total of the results in the two different bacterial systems allows us to exemplify approaches and techniques that we believe are generally applicable to the mapping and characterization of human immune responses to bacterial pathogens. Finally, we add, as a disclaimer, that this review by design is focused on the work produced by our laboratory as an illustration of approaches to the study of T cell responses to Mtb and BP, and is not meant to be comprehensive, nor to detract from the excellent work performed by many other groups

Cancer risk and tumour spectrum in 172 patients with a germline SUFU pathogenic variation : a collaborative study of the SIOPE Host Genome Working Group

Background Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome. Methods To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator. Results Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated. Conclusion Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.Peer reviewe

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses

A Web-Based Platform for Designing Vaccines against Existing and Emerging Strains of Mycobacterium tuberculosis.

UNLABELLED:Development of an effective vaccine against drug-resistant Mycobacterium tuberculosis (Mtb) is crucial for saving millions of premature deaths every year due to tuberculosis. This paper describes a web portal developed for assisting researchers in designing vaccines against emerging Mtb strains using traditional and modern approaches. Firstly, we annotated 59 genomes of Mycobacterium species to understand similarity/dissimilarity between tuberculoid, non-tuberculoid and vaccine strains at genome level. Secondly, antigen-based vaccine candidates have been predicted in each Mtb strain. Thirdly, epitopes-based vaccine candidates were predicted/discovered in above antigen-based vaccine candidates that can stimulate all arms of immune system. Finally, a database of predicted vaccine candidates at epitopes as well at antigen level has been developed for above strains. In order to design vaccine against a newly sequenced genome of Mtb strain, server integrates three modules for identification of strain-, antigen-, epitope-specific vaccine candidates. We observed that 103,522 unique peptides (9mers) had the potential to induce an antibody response and/or promiscuous binder to MHC alleles and/or have the capability to stimulate T lymphocytes. In summary, this web-portal will be useful for researchers working on designing vaccines against Mtb including drug-resistant strains. AVAILABILITY:The database is available freely at http://crdd.osdd.net/raghava/mtbveb/