Autoinflammation: Interferonopathies and Other Autoinflammatory Diseases

Savic, Sinisa; Coe, James; Laws, Philip

doi:10.1016/j.jid.2021.07.189

Cited by 8 publications

(5 citation statements)

References 102 publications

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“…By contrast, genetic disorders involving genes of the 19S regulatory particle such as the Stankiewicz-Isidor syndrome [STISS; Mendelian Inheritance in Man (MIM): 617516] caused by truncating variants of PSMD12 (also referred to as Rpn5) are neurodevelopmental polymalformative syndromes (34) with subclinical activation of type I IFN signaling (35,36). These observations place both PRAAS and STISS in the category of type I interferonopathies, a recent family of genetically determined rare autoinflammatory syndromes with dysregulated type I IFN signaling that includes Aicardi-Goutières syndrome and familial chilblain lupus (37,38). Clinically, these diseases are complex, demonstrating multiple organ involvement (often brain and skin), encompassing a broad range of phenotypes, and being associated with high morbidity and mortality (39).…”

Section: Introductionmentioning

confidence: 99%

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

et al. 2023

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A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26 S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.

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Section: Introductionmentioning

confidence: 99%

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

et al. 2023

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“…Individual patients may tolerate or respond differently to the various preparations [ 7 , 8 , 9 , 10 , 11 ]. However, certain patients may not tolerate or respond effectively to colchicine and, therefore, require alternative treatments such as IL-1 targeting agents [ 13 , 14 , 15 , 16 ]. Patients requiring biological drugs often encounter accessibility challenges, such as physicians refusing to prescribe medications due to high costs, insurance companies not approving biological medications, limited approval (only a small number of patients are allocated to receive medication), or the drugs not being available in the patient’s country of residence.…”

Section: Discussionmentioning

confidence: 99%

“…Interleukin (IL)-1 inhibitors such as anakinra, canakinumab, and rilonacept are effective in the treatment of many different AIDs [ 6 , 7 , 8 , 9 , 10 ]. However, these biological drugs are not available in all countries, making effective disease control difficult [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Patient Experiences and Challenges in the Management of Autoinflammatory Diseases—Data from the International FMF & AID Global Association Survey

Rech,

Schett,

Tufan

et al. 2024

JCM

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Background: Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was developed in collaboration between the FMF & AID Global Association and the Erlangen Center for Periodic Systemic Autoinflammatory Diseases. Methods: A t. The aim of the survey was to collect the personal assessment of affected patients with regard to their current status in terms of diagnostic timeframes, the interpretation of genetic tests, the number of misdiagnoses, and pain and fatigue despite treatment. Results: In total, data from 1043 AID patients (829 adults and 214 children/adolescents) from 52 countries were collected and analyzed. Familial Mediterranean fever (FMF) (521/50%) and Behçet’s disease (311/30%) were the most frequently reported diseases. The average time to diagnosis was 3 years for children/adolescents and 14 years for adults. Prior to the diagnosis of autoinflammatory disease, patients received several misdiagnoses, including psychosomatic disorders. he vast majority of patients reported that genetic testing was available (92%), but only 69% were tested. A total of 217 patients reported that no increase in acute-phase reactants was detected during their disease episodes. The intensity of pain and fatigue was measured in AID patients and found to be high. A total of 88% of respondents received treatment again, while 8% reported no treatment. Conclusions: AID patients, particularly adults, suffer from significant delays in diagnosis, misdiagnosis, and a variety of symptoms, including pain and fatigue. Based on the results presented, raising awareness of these diseases in the wider medical community is crucial to improving patient care and, therefore, the likely quality of life.

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“…Dysregulated innate viral defense mechanisms induce hyperactive JAK/STAT-signaling and Type-I-mediated gene expression reminiscent of type-I-interferonopathies, presenting with usually severe autoinflammatory diseases such as SLE-type or Aicardi-Goutières-syndrome ( 38 , 39 ). Despite the overactivation of JAK/STAT-signaling in SOCS1-HI, we do not see upregulated Type-I Interferon mediated gene expression in all affected individuals ( 11 ).…”

Section: Socs1 Perspectivesmentioning

confidence: 99%

One gene to rule them all – clinical perspectives of a potent suppressor of cytokine signaling – SOCS1

Körholz,

Chen,

Strauss

et al. 2024

Front. Immunol.

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The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

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Autoinflammation: Interferonopathies and Other Autoinflammatory Diseases

Cited by 8 publications

References 102 publications

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production

Patient Experiences and Challenges in the Management of Autoinflammatory Diseases—Data from the International FMF & AID Global Association Survey

One gene to rule them all – clinical perspectives of a potent suppressor of cytokine signaling – SOCS1

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