scholarly journals Joint analysis reveals shared autoimmune disease associations and identifies common mechanisms

2021 ◽  
Author(s):  
Matthew R Lincoln ◽  
Noah Connally ◽  
Pierre-Paul Axisa ◽  
Christiane Gasperi ◽  
Mitja Mitrovic ◽  
...  
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Fine Mapping ◽  
Inflammatory Diseases ◽  
Underlying Mechanism ◽  
Joint Analysis ◽  
Risk Alleles ◽  
Disease Associations ◽  
Autoimmune And Inflammatory Diseases ◽  
Shared Alleles

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents deter- mining if the same allele is responsible, indicating a shared underlying mechanism. Using a collection of 129,058 cases and controls across six diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles two-fold by combining cases and controls across diseases, allowing us to identify more eQTLs driven by the shared alleles. The patterns of sharing indicate widespread shared mechanisms, but not a single global autoimmune mecha- nism. Our approach can be applied to any set of traits, and is particularly valuable as sample collections become depleted.

scholarly journals Neuroendocrine Immunoregulation in Multiple Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-23 ◽  
Author(s):  
Nathalie Deckx ◽  
Wai-Ping Lee ◽  
Zwi N. Berneman ◽  
Nathalie Cools
Keyword(s):  
Multiple Sclerosis ◽  
Immune System ◽  
Inflammatory Diseases ◽  
Neuroendocrine System ◽  
Extrinsic Factors ◽  
Inflammatory Stress ◽  
Factors Affecting ◽  
New Therapeutic Approaches ◽  
Messenger Molecules ◽  
Autoimmune And Inflammatory Diseases

Currently, it is generally accepted that multiple sclerosis (MS) is a complex multifactorial disease involving genetic and environmental factors affecting the autoreactive immune responses that lead to damage of myelin. In this respect, intrinsic or extrinsic factors such as emotional, psychological, traumatic, or inflammatory stress as well as a variety of other lifestyle interventions can influence the neuroendocrine system. On its turn, it has been demonstrated that the neuroendocrine system has immunomodulatory potential. Moreover, the neuroendocrine and immune systems communicate bidirectionally via shared receptors and shared messenger molecules, variously called hormones, neurotransmitters, or cytokines. Discrepancies at any level can therefore lead to changes in susceptibility and to severity of several autoimmune and inflammatory diseases. Here we provide an overview of the complex system of crosstalk between the neuroendocrine and immune system as well as reported dysfunctions involved in the pathogenesis of autoimmunity, including MS. Finally, possible strategies to intervene with the neuroendocrine-immune system for MS patient management will be discussed. Ultimately, a better understanding of the interactions between the neuroendocrine system and the immune system can open up new therapeutic approaches for the treatment of MS as well as other autoimmune diseases.

scholarly journals The Kynurenine Pathway—New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies

2021 ◽  
Vol 22 (18) ◽  
pp. 9879
Author(s):  
Anna Krupa ◽  
Irina Kowalska
Keyword(s):  
Immune System ◽  
Adaptive Immunity ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Kynurenine Pathway ◽  
Wide Range ◽  
Organ Specific ◽  
Autoimmune And Inflammatory Diseases

The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells’ differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies—type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.

scholarly journals Therapeutic Application of Exosomes in Inflammatory Diseases

2021 ◽  
Vol 22 (3) ◽  
pp. 1144
Author(s):  
Ju Hun Suh ◽  
Hyeon Su Joo ◽  
Eun Be Hong ◽  
Hyeon Ji Lee ◽  
Jung Min Lee
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Human Body ◽  
Therapeutic Strategy ◽  
State Of The Art ◽  
Inflammatory Diseases ◽  
Defense System ◽  
Therapeutic Application

Immunomodulation is on the cusp of being an important therapy for treating many diseases, due to the significant role of the immune system in defending the human body. Although the immune system is an essential defense system, overactivity can result in diverse sicknesses such as inflammation and autoimmune disease. Exosomes are emerging as a state-of-the-art therapeutic strategy for treating an overactive immune system. Thus, in this review, we will thoroughly review therapeutic applications of exosomes in various inflammatory and autoimmune diseases. Finally, issues for an outlook to the future of exosomal therapy will be introduced.

TREX1 As a Potential Therapeutic Target for Autoimmune and Inflammatory Diseases

2019 ◽  
Vol 25 (30) ◽  
pp. 3239-3247 ◽  
Author(s):  
Sha-Sha Tao ◽  
Guo-Cui Wu ◽  
Qin Zhang ◽  
Tian-Ping Zhang ◽  
Rui-Xue Leng ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Therapeutic Target ◽  
Mammalian Cells ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Autoimmune Response ◽  
Autoimmune And Inflammatory Diseases ◽  
Functional Mechanisms

Background and Objectives: The 3’ repair exonuclease 1 (TREX1) gene is the major DNA-specific 3’–5 ’exonuclease of mammalian cells which reduces single- and double-stranded DNA (ssDNA and dsDNA) to prevent undue immune activation mediated by the nucleic acid. TREX1 is also a crucial suppressor of selfrecognition that protects the host from inappropriate autoimmune activations. It has been revealed that TREX1 function is necessary to prevent host DNA accumulating after cell death which could actuate an autoimmune response. In the manuscript, we will discuss in detail the latest advancement to study the role of TREX1 in autoimmune disease. Methods: As a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as an antiinflammatory molecule, the functional mechanisms of TREX1 were multifactorial. In this review, we will briefly summarize the latest advancement in studying the role of TREX1 in autoimmune disease, and discuss its potential as a therapeutic target for these diseases. Results: Deficiency of TREX1 in human patients and murine models is characterized by systemic inflammation and the disorder of TREX1 functions drives inflammatory responses leading to autoimmune disease. Moreover, much more studies revealed that mutations in TREX1 have been associated with a range of autoimmune disorders. But it is also unclear whether the mutations of TREX1 play a causal role in the disease progression, and whether manipulation of TREX1 has a beneficial effect in the treatment of autoimmune diseases. Conclusion: Integration of functional TREX1 biology into autoimmune diseases may further deepen our understanding of the development and pathogenesis of autoimmune diseases and provide new clues and evidence for the treatment of autoimmune diseases.

scholarly journals Integrative genetic and epigenetic analysis uncovers regulatory mechanisms of autoimmune disease

2016 ◽  
Author(s):  
Parisa Shooshtari ◽  
Hailieng Huang ◽  
Chris Cotsapas
Keyword(s):  
Disease Risk ◽  
Inflammatory Diseases ◽  
Association Studies ◽  
Single Gene ◽  
Genome Wide Association Studies ◽  
Regulatory Regions ◽  
Risk Alleles ◽  
Molecular Events ◽  
Public Data ◽  
Autoimmune And Inflammatory Diseases

Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk1,2. These associations are preferentially located in non-coding DNA regions3,4 and in particular to tissue-specific Dnase I hypersensitivity sites (DHS)5,6. Whilst these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples, and connect them to the genes they control through robust re-analysis of public data. We find substantial evidence of regulatory potential in 132/301 (44%) risk loci across nine autoimmune and inflammatory diseases, and are able to prioritize a single gene in 104/132 (79%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.

scholarly journals Computational design of a synthetic PD-1 agonist

2021 ◽  
Vol 118 (29) ◽  
pp. e2102164118
Author(s):  
Cassie M. Bryan ◽  
Gabriel J. Rocklin ◽  
Matthew J. Bick ◽  
Alex Ford ◽  
Sonia Majri-Morrison ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Inflammatory Diseases ◽  
Computational Design ◽  
Activated T Cells ◽  
Autoimmune And Inflammatory Diseases ◽  
Cell Death Protein

Programmed cell death protein-1 (PD-1) expressed on activated T cells inhibits T cell function and proliferation to prevent an excessive immune response, and disease can result if this delicate balance is shifted in either direction. Tumor cells often take advantage of this pathway by overexpressing the PD-1 ligand PD-L1 to evade destruction by the immune system. Alternatively, if there is a decrease in function of the PD-1 pathway, unchecked activation of the immune system and autoimmunity can result. Using a combination of computation and experiment, we designed a hyperstable 40-residue miniprotein, PD-MP1, that specifically binds murine and human PD-1 at the PD-L1 interface with a Kd of ∼100 nM. The apo crystal structure shows that the binder folds as designed with a backbone RMSD of 1.3 Å to the design model. Trimerization of PD-MP1 resulted in a PD-1 agonist that strongly inhibits murine T cell activation. This small, hyperstable PD-1 binding protein was computationally designed with an all-beta interface, and the trimeric agonist could contribute to treatments for autoimmune and inflammatory diseases.

scholarly journals Prevotella Copri and Microbiota in Rheumatoid Arthritis: Fully Convincing Evidence?

2019 ◽  
Vol 8 (11) ◽  
pp. 1837 ◽  
Author(s):  
Drago
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune System ◽  
Gut Microbiota ◽  
Inflammatory Diseases ◽  
Convincing Evidence ◽  
Immune Network ◽  
Positive Balance ◽  
Autoimmune And Inflammatory Diseases

: Gut microbiota regulates the host's immune system. Microorganisms and their compounds can co-exist peacefully with the immune system and coordinate its function and regulation. Some microbial clusters may be harmful and others helpful in the respective negative or positive balance of the immune network. These insights have revealed important mechanisms for understanding and treating autoimmune and inflammatory diseases. This Editorial aims to clarify the role of specific genus of gut microbiota, such as Prevotella, in influencing the pathogenesis of Rheumatoid Arthritis (RA).

Pathway of Inflammation due to Asbestiform fiber "Fluoro-edenite" Exposure: an Update

2020 ◽  
Vol 16 ◽  
Author(s):  
Caterina Ledda ◽  
Claudia Lombardo ◽  
Elisabetta A. Tendi ◽  
Maria Hagnas ◽  
Gianluca Paravizzini ◽  
...  
Keyword(s):  
Immune System ◽  
Autoimmune Disease ◽  
Early Response ◽  
The Body ◽  
Volcanic Area ◽  
Asbestos Fibers ◽  
Inflammatory Processes

: Fluoro-edenite (FE) is an asbestos-like amphibole present in the bentonitic lavas extracted from a stone quarry in Biancavilla, a village sited in the Etnean Volcanic Area (Italy). : Thoracic pathologies are the results of excessive inflammatory processes that are the early response of the immune system to inhaled fibers. As demonstrated for asbestos, fibers may trigger immune system cells in an acute and/or chronic manner. This review aims to clarify the pathways of inflammation in workers exposed to FE fibers. : Based on the articles reviewed, it seems that a permanent stimulus created by repeatedly inhaling the FE fibers and their persistence in the body can act as trigger both in promoting inflammatory processes and in immunological induction of autoimmune disease.

scholarly journals Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna C. Aschenbrenner ◽  
◽  
Maria Mouktaroudi ◽  
Benjamin Krämer ◽  
Marie Oestreich ◽  
...  
Keyword(s):  
Immune System ◽  
Disease Severity ◽  
Whole Blood ◽  
Viral Infections ◽  
Inflammatory Diseases ◽  
Target Prediction ◽  
Data Driven ◽  
Host Responses ◽  
Drug Candidates ◽  
Drug Target Prediction

Abstract Background The SARS-CoV-2 pandemic is currently leading to increasing numbers of COVID-19 patients all over the world. Clinical presentations range from asymptomatic, mild respiratory tract infection, to severe cases with acute respiratory distress syndrome, respiratory failure, and death. Reports on a dysregulated immune system in the severe cases call for a better characterization and understanding of the changes in the immune system. Methods In order to dissect COVID-19-driven immune host responses, we performed RNA-seq of whole blood cell transcriptomes and granulocyte preparations from mild and severe COVID-19 patients and analyzed the data using a combination of conventional and data-driven co-expression analysis. Additionally, publicly available data was used to show the distinction from COVID-19 to other diseases. Reverse drug target prediction was used to identify known or novel drug candidates based on finding from data-driven findings. Results Here, we profiled whole blood transcriptomes of 39 COVID-19 patients and 10 control donors enabling a data-driven stratification based on molecular phenotype. Neutrophil activation-associated signatures were prominently enriched in severe patient groups, which was corroborated in whole blood transcriptomes from an independent second cohort of 30 as well as in granulocyte samples from a third cohort of 16 COVID-19 patients (44 samples). Comparison of COVID-19 blood transcriptomes with those of a collection of over 3100 samples derived from 12 different viral infections, inflammatory diseases, and independent control samples revealed highly specific transcriptome signatures for COVID-19. Further, stratified transcriptomes predicted patient subgroup-specific drug candidates targeting the dysregulated systemic immune response of the host. Conclusions Our study provides novel insights in the distinct molecular subgroups or phenotypes that are not simply explained by clinical parameters. We show that whole blood transcriptomes are extremely informative for COVID-19 since they capture granulocytes which are major drivers of disease severity.

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