Adaptive Immune System and the Eye: T Cell-Mediated Immunity

2010 ◽  
pp. 41-47
Author(s):  
K.C. McKenna ◽  
R.D. Vicetti Miguel
Keyword(s):  
Immune System ◽  
T Cell ◽  
Adaptive Immune System ◽  
Cell Mediated Immunity ◽  
Adaptive Immune

scholarly journals Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

2013 ◽  
Vol 110 (31) ◽  
pp. E2905-E2914 ◽  
Author(s):  
C. Sinclair ◽  
I. Bains ◽  
A. J. Yates ◽  
B. Seddon
Keyword(s):  
Immune System ◽  
T Cell ◽  
Adaptive Immune System ◽  
Cd8 T Cell ◽  
Cell Ratio ◽  
Adaptive Immune

Reduction Of Immune Repertoire Diversity Through DNA Sequence Constraints At VDJ Junctions

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4944-4944
Author(s):  
Bryan Howie ◽  
Harlan Robins ◽  
Christopher S Carlson
Keyword(s):  
Immune System ◽  
T Cell ◽  
T Cell Receptor ◽  
Adaptive Immune System ◽  
Cell Receptor ◽  
Immune Repertoire ◽  
Adaptive Immune ◽  
Repertoire Diversity ◽  
Equity Ownership ◽  
Junctional Diversity

Abstract B and T lymphocytes are effector cells of the adaptive immune system. These cells express surface receptors that bind a huge variety of antigens, and together they comprise a person’s immune repertoire. A diverse repertoire is essential for mounting robust immune responses against a wide range of pathogens, and repertoire diversity affects the probability that DNA sequencing can uniquely tag a clonally expanded population of cells for the detection of minimum residual disease (MRD) during cancer treatment. Immune repertoire diversity arises partly through the combinatorial splicing of gene segments from the variable (V), diversity (D), and joining (J) regions of a B or T cell receptor locus. Much additional diversity is created through the stochastic insertion and deletion of nucleotides at the splice junctions, and by somatic hypermutation (SHM) in maturing lymphocytes. The generation of junctional diversity is an important part of this process, but it may be constrained by the underlying biological mechanisms. To explore the landscape of junctional diversity among immune receptor loci, we developed a likelihood model that can annotate VDJ junctions in the presence of SHM and compute the probability that a given receptor sequence was generated only once in a person’s repertoire, which is essential for tracking MRD. Using high-throughput sequencing data from several individuals and a range of receptor loci, we identify mechanistic constraints that limit B and T cell receptor diversity. For example, we show that the usual variability in CDR3 length is reduced at the immunoglobulin kappa (IgK) locus, and we connect this finding to sequence motifs that constrain nucleotide deletion at the ends of IgK gene segments. Our findings will inform future genetic studies of the adaptive immune system, and they provide quantitative guidance for deciding which cancer clones can be tracked for reliable MRD detection. Disclosures: Howie: Adaptive Biotechnologies: Employment, Equity Ownership. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Carlson:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

2021 ◽  
Vol 22 (6) ◽  
pp. 2954
Author(s):  
Alison Jee ◽  
Samantha Christine Sernoskie ◽  
Jack Uetrecht
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Liver Injury ◽  
Clinical Manifestations ◽  
Adaptive Immune System ◽  
Human Leukocyte ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Adaptive Immune

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.

scholarly journals Uremia-Associated Ageing of the Thymus and Adaptive Immune Responses

Toxins ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 224
Author(s):  
Michiel GH Betjes
Keyword(s):  
T Cells ◽  
Renal Function ◽  
Immune System ◽  
T Cell ◽  
Memory T Cells ◽  
Adaptive Immune System ◽  
Low Grade ◽  
Mortality And Morbidity ◽  
Adaptive Immune ◽  
Esrd Patients

Progressive loss of renal function is associated with a series of changes of the adaptive immune system which collectively constitute premature immunological ageing. This phenomenon contributes significantly to the mortality and morbidity of end-stage renal disease (ESRD) patients. In this review, the effect of ESRD on the T cell part of the adaptive immune system is highlighted. Naïve T cell lymphopenia, in combination with the expansion of highly differentiated memory T cells, are the hallmarks of immunological ageing. The decreased production of newly formed T cells by the thymus is critically involved. This affects both the CD4 and CD8 T cell compartment and may contribute to the expansion of memory T cells. The expanding populations of memory T cells have a pro-inflammatory phenotype, add to low-grade inflammation already present in ESRD patients and destabilize atherosclerotic plaques. The effect of loss of renal function on the thymus is not reversed after restoring renal function by kidney transplantation and constitutes a long-term mortality risk factor. Promising results from animal experiments have shown that rejuvenation of the thymus is a possibility, although not yet applicable in humans.

scholarly journals S184. IN SILICO PREDICTION OF T-CELL-MEDIATED MOLECULAR MIMICRY IN TOXOPLASMOSIS AND SCHIZOPHRENIA

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S108-S108
Author(s):  
David Thylur ◽  
Adriana Lori ◽  
Dimitri Avramopoulos ◽  
Jennifer Mulle ◽  
Fernando Goes ◽  
...  
Keyword(s):  
T Cells ◽  
Immune System ◽  
T Cell ◽  
In Silico ◽  
Molecular Mimicry ◽  
Adaptive Immune System ◽  
Autoimmune Response ◽  
Host Proteins ◽  
Adaptive Immune ◽  
Local Sequence

Abstract Background Exposure to Toxoplasma gondii (TOXO) has been consistently associated with the development of schizophrenia, but the neurobiological mechanism through which this occurs is not well elucidated. Emerging data has broadly implicated the adaptive immune system as a possible pathway from TOXO infection to schizophrenia. In order to explore the hypothesis that crossreactive T cells could help mediate this relationship, we built upon the genetic analysis from our psychiatrically-enriched Ashkenazi Jewish cohort using an in silico approach to predict HLA reactivity to TOXO epitopes, with the aim of identifying host proteins that could be susceptible to T-cell-mediated molecular mimicry. Methods We used netMHCpan v4.0 to generate a library of 2182 oligopeptides from the TOXO proteome that were predicted to be strongly antigenic for individuals with HLA-C*04:01, an allele of interest since our analysis indicated that the odds ratio for TOXO infection were in the opposite direction for those with schizophrenia compared to controls. A predicted binding affinity less than 500 nM was used to identify epitopes that were likely to be biologically relevant. Epitopes identified by this approach were compared with human peptides for local sequence similarity using BLAST optimized for short peptide sequences in order to identify host proteins that could mimic TOXO antigens. Ingenuity Pathway Analysis was then used to interpret and synthesize possible biological relationships between predicted autoantigens and schizophrenia. Results Our pipeline identified 38 candidate proteins for molecular mimicry at a threshold of P<.05 after correcting for multiple testing. A number of these genes have been strongly linked to schizophrenia through genetic studies, including HSPA9, PSMA4, and ZDHHC5. Pathway and gene ontology analysis revealed that these genes were involved in networks of regulation of gene expression as well as ubiquitination, which participates in antigen presentation. Discussion Using an in silico approach, we identified 38 human proteins that could be targeted by a crossreactive T cell autoimmune response after exposure to TOXO. Several of these candidate proteins are highly relevant for genetic risk of schizophrenia and participate in molecular pathways that mediate antigen processing. CD8+ T cells contribute to autoimmunity through cytokine release and have been implicated in the relationship between TOXO exposure and schizophrenia. Though these results will need experimental confirmation, we hope that they will spur further research on the role of the adaptive immune system in toxoplasmosis and schizophrenia.

Preface

Parasitology ◽  
1997 ◽  
Vol 115 (7) ◽  
pp. 3-3
Author(s):  
M. J. Doenhoff ◽  
L. H. Chappell
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Molecular Mimicry ◽  
Adaptive Immune System ◽  
T Cell Subsets ◽  
Survival Strategies ◽  
Molecular Component ◽  
Immunocompetent Host ◽  
Adaptive Immune

The papers in this volume draw attention to both new and recent information on the mechanisms employed by infectious pathogens to underpin their survival in the immunocompetent host and to facilitate their transmission between hosts. Classical survival strategies include induction of immuno- suppression, antigenic variety and variation, host antigen sequestration, molecular mimicry, antibody destruction and invasion of cells or privileged sites. To these we can now add novel and diverse mechanisms with which the invader may manipulate the host for its own ends. They range from making use of a single molecular component of the immune system, through more sophisticated mechanisms of evasion to modulation of the immune response in the pathogen's favour, particularly by manipulation of T cell subsets and cytokine fluxes. There are then examples of pure exploitation of the adaptive immune system by the generation of specific humoral and cell-mediated responses that prolong the invader's survival and aid transmission. The order of the chapters in this volume is intended to reflect this increasing level of complexity.It is our hope that the studies described in this multi-disciplinary assemblage of papers will stimulate further research in this important area. We would like to thank all our contributing authors and the anonymous refereees for their commitment and help in seeing this project through to completion.

The Basics of Immunology

2021 ◽  
Author(s):  
Heinz-Josef Schmitt ◽  
Nathalie Garçon
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Geometric Mean ◽  
Adaptive Immune System ◽  
Antibody Responses ◽  
Cell Mediated Immunity ◽  
Effective Response ◽  
Post Vaccination ◽  
Chemical Structures ◽  
Adaptive Immune

Humans have defense mechanisms against micro-organisms exemplified by the immune system that consists of an unspecific (“innate immunity”) and specific (“adaptive immunity”) arm, leading to an effective response via humoral and cellular mechanisms. Innate immunity is activable at any time (skin, tears, ciliae, …). It includes recognition of various chemical patterns on microorganisms. Such chemical structures are detected by macrophages or dendritic cells, which travel to the draining lymph nodes and are presented to cells of the adaptive immune system. The adaptive immune system is highly specific against individual microorganisms and directed against non-self-structures. It needs days to weeks to be effective and it induces immune memory, allowing for an immediate defense response upon re-infection. As a result of presentation of non-self-structures to the adaptive immune system, highly specific antibodies and cells are generated which may kill/neutralize microbial invaders. Currently, antibody responses are the cornerstone to vaccine licensure. Functional antibody tests detecting killing/neutralizing ability are the cornerstone of vaccine-induced immunity. Tests for cell-mediated immunity are also considered. Antibody responses to vaccines can be evaluated as o Geometric Mean Titer (GMT) or Geometric Mean Concentration (GMC) o Fold-rise pre/post vaccination o Percentage of study subjects achieving a clinically relevant amount of antibody (“sero-responders”) o Reverse Cumulative Distributions (RCDs), ideally showing data pre- and post-vaccination.

Stochastic cancer-immune coevolution: Implications for cancer incidence and immunotherapeutic efficacy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14023-e14023
Author(s):  
Jason T George ◽  
Herbert Levine ◽  
Jeffrey J. Molldrem ◽  
Haven Garber
Keyword(s):  
Immune System ◽  
T Cell ◽  
Cancer Incidence ◽  
Adaptive Immune System ◽  
Turnover Rates ◽  
Cell Repertoire ◽  
Adaptive Immune ◽  
Cell Immunotherapy ◽  
Cell Diversity ◽  
T Cell Immunotherapy

e14023 Background: Despite recent progress, robust treatment strategies that lead to durable remission are still lacking for many cancer types. This disease is difficult to treat owing in part to the complexity introduced by a heterogeneous population of cancer cells capable of evolving mechanisms of resistance to traditional therapy. Nonetheless, the discovery and continued optimization of T-cell immunotherapy has revolutionized the treatment of many cancers. This treatment strategy stands out from other approaches in its unique ability to co-evolve alongside an evading tumor. While promising, such therapies are also complex. For example, allogeneic stem cell transplantation leverages a donor-derived T-cell repertoire to treat patients with refractory hematologic malignancies and relies upon a delicate balance between desirable anti-tumor effects and potentially life-threatening graft-versus-host-disease. Currently, the decision to utilize this therapy and others like it is largely influenced by prior empirical evidence. Thus, there is great need for quantitative models of the cancer-immune interaction to generate testable predictions of treatment outcome, which could then be validated prior to T-cell immunotherapy administration. Methods: We develop a foundational mathematical model to investigate the properties of stochastic tumor-immune co-evolution using applied stochastic process theory and probabilistic analysis. We use this model to predict the effects of reduced immunity, T-cell diversity, and thymic turnover rates on cancer incidence, and compare model simulations to cancer evolutionary data. Results: We predict that changes in T-cell diversity, and to a lesser degree thymic turnover, increase the chance of tumor progression. When applied to experimental data, we demonstrate that the observations are consistent with co-evolution between an indolent cancer population and the adaptive immune system prior to clinical disease. Conclusions: Our results provide a fundamental framework for analyzing the interaction dynamics of an evolving threat like cancer and the adaptive immune system in order to better understand and predict immunotherapeutic efficacy.

Sign in / Sign up

Export Citation Format

Share Document