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1.
Frontiers in Pediatrics ; 10, 2022.
Article in English | Web of Science | ID: covidwho-2005893

ABSTRACT

Central nervous system (CNS) involvement in monogenic autoinflammatory disorders (AID) is increasingly recognized and can be life threatening. Therefore, a low threshold to consider CNS disease should be maintained in patients with systemic inflammation. Hyperinflammation is also a key feature of severe acute COVID-19 and post COVID-19 entities such as multisystem inflammatory syndrome in children. Like AID, COVID-19 patients can present with severe CNS involvement. The impact of COVID-19 on AID and CNS involvement in particular is still obscure, nevertheless dreaded. In the current review, we synthesize the spectrum of CNS manifestations in monogenic AID. We explore common pathophysiological and clinical features of AID and COVID-19. Moreover, we assess the impact of immune dysregulation associated with SARS-CoV-2 infections and post COVID-19 hyperinflammation in AID. The striking commonalities found between both disease entities warrant caution in the management of AID patients during the current pandemic.

2.
Pharmacol Res ; 182: 106293, 2022 08.
Article in English | MEDLINE | ID: covidwho-1882440

ABSTRACT

The innate immune system is critically involved in the pathogenesis of familial Mediterranean fever (FMF), characterized by dysregulated inflammasome activity and recurrent inflammatory attacks: this is the most common among monogenic autoinflammatory diseases, which shares some biochemical pathways with the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. In this short review we explore the overlap in the pathophysiology of FMF and SARS-CoV-2 infection, discussing how to understand better the interaction between the two diseases and optimize management. A poorer outcome of SARS-CoV-2 infection seems not to be present in infected FMF patients in terms of hospitalization time, need for oxygen support, need for intensive care, rate of complications and exitus. Long-term surveillance will confirm the relatively low risk of a worse prognosis observed so far in SARS-CoV-2-infected people with FMF. In these patients COVID-19 vaccines are recommended and their safety profile is expected to be similar to the general population.


Subject(s)
COVID-19 , Familial Mediterranean Fever , COVID-19 Vaccines , Colchicine , Familial Mediterranean Fever/complications , Familial Mediterranean Fever/genetics , Humans , SARS-CoV-2
3.
Int J Mol Sci ; 23(8)2022 Apr 12.
Article in English | MEDLINE | ID: covidwho-1785752

ABSTRACT

Systemic juvenile idiopathic arthritis (sJIA) is a serious multifactorial autoinflammatory disease with a significant mortality rate due to macrophage activation syndrome (MAS). Recent research has deepened the knowledge about the pathophysiological mechanisms of sJIA-MAS, facilitating new targeted treatments, and biological disease-modifying antirheumatic drugs (bDMARDs), which significantly changed the course of the disease and prognosis. This review highlights that children are less likely to suffer severe COVID-19 infection, but at approximately 2-4 weeks, some cases of multisystem inflammatory syndrome in children (MIS-C) have been reported, with a fulminant course. Previous established treatments for cytokine storm syndrome (CSS) have guided COVID-19 therapeutics. sJIA-MAS is different from severe cases of COVID-19, a unique immune process in which a huge release of cytokines will especially flood the lungs. In this context, MIS-C should be reinterpreted as a special MAS, and long-term protection against SARS-CoV-2 infection can only be provided by the vaccine, but we do not yet have sufficient data. COVID-19 does not appear to have a substantial impact on rheumatic and musculoskeletal diseases (RMDs) activity in children treated with bDMARDs, but the clinical features, severity and outcome in these patients under various drugs are not yet easy to predict. Multicenter randomized controlled trials are still needed to determine when and by what means immunoregulatory products should be administered to patients with sJIA-MAS with a negative corticosteroid response or contraindications, to optimize their health and safety in the COVID era.


Subject(s)
Antirheumatic Agents , Arthritis, Juvenile , COVID-19 , Macrophage Activation Syndrome , Antirheumatic Agents/therapeutic use , COVID-19/complications , Child , Humans , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/etiology , Multicenter Studies as Topic , SARS-CoV-2 , Systemic Inflammatory Response Syndrome
4.
European Journal of Immunology ; 51:362-362, 2021.
Article in English | Web of Science | ID: covidwho-1716882
5.
Biomolecules ; 11(9)2021 09 08.
Article in English | MEDLINE | ID: covidwho-1438506

ABSTRACT

The majority of critically ill intensive care unit (ICU) patients with severe sepsis develop ICU-acquired weakness (ICUAW) characterized by loss of muscle mass, reduction in myofiber size and decreased muscle strength leading to persisting physical impairment. This phenotype results from a dysregulated protein homeostasis with increased protein degradation and decreased protein synthesis, eventually causing a decrease in muscle structural proteins. The ubiquitin proteasome system (UPS) is the predominant protein-degrading system in muscle that is activated during diverse muscle atrophy conditions, e.g., inflammation. The specificity of UPS-mediated protein degradation is assured by E3 ubiquitin ligases, such as atrogin-1 and MuRF1, which target structural and contractile proteins, proteins involved in energy metabolism and transcription factors for UPS-dependent degradation. Although the regulation of activity and function of E3 ubiquitin ligases in inflammation-induced muscle atrophy is well perceived, the contribution of the proteasome to muscle atrophy during inflammation is still elusive. During inflammation, a shift from standard- to immunoproteasome was described; however, to which extent this contributes to muscle wasting and whether this changes targeting of specific muscular proteins is not well described. This review summarizes the function of the main proinflammatory cytokines and acute phase response proteins and their signaling pathways in inflammation-induced muscle atrophy with a focus on UPS-mediated protein degradation in muscle during sepsis. The regulation and target-specificity of the main E3 ubiquitin ligases in muscle atrophy and their mode of action on myofibrillar proteins will be reported. The function of the standard- and immunoproteasome in inflammation-induced muscle atrophy will be described and the effects of proteasome-inhibitors as treatment strategies will be discussed.


Subject(s)
Inflammation/pathology , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Proteasome Endopeptidase Complex/metabolism , Ubiquitin/metabolism , Animals , Cytokines/metabolism , Humans , Proteolysis
6.
Z Rheumatol ; 80(7): 647-657, 2021 Sep.
Article in German | MEDLINE | ID: covidwho-1258199

ABSTRACT

Colchicine, the toxin of the autumn crocus, has various anti-inflammatory effects. For this reason, it is being used for the treatment of several autoinflammatory diseases, such as gout or familial Mediterranean fever (FMF). In addition, some interesting studies have been published which suggest the benefits of colchicine in cardiovascular diseases. Furthermore, various anti-inflammatory therapeutic approaches are currently being tested in clinical trials for the treatment of COVID-19. First publications suggest a potential benefit of colchicine in certain disease phases of the virus infection. This article provides an overview of the mechanisms of action, benefits and side effects as well as the various possible uses of colchicine in rheumatology. Furthermore, a brief preview of potential new areas for use of the drug, which are also of interest to rheumatologists, are presented.


Subject(s)
COVID-19 , Familial Mediterranean Fever , Rheumatology , Colchicine/therapeutic use , Humans , SARS-CoV-2
7.
J Allergy Clin Immunol Pract ; 9(2): 641-650, 2021 02.
Article in English | MEDLINE | ID: covidwho-1062428

ABSTRACT

Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease. Further evidence supports a role for innate immunity in normally regulating adaptive immune responses. Thus, changes in immune responses that normally occur with age may help explain an apparent protective role of immune immaturity during virus infections.


Subject(s)
Aging/immunology , Virus Diseases/immunology , Adaptive Immunity , Animals , Humans , Immunity, Innate
9.
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
10.
Cell Rep ; 33(7): 108407, 2020 11 17.
Article in English | MEDLINE | ID: covidwho-927290

ABSTRACT

Individuals with Down syndrome (DS; trisomy 21) display hyperactivation of interferon (IFN) signaling and chronic inflammation, which could potentially be explained by the extra copy of four IFN receptor (IFNR) genes encoded on chromosome 21. However, the clinical effects of IFN hyperactivity in DS remain undefined. Here, we report that a commonly used mouse model of DS overexpresses IFNR genes and shows hypersensitivity to IFN ligands in diverse immune cell types. When treated repeatedly with a TLR3 agonist to induce chronic inflammation, these animals overexpress key IFN-stimulated genes, induce cytokine production, exhibit liver pathology, and undergo rapid weight loss. Importantly, the lethal immune hypersensitivity and cytokine production and the ensuing pathology are ameliorated by JAK1 inhibition. These results indicate that individuals with DS may experience harmful hyperinflammation upon IFN-inducing immune stimuli, as observed during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, pointing to JAK1 inhibition as a strategy to restore immune homeostasis in DS.


Subject(s)
Azetidines/therapeutic use , Down Syndrome/immunology , Hypersensitivity/drug therapy , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Animals , Down Syndrome/complications , Female , Hypersensitivity/etiology , Hypersensitivity/immunology , Immunity, Innate , Interferon-alpha/metabolism , Liver/immunology , Male , Mice , Mice, Inbred C57BL , Purines , Pyrazoles , Toll-Like Receptors/metabolism
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