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.

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 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.

scholarly journals Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Sofya A Kasatskaya ◽  
Kristin Ladell ◽  
Evgeniy S Egorov ◽  
Kelly L Miners ◽  
Alexey N Davydov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptors ◽  
Adaptive Immune System ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Intrinsic Properties ◽  
Antigen Specificity ◽  
Adaptive Immune ◽  
Transition Pathways

The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

scholarly journals The impact of body mass index on adaptive immune cells in the human bone marrow

2020 ◽  
Author(s):  
Luca Pangrazzi ◽  
Erin Naismith ◽  
Carina Miggitsch ◽  
Jose’ Antonio Carmona Arana ◽  
Michael Keller ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Immune Cells ◽  
Memory T Cells ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Abstract Background. Obesity has been associated with chronic inflammation and oxidative stress. Both conditions play a determinant role in the pathogenesis of age-related diseases, such as immunosenescence. Adipose tissue can modulate the function of the immune system with the secretion of molecules influencing the phenotype of immune cells. The importance of the bone marrow (BM) in the maintenance of antigen-experienced adaptive immune cells has been documented in mice. Recently, some groups have investigated the survival of effector/memory T cells in the human BM. Despite this, whether high body mass index (BMI) may affect immune cells in the BM and the production of molecules supporting the maintenance of these cells it is unknown.Methods. Using flow cytometry, the frequency and the phenotype of immune cell populations were measured in paired BM and PB samples obtained from persons with different BMI. Furthermore, the expression of BM cytokines was assessed. The influence of cytomegalovirus (CMV) on T cell subsets was additionally considered, dividing the donors into the CMV- and CMV+ groups.Results. Our study suggests that increased BMI may affect both the maintenance and the phenotype of adaptive immune cells in the BM. While the BM levels of IL-15 and IL-6, supporting the survival of highly differentiated T cells, and oxygen radicals increased in overweight persons, the production of IFNγ and TNF by CD8+ T cells was reduced. In addition, the frequency of B cells and CD4+ T cells positively correlated with BMI in the BM of CMV- persons. Finally, the frequency of several T cell subsets, and the expression of senescence/exhaustion markers within these subpopulations, were affected by BMI. In particular, the levels of bona fide memory T cells may be reduced in overweight persons.Conclusion. Our work suggests that, in addition to aging and CMV, obesity may represent an additional risk factor for immunosenescence in adaptive immune cells. Metabolic interventions may help in improving the fitness of the immune system in the elderly.

Body mass index affects adaptive immune cells in the human bone marrow

2020 ◽  
Author(s):  
Luca Pangrazzi ◽  
Erin Naismith ◽  
Carina Miggitsch ◽  
Jose’ Antonio Carmona Arana ◽  
Michael Keller ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Bone Marrow ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Body Mass ◽  
Immune Cells ◽  
T Cell Subsets ◽  
Adaptive Immune ◽  
Adaptive Immune Cells

Abstract Background. Obesity has been associated with chronic inflammation and oxidative stress. Both conditions play a determinant role in the pathogenesis of age-related diseases, such as immunosenescence. Adipose tissue can modulate the function of the immune system with the secretion of molecules influencing the phenotype of immune cells. Recently, the importance of the bone marrow (BM) in the maintenance of antigen-experienced adaptive immune cells has been documented. Despite this, whether high body mass index (BMI) may affect immune cells in the BM and the production of molecules supporting the maintenance of these cells it is unknown. Methods. Using flow cytometry, the frequency and the phenotype of immune cell populations were measured in paired BM and PB samples obtained from persons with different BMI. Furthermore, the expression of BM cytokines was assessed. The influence of cytomegalovirus (CMV) on T cell subsets was additionally considered, dividing the donors into the CMV - and CMV + groups. Results. Our study suggests that increased BMI may affect both the maintenance and the phenotype of adaptive immune cells in the BM. While the BM levels of IL-15 and IL-6, supporting the survival of highly differentiated T cells, and oxygen radicals increased in overweight persons, the production of IFNγ and TNF by CD8 + T cells was reduced. In addition, the frequency of B cells and CD4 + T cells positively correlated with BMI in the BM of CMV - persons. Finally, the frequency of several T cell subsets, and the expression of senescence/exhaustion markers within these subpopulations, were affected by BMI. In particular, the levels of bona fide memory T cells may be reduced in overweight persons. Conclusion. Our work suggests that obesity may represent an independent risk factor supporting immunosenescence, in addition to aging and CMV. Metabolic interventions may help in improving the fitness of the immune system in the elderly.

Introduction to Clinical Immunology: Overview of the Immune Response, Autoimmune Conditions, and Immunosuppressive Therapeutics for Rheumatic Diseases

2016 ◽  
Author(s):  
Steven K. Lundy ◽  
Alison Gizinski ◽  
David A. Fox
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Immune Responses ◽  
Autoimmune Diseases ◽  
Adaptive Immunity ◽  
Cell Populations ◽  
Hematopoietic Stem ◽  
Innate And Adaptive Immunity ◽  
Adaptive Immune

The immune system is a complex network of cells and mediators that must balance the task of protecting the host from invasive threats. From a clinical perspective, many diseases and conditions have an obvious link to improper functioning of the immune system, and insufficient immune responses can lead to uncontrolled acute and chronic infections. The immune system may also be important in tumor surveillance and control, cardiovascular disease, health complications related to obesity, neuromuscular diseases, depression, and dementia. Thus, a working knowledge of the role of immunity in disease processes is becoming increasingly important in almost all aspects of clinical practice. This review provides an overview of the immune response and discusses immune cell populations and major branches of immunity, compartmentalization and specialized immune niches, antigen recognition in innate and adaptive immunity, immune tolerance toward self antigens, inflammation and innate immune responses, adaptive immune responses and helper T (Th) cell subsets, components of the immune response that are important targets of treatment in autoimmune diseases, mechanisms of action of biologics used to treat autoimmune diseases and their approved uses, and mechanisms of other drugs commonly used in the treatment of autoimmune diseases. Figures show the development of erythrocytes, platelets, lymphocytes, and other immune system cells originating from hematopoietic stem cells that first reside in the fetal liver and later migrate to the bone marrow, antigen–major histocompatibility complex recognition by T cell receptor control of T cell survival and activation, and Th cells as central determinants of the adaptive immune response toward different stimuli. Tables list cell populations involved in innate and adaptive immunity, pattern recognition receptors with known ligands, autoantibody-mediated human diseases: examples of pathogenic mechanisms, selected Food and Drug Administration–approved autoimmune disease indications for biologics, and mechanism of action of biologics used to treat autoimmune diseases.   This review contains 3 highly rendered figures, 5 tables, and 64 references.

scholarly journals Suppression of the Peripheral Immune System Limits the Central Immune Response Following Cuprizone-Feeding: Relevance to Modelling Multiple Sclerosis

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1314 ◽  
Author(s):  
Sen ◽  
Almuslehi ◽  
Gyengesi ◽  
Myers ◽  
Shortland ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Synaptic Function ◽  
Adaptive Immune ◽  
Splenic Atrophy ◽  
The Impact ◽  
The Brain ◽  
Inside Out

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the ‘inside-out’ theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the ‘inside-out’ role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement.

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

scholarly journals Immune Regulation of Cancer

2010 ◽  
Vol 28 (29) ◽  
pp. 4531-4538 ◽  
Author(s):  
Mary L. Disis
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Tumor Stroma ◽  
Tissue Destruction ◽  
Cancer Proliferation ◽  
Patients With Cancer ◽  
Adaptive Immune ◽  
Improved Outcomes ◽  
Tumor Types

Innate and adaptive immune system cells play a major role in regulating the growth of cancer. Although it is commonly thought that an immune response localized to the tumor will inhibit cancer growth, it is clear that some types of inflammation induced in a tumor may also lead to cancer proliferation, invasion, and dissemination. Recent evidence suggests, however, that some patients with cancer can mount an antitumor immune response that has the potential to control or eliminate cancer. Indeed, a so-called “immune response” signature has been described in malignancy that is associated with improved outcomes in several tumor types. Moreover, the presence of specific subsets of T cells, which have the capability to penetrate tumor stroma and infiltrate deep into the parenchyma, identifies patients with an improved prognosis. Immune-based therapies have the potential to modulate the tumor microenvironment by eliciting immune system cells that will initiate acute inflammation that leads to tissue destruction.

scholarly journals Fierce selection and interference in B-cell repertoire response to chronic HIV-1

2018 ◽  
Author(s):  
Armita Nourmohammad ◽  
Jakub Otwinowski ◽  
Marta Łuksza ◽  
Thierry Mora ◽  
Aleksandra M Walczak
Keyword(s):  
Immune Response ◽  
Population Genetics ◽  
Immune System ◽  
B Cell ◽  
Adaptive Immune System ◽  
Clonal Interference ◽  
Cell Repertoire ◽  
Beneficial Mutations ◽  
Adaptive Immune ◽  
Hiv 1

AbstractDuring chronic infection, HIV-1 engages in a rapid coevolutionary arms race with the host’s adaptive immune system. While it is clear that HIV exerts strong selection on the adaptive immune system, the characteristics of the somatic evolution that shape the immune response are still unknown. Traditional population genetics methods fail to distinguish chronic immune response from healthy repertoire evolution. Here, we infer the evolutionary modes of B-cell repertoires and identify complex dynamics with a constant production of better B-cell receptor mutants that compete, maintaining large clonal diversity and potentially slowing down adaptation. A substantial fraction of mutations that rise to high frequencies in pathogen engaging CDRs of B-cell receptors (BCRs) are beneficial, in contrast to many such changes in structurally relevant frameworks that are deleterious and circulate by hitchhiking. We identify a pattern where BCRs in patients who experience larger viral expansions undergo stronger selection with a rapid turnover of beneficial mutations due to clonal interference in their CDR3 regions. Using population genetics modeling, we show that the extinction of these beneficial mutations can be attributed to the rise of competing beneficial alleles and clonal interference. The picture is of a dynamic repertoire, where better clones may be outcompeted by new mutants before they fix.

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