Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 15 de 15
Filter
1.
J Immunol Res ; 2022: 1433323, 2022.
Article in English | MEDLINE | ID: covidwho-1697599

ABSTRACT

We performed a database mining on 102 transcriptomic datasets for the expressions of 29 m6A-RNA methylation (epitranscriptomic) regulators (m6A-RMRs) in 41 diseases and cancers and made significant findings: (1) a few m6A-RMRs were upregulated; and most m6A-RMRs were downregulated in sepsis, acute respiratory distress syndrome, shock, and trauma; (2) half of 29 m6A-RMRs were downregulated in atherosclerosis; (3) inflammatory bowel disease and rheumatoid arthritis modulated m6A-RMRs more than lupus and psoriasis; (4) some organ failures shared eight upregulated m6A-RMRs; end-stage renal failure (ESRF) downregulated 85% of m6A-RMRs; (5) Middle-East respiratory syndrome coronavirus infections modulated m6A-RMRs the most among viral infections; (6) proinflammatory oxPAPC modulated m6A-RMRs more than DAMP stimulation including LPS and oxLDL; (7) upregulated m6A-RMRs were more than downregulated m6A-RMRs in cancer types; five types of cancers upregulated ≥10 m6A-RMRs; (8) proinflammatory M1 macrophages upregulated seven m6A-RMRs; (9) 86% of m6A-RMRs were differentially expressed in the six clusters of CD4+Foxp3+ immunosuppressive Treg, and 8 out of 12 Treg signatures regulated m6A-RMRs; (10) immune checkpoint receptors TIM3, TIGIT, PD-L2, and CTLA4 modulated m6A-RMRs, and inhibition of CD40 upregulated m6A-RMRs; (11) cytokines and interferons modulated m6A-RMRs; (12) NF-κB and JAK/STAT pathways upregulated more than downregulated m6A-RMRs whereas TP53, PTEN, and APC did the opposite; (13) methionine-homocysteine-methyl cycle enzyme Mthfd1 downregulated more than upregulated m6A-RMRs; (14) m6A writer RBM15 and one m6A eraser FTO, H3K4 methyltransferase MLL1, and DNA methyltransferase, DNMT1, regulated m6A-RMRs; and (15) 40 out of 165 ROS regulators were modulated by m6A eraser FTO and two m6A writers METTL3 and WTAP. Our findings shed new light on the functions of upregulated m6A-RMRs in 41 diseases and cancers, nine cellular and molecular mechanisms, novel therapeutic targets for inflammatory disorders, metabolic cardiovascular diseases, autoimmune diseases, organ failures, and cancers.


Subject(s)
Atherosclerosis/genetics , Epigenesis, Genetic , Neoplasms/genetics , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolism , Adenosine/analogs & derivatives , Adenosine/metabolism , Autoimmune Diseases/genetics , Datasets as Topic , Gene Expression Profiling , Humans , Inflammation/genetics , Metabolic Diseases/genetics , Methylation
2.
Curr Opin Immunol ; 72: 230-238, 2021 10.
Article in English | MEDLINE | ID: covidwho-1603901

ABSTRACT

The study of monogenic autoimmune diseases has provided key insights into molecular mechanisms involved in development of autoimmunity and immune tolerance. It has also become clear that such inborn errors of immunity (IEIs) frequently present clinically not only with autoimmune diseases, but also frequently have increased susceptibility to infection. The genes associated with monogenic autoimmunity influence diverse functional pathways, and the resulting immune dysregulation also impacts the complex and coordinated immune response to pathogens, for example type I interferon and cytokine signaling, the complement pathway and proper differentiation of the immune response. The SARS-CoV-2 pandemic has highlighted how monogenic autoimmunity can increase risk for serious infection with the discovery of severe disease in patients with pre-existing antibodies to Type I IFNs. This review discusses recent insight into the relationship between monogenic autoimmunity and infectious diseases.


Subject(s)
Autoimmune Diseases/immunology , COVID-19/immunology , Communicable Diseases/immunology , SARS-CoV-2/physiology , Animals , Autoimmune Diseases/genetics , COVID-19/genetics , Communicable Diseases/genetics , Disease Susceptibility , Humans , Interferon Type I/metabolism
3.
Mol Cells ; 44(12): 861-878, 2021 Dec 31.
Article in English | MEDLINE | ID: covidwho-1592997

ABSTRACT

The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.


Subject(s)
Autoimmune Diseases/genetics , Endogenous Retroviruses/genetics , Gene Expression Regulation , Models, Animal , Neoplasms/genetics , Terminal Repeat Sequences/genetics , Animals , Autoimmune Diseases/virology , COVID-19/genetics , COVID-19/virology , Humans , Neoplasms/virology , SARS-CoV-2/physiology
4.
Biomolecules ; 11(10)2021 09 28.
Article in English | MEDLINE | ID: covidwho-1480575

ABSTRACT

BACKGROUND: Acute myocarditis often progresses to heart failure because there is no effective, etiology-targeted therapy of this disease. Simvastatin has been shown to be cardioprotective by decreasing matrix metalloproteinases' (MMPs) activity. The study was designed to determine whether simvastatin inhibits MMPs activity, decreases the severity of inflammation and contractile dysfunction of the heart in experimental autoimmune myocarditis (EAM). METHODS: Simvastatin (3 or 30 mg/kg/day) was given to experimental rats with EAM by gastric gavage for 21 days. Then transthoracic echocardiography was performed, MMPs activity and troponin I level were determined and tissue samples were assessed under a light and transmission electron microscope. RESULTS: Hearts treated with simvastatin did not show left ventricular enlargement. As a result of EAM, there was an enhanced activation of MMP-9, which was significantly reduced in the high-dose simvastatin group compared to the low-dose group. It was accompanied by prevention of myofilaments degradation and reduction of severity of inflammation. CONCLUSIONS: The cardioprotective effects of simvastatin in the acute phase of EAM are, at least in part, due to its ability to decrease MMP-9 activity and subsequent decline in myofilaments degradation and suppression of inflammation. These effects were achieved in doses equivalent to therapeutic doses in humans.


Subject(s)
Inflammation/drug therapy , Metalloproteases/genetics , Myocarditis/drug therapy , Simvastatin/pharmacology , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Cardiotonic Agents/pharmacology , Echocardiography , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Inflammation/genetics , Inflammation/immunology , Inflammation/pathology , Metalloproteases/antagonists & inhibitors , Models, Animal , Myocarditis/genetics , Myocarditis/immunology , Myocarditis/pathology , Rats , Ventricular Dysfunction, Left/drug therapy , Ventricular Dysfunction, Left/pathology , Ventricular Dysfunction, Left/prevention & control
6.
Front Immunol ; 11: 631743, 2020.
Article in English | MEDLINE | ID: covidwho-1389175

ABSTRACT

The concept of trained immunity has recently emerged as a mechanism contributing to several immune mediated inflammatory conditions. Trained immunity is defined by the immunological memory developed in innate immune cells after a primary non-specific stimulus that, in turn, promotes a heightened inflammatory response upon a secondary challenge. The most characteristic changes associated to this process involve the rewiring of cell metabolism and epigenetic reprogramming. Under physiological conditions, the role of trained immune cells ensures a prompt response. This action is limited by effective resolution of inflammation and tissue repair in order to restore homeostasis. However, unrestrained activation of innate immune cells contributes to the development of chronic inflammation and tissue destruction through the secretion of inflammatory cytokines, proteases and growth factors. Therefore, interventions aimed at reversing the changes induced by trained immunity provide potential therapeutic approaches to treat inflammatory and autoimmune diseases like rheumatoid arthritis (RA). We review cellular approaches that target metabolism and the epigenetic reprogramming of dendritic cells, macrophages, natural killer cells, and other trained cells in the context of autoimmune inflammatory diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmunity/drug effects , Biological Products/therapeutic use , Immune System/drug effects , Inflammation/drug therapy , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , COVID-19/drug therapy , COVID-19/immunology , Energy Metabolism/drug effects , Epigenesis, Genetic/drug effects , Humans , Immune System/immunology , Immune System/metabolism , Immunity, Innate/drug effects , Immunologic Memory/drug effects , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Signal Transduction
7.
Exp Dermatol ; 30(9): 1254-1257, 2021 09.
Article in English | MEDLINE | ID: covidwho-1255381

ABSTRACT

The SARS-CoV-2 pandemic has evolved to a global health problem with a dramatic morbidity and mortality rate impacting our daily life and those of many patients. While there is evidence that some diseases are associated with an increased risk for development of a more severe course of COVID-19, little is known on protective conditions. Importantly, clearance of viral infection and protection against disease manifestation crucially depends on functional innate and adaptive immunity and the interferon signalling axis. Here, we hypothesize that patients with non-segmental vitiligo (NSV), an autoimmune skin (and mucosal) disorder, may clear SARS-CoV-2 infection more efficiently and have a lower risk of COVID-19 development. Conversely, in case of COVID-19 development, vitiligo autoimmunity may influence the cytokine storm-related disease burden. In addition, immune activation during SARS-CoV-2 infection or COVID-19 disease might increase vitiligo disease activity. Our hypothesis is based on the shift of the immune system in NSV towards adaptive type 1 (IFNγ and CD8 T cells) and innate immune responses. Identified susceptibility genes of NSV patients may further confer increased antiviral activity. To validate our hypothesis, we suggest an international consortium to perform a retrospective data registry and patient-reported study on a large number of NSV patients worldwide during the COVID-19 pandemic.


Subject(s)
Autoimmune Diseases/epidemiology , COVID-19/epidemiology , Vitiligo/epidemiology , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Genetic Predisposition to Disease , Humans , Immunity, Innate , Protective Factors , SARS-CoV-2 , Vitiligo/genetics , Vitiligo/immunology
8.
Eur J Gastroenterol Hepatol ; 33(1S Suppl 1): e1051-e1056, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1242125

ABSTRACT

Gut involvement is frequent in immunologic disorders, especially with inflammatory manifestations but also with cancer. In the last years, advances in functional and genetic testing have improved the diagnostic and therapeutic approach to immune dysregulation syndromes. CTLA-4 deficiency is a rare disease with variable phenotype, ranging from absence of symptoms to severe multisystem manifestations and complications. We describe a rare case of CTLA-4 deficiency in a boy with gastric cancer, very early onset inflammatory bowel disease and polyautoimmunity, the second-ever reported in the literature with the same characteristics. A 17-year-old boy was referred to Bambino Gesù Children's Hospital of Rome, a tertiary care center, for a gastric mass and a long-term history of very early onset inflammatory bowel disease, diabetes mellitus type 1, polyarthritis and psoriasis. Histology of gastric biopsies revealed the presence of neoplastic signet ring cells. Imaging staging showed localized cancer; therefore, the patient underwent subtotal gastrectomy with termino-lateral gastro-jejunal anastomosis. Immunological work up and genetic testing by next-generation sequencing panels for primary immunodeficiencies led to the diagnosis of CTLA-4 deficiency. Good disease control was obtained with the administration of Abatacept. The patient experienced an asymptomatic SARS-CoV-2 infection without any concern. Eighteen months after treatment initiation, the patient is alive and well. Immunologic and genetic testing, such as next-generation sequencing, should always be part of the diagnostic approach to patients with complex immune dysregulation syndrome, severe clinical course, poor response to treatments or cancer. The early recognition of the monogenic disease is the key for disease management and targeted therapy.


Subject(s)
Abatacept/therapeutic use , Autoimmune Diseases , CTLA-4 Antigen/deficiency , Inflammatory Bowel Diseases , Stomach Neoplasms , Adolescent , Asymptomatic Infections , Autoimmune Diseases/diagnosis , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , COVID-19 , CTLA-4 Antigen/genetics , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Male , Stomach Neoplasms/diagnosis , Stomach Neoplasms/drug therapy , Stomach Neoplasms/genetics
9.
Cytokine Growth Factor Rev ; 58: 134-140, 2021 04.
Article in English | MEDLINE | ID: covidwho-1074698

ABSTRACT

Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.


Subject(s)
Autoimmunity , COVID-19/genetics , COVID-19/immunology , Cytokines/physiology , Interferons/physiology , Autoimmune Diseases/complications , Autoimmune Diseases/epidemiology , Autoimmune Diseases/genetics , Autoimmunity/genetics , Autoimmunity/immunology , COVID-19/epidemiology , COVID-19/therapy , Genetic Diseases, Inborn/complications , Genetic Diseases, Inborn/epidemiology , Genetic Diseases, Inborn/immunology , Genetic Predisposition to Disease/genetics , Humans
10.
J Exp Med ; 218(4)2021 04 05.
Article in English | MEDLINE | ID: covidwho-1066211

ABSTRACT

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Subject(s)
Antibodies, Neutralizing/immunology , Autoantibodies/immunology , Autoimmune Diseases , COVID-19 , Genetic Diseases, Inborn , Interferon-alpha , Receptor, Interferon alpha-beta , SARS-CoV-2 , Yellow Fever Vaccine , Yellow fever virus , Adolescent , Adult , Aged , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , COVID-19/genetics , COVID-19/immunology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , HEK293 Cells , Humans , Interferon-alpha/genetics , Interferon-alpha/immunology , Male , Middle Aged , Receptor, Interferon alpha-beta/deficiency , Receptor, Interferon alpha-beta/immunology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccines, Attenuated/genetics , Vaccines, Attenuated/immunology , Yellow Fever Vaccine/adverse effects , Yellow Fever Vaccine/genetics , Yellow Fever Vaccine/immunology , Yellow fever virus/genetics , Yellow fever virus/immunology
11.
Front Immunol ; 11: 586111, 2020.
Article in English | MEDLINE | ID: covidwho-1016060

ABSTRACT

COVID-19 presentation is very heterogeneous across cases, and host factors are at the forefront for the variables affecting the disease manifestation. The immune system has emerged as a key determinant in shaping the outcome of SARS-CoV-2 infection. It is mainly the deleterious unconstrained immune response, rather than the virus itself, which leads to severe cases of COVID-19 and the associated mortality. Genetic susceptibility to dysregulated immune response is highly likely to be among the host factors for adverse disease outcome. Given that such genetic susceptibility has also been observed in autoimmune diseases (ADs), a number of critical questions remain unanswered; whether individuals with ADs have a significantly different risk for COVID-19-related complications compared to the general population, and whether studies on the genetics of ADs can shed some light on the host factors in COVID-19. In this perspective, we discuss the host genetic factors, which have been under investigation in association with COVID-19 severity. We touch upon the intricate link between autoimmunity and COVID-19 pathophysiology. We put forth a number of autoimmune susceptibility genes, which have the potential to be additional host genetic factors for modifying the severity of COVID-19 presentation. In summary, host genetics at the intersection of ADs and COVID-19 may serve as a source for understanding the heterogeneity of COVID-19 severity, and hence, potentially holds a key in achieving effective strategies in risk group identification, as well as effective treatments.


Subject(s)
Autoimmune Diseases/genetics , COVID-19/genetics , SARS-CoV-2 , Autoimmunity/genetics , Genetic Predisposition to Disease , Humans , Severity of Illness Index
12.
Probl Endokrinol (Mosk) ; 66(4): 9-15, 2020 09 01.
Article in Russian | MEDLINE | ID: covidwho-994559

ABSTRACT

Genes of HLA system (Human Leukocyte Antigen) play an essential role in the normal functioning of the immune system. There are three classes of genes: I, II, and III. The function of HLA molecules class I is to present antigens of peptides from the cytoplasm to T-lymphocytes on the cell surface, and class II - to present antigens of peptides from the extracellular space. In the classical view, the pathological activation of the immune system in patients with a genetic predisposition can result in the development of autoimmune diseases. However, the influence of this system on the development of non-autoimmune diseases, their severity and prognosis, has been recently considered. Besides, HLA molecules provide a presentation of various infectious agents. In this connection, the loci of the main histocompatibility complex can be considered candidates for determining the genetic predisposition to infectious diseases themselves and their course. This review hypothesizes that specific variants of HLA genes may cause the formation of a «cytokine storm¼ in patients with COVID-19. Identification of a group of patients with particular genetic variations that cause violation of immune tolerance and hyperresponse in the setting of viral infection will help to optimize the algorithm for disease prevention and treatment of such patients and, as a result, to reduce the severity of the epidemiological situation.


Subject(s)
Autoimmune Diseases/immunology , COVID-19/genetics , Cytokine Release Syndrome/genetics , HLA Antigens/immunology , Alleles , Autoimmune Diseases/epidemiology , Autoimmune Diseases/genetics , Autoimmune Diseases/virology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Genetic Predisposition to Disease , HLA Antigens/genetics , Humans , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
13.
Clin Rev Allergy Immunol ; 61(2): 156-170, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-942613

ABSTRACT

Inflammasomes are multiprotein complexes capable of sensing pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and cellular perturbations. Upon stimulation, the inflammasomes activate the production of the pro-inflammatory cytokines IL-1ß and IL-18 and induce gasdermin D-mediated pyroptosis. Dysregulated inflammasome signaling could lead to hyperinflammation in response to environmental triggers, thus contributing to the pathogenesis of childhood autoimmune/autoinflammatory diseases. In this review, we group childhood rheumatic diseases into the autoinflammation to autoimmunity spectrum and discuss about the involvement of inflammasomes in disease mechanisms. Genetic mutations in inflammasome components cause monogenic autoinflammatory diseases, while inflammasome-related genetic variants have been implicated in polygenic childhood rheumatic diseases. We highlight the reported associations of inflammasome signaling-related genetic polymorphisms/protein levels with pediatric autoimmune disease susceptibility and disease course. Furthermore, we discuss about the use of IL-1 receptor antagonist as an adjunctive therapy in several childhood autoimmune diseases, including macrophage activation syndrome (MAS) and multisystem inflammatory syndrome in children (MIS-C) related to COVID-19. A comprehensive multi-cohort comparison on inflammasome gene expression profile in different pediatric rheumatic diseases is needed to identify patient subsets that might benefit from the adjunctive therapy of IL-1ß inhibitors.


Subject(s)
Autoimmune Diseases/genetics , Autoimmune Diseases/metabolism , Inflammasomes/genetics , Inflammasomes/metabolism , Animals , Autoimmunity/genetics , Child , Cytokines/genetics , Humans , Mutation/genetics , Rheumatic Diseases/genetics , Rheumatic Diseases/metabolism , Signal Transduction/genetics
14.
Cytokine ; 132: 155109, 2020 08.
Article in English | MEDLINE | ID: covidwho-102306
SELECTION OF CITATIONS
SEARCH DETAIL