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Pediatric Rheumatology Online Journal Oct 2023Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This...
BACKGROUND
Monogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs.
METHODS
This was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses.
RESULTS
A total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions.
CONCLUSION
The largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.
Topics: Humans; Child; Thalidomide; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Hereditary Autoinflammatory Diseases; Familial Mediterranean Fever; Cryopyrin-Associated Periodic Syndromes
PubMed: 37848905
DOI: 10.1186/s12969-023-00881-0 -
Accounts of Chemical Research Sep 2023The term RNA editing refers to any structural change in an RNA molecule ( insertion, deletion, or base modification) that changes its coding properties and is not a...
The term RNA editing refers to any structural change in an RNA molecule ( insertion, deletion, or base modification) that changes its coding properties and is not a result of splicing. An important class of enzymes involved in RNA editing is the ADAR family (adenosine deaminases acting on RNA), which facilitate the deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). Inosines are decoded as guanosines (G) in most cellular processes; hence, A-to-I editing can be considered an A-to-G substitution. Among the RNA editing enzymes, ADARs are of particular interest because a large portion of RNA editing events are due to A-to-I editing by the two catalytically active human ADARs (ADAR1 and ADAR2). ADARs have diverse roles in RNA processing, gene expression regulation, and innate immunity; and mutations in the ADAR genes and dysregulated ADAR activity have been associated with cancer, autoimmune diseases, and neurological disorders. A-to-I editing is also currently being explored for correcting disease-causing mutations in the RNA, where therapeutic guide oligonucleotides complementary to the target transcript are used to form a dsRNA substrate and site-specifically direct ADAR editing. Knowledge of the mechanism of ADAR-catalyzed reaction and the origin of its substrate selectivity will allow understanding of ADAR’s role in disease biology and expedite the process of developing ADAR-targeted therapeutics. Chemically modified oligonucleotides provide a versatile platform for modulating the activity and interrogating the structure, function, and selectivity of nucleic acid binding or modifying proteins. In this account, we provide an overview of oligonucleotide modifications that have allowed us to gain deeper understanding of ADAR’s molecular mechanisms, which we utilize in the rational design and optimization of ADAR activity modulators. First, we describe the use of the nucleoside analog 8-azanebularine (8-azaN) to generate high-affinity ADAR-RNA complexes for biochemical and biophysical studies with ADARs, with particular emphasis on X-ray crystallography. We then discuss key observations derived from the crystal structures of ADAR bound to 8-azaN-modified RNA duplexes and describe how these findings provided insight into ADAR editing optimization by introducing nucleoside modifications at various positions in synthetic guide strands. We also present the informed design of 8-azaN-modified RNA duplexes that selectively bind and inhibit ADAR1 but not the closely-related ADAR2 enzyme. Finally, we conclude with some open questions on ADAR structure and substrate recognition and share our current endeavors in the development of ADAR guide oligonucleotides and inhibitors.
Topics: Humans; RNA; Adenosine Deaminase; Hydrolases; Adenosine; Autoimmune Diseases
PubMed: 37665999
DOI: 10.1021/acs.accounts.3c00390 -
Science Advances Mar 2024Chronic and aberrant nucleic acid sensing causes type I IFN-driven autoimmune diseases, designated type I interferonopathies. We found a significant reduction of...
Chronic and aberrant nucleic acid sensing causes type I IFN-driven autoimmune diseases, designated type I interferonopathies. We found a significant reduction of regulatory T cells (T) in patients with type I interferonopathies caused by mutations in or (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that T-specific deletion of caused peripheral T loss and -like lethal autoimmune disorders. Similarly, knock-in mice with T-specific expression of an MDA5 gain-of-function mutant caused apoptosis of peripheral T and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on T is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of T homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies.
Topics: Humans; Mice; Animals; Autoimmunity; RNA; T-Lymphocytes, Regulatory; Autoimmune Diseases; Nucleic Acids; Adenosine Deaminase
PubMed: 38427731
DOI: 10.1126/sciadv.adk0820 -
Scientific Reports Oct 2023The Asian tiger mosquito, Aedes albopictus, is an important vector for the transmission of arboviruses such as dengue virus (DENV). Adenosine deaminase (ADA) is a...
The Asian tiger mosquito, Aedes albopictus, is an important vector for the transmission of arboviruses such as dengue virus (DENV). Adenosine deaminase (ADA) is a well-characterized metabolic enzyme involved in facilitating blood feeding and (or) arbovirus transmission in some hematophagous insect species. We previously reported the immunologic function of ADA by investigating its effect on mast cell activation and the interaction with mast cell tryptase and chymase. The 2-D gel electrophoresis and mass spectrometry analysis in the current study revealed that ADA is present and upregulated following mosquito blood feeding, as confirmed by qRT-PCR and western blot. In addition, the recombinant ADA efficiently converted adenosine to inosine. Challenging the Raw264.7 and THP-1 cells with recombinant ADA resulted in the upregulation of IL-1β, IL-6, TNF-α, CCL2, IFN-β, and ISG15. The current study further identified recombinant ADA as a positive regulator in NF-κB signaling targeting TAK1. It was also found that recombinant Ae. albopictus ADA facilitates the replication of DENV-2. Compared with cells infected by DENV-2 alone, the co-incubation of recombinant ADA with DENV-2 substantially increased IL-1β, IL-6, TNF-α, and CCL2 gene transcripts in Raw264.7 and THP-1 cells. However, the expression of IFN-β and ISG15 were markedly downregulated in Raw264.7 cells but upregulated in THP-1 cells. These findings suggest that the immunomodulatory protein, Ae. albopictus ADA is involved in mosquito blood feeding and may modulate DENV transmission via macrophage or monocyte-driven immune response.
Topics: Animals; Dengue Virus; Aedes; Mosquito Vectors; Tumor Necrosis Factor-alpha; Adenosine Deaminase; Interleukin-6; Virus Replication; Dengue; Immunity
PubMed: 37794048
DOI: 10.1038/s41598-023-43751-1 -
The Journal of Biological Chemistry Jul 2023Adenosine-to-inosine RNA editing is catalyzed by nuclear adenosine deaminase acting on RNA 1 (ADAR1) p110 and ADAR2, and cytoplasmic ADAR1 p150 in mammals, all of which...
Adenosine-to-inosine RNA editing is catalyzed by nuclear adenosine deaminase acting on RNA 1 (ADAR1) p110 and ADAR2, and cytoplasmic ADAR1 p150 in mammals, all of which recognize dsRNAs as targets. RNA editing occurs in some coding regions, which alters protein functions by exchanging amino acid sequences, and is therefore physiologically significant. In general, such coding sites are edited by ADAR1 p110 and ADAR2 before splicing, given that the corresponding exon forms a dsRNA structure with an adjacent intron. We previously found that RNA editing at two coding sites of antizyme inhibitor 1 (AZIN1) is sustained in Adar1 p110/Aadr2 double KO mice. However, the molecular mechanisms underlying RNA editing of AZIN1 remain unknown. Here, we showed that Azin1 editing levels were increased upon type I interferon treatment, which activated Adar1 p150 transcription, in mouse Raw 264.7 cells. Azin1 RNA editing was observed in mature mRNA but not precursor mRNA. Furthermore, we revealed that the two coding sites were editable only by ADAR1 p150 in both mouse Raw 264.7 and human embryonic kidney 293T cells. This unique editing was achieved by forming a dsRNA structure with a downstream exon after splicing, and the intervening intron suppressed RNA editing. Therefore, deletion of a nuclear export signal from ADAR1 p150, shifting its localization to the nucleus, decreased Azin1 editing levels. Finally, we demonstrated that Azin1 RNA editing was completely absent in Adar1 p150 KO mice. Thus, these findings indicate that RNA editing of AZIN1 coding sites is exceptionally catalyzed by ADAR1 p150 after splicing.
Topics: Animals; Humans; Mice; Adenosine Deaminase; Carrier Proteins; Catalysis; RNA Editing; RNA, Double-Stranded; RNA, Messenger; HEK293 Cells; Mice, Knockout; RAW 264.7 Cells; Interferons; Protein Transport
PubMed: 37209819
DOI: 10.1016/j.jbc.2023.104840 -
Transcriptome analysis identification of A-to-I RNA editing in granulosa cells associated with PCOS.Frontiers in Endocrinology 2023Polycystic ovary syndrome (PCOS) is a complex, multifactor disorder in women of reproductive age worldwide. Although RNA editing may contribute to a variety of diseases,...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a complex, multifactor disorder in women of reproductive age worldwide. Although RNA editing may contribute to a variety of diseases, its role in PCOS remains unclear.
METHODS
A discovery RNA-Seq dataset was obtained from the NCBI Gene Expression Omnibus database of granulosa cells from women with PCOS and women without PCOS (controls). A validation RNA-Seq dataset downloaded from the European Nucleotide Archive Databank was used to validate differential editing. Transcriptome-wide investigation was conducted to analyze adenosine-to-inosine (A-to-I) RNA editing in PCOS and control samples.
RESULTS
A total of 17,395 high-confidence A-to-I RNA editing sites were identified in 3,644 genes in all GC samples. As for differential RNA editing, there were 545 differential RNA editing (DRE) sites in 259 genes with Nucleoporin 43 (), Retinoblastoma Binding Protein 4 (), and leckstrin homology-like domain family A member 1 () showing the most significant three 3'-untranslated region (3'UTR) editing. Furthermore, we identified 20 DRE sites that demonstrated a significant correlation between editing levels and gene expression levels. Notably, MIR193b-365a Host Gene () and Hook Microtubule Tethering Protein 3 () exhibited significant differential expression between PCOS and controls. Functional enrichment analysis showed that these 259 differentially edited genes were mainly related to apoptosis and necroptosis pathways. RNA binding protein (RBP) analysis revealed that RNA Binding Motif Protein 45 (RBM45) was predicted as the most frequent RBP binding with RNA editing sites. Additionally, we observed a correlation between editing levels of differential editing sites and the expression level of the RNA editing enzyme Adenosine Deaminase RNA Specific B1 (). Moreover, the existence of 55 common differentially edited genes and nine differential editing sites were confirmed in the validation dataset.
CONCLUSION
Our current study highlighted the potential role of RNA editing in the pathophysiology of PCOS as an epigenetic process. These findings could provide valuable insights into the development of more targeted and effective treatment options for PCOS.
Topics: Humans; Female; RNA; Polycystic Ovary Syndrome; RNA Editing; Gene Expression Profiling; Granulosa Cells; Nerve Tissue Proteins; RNA-Binding Proteins
PubMed: 37547318
DOI: 10.3389/fendo.2023.1170957 -
Research Square Apr 2024There is currently no prophylactic vaccine available for human immunodeficiency virus (HIV). Research efforts have resulted in improved immunogens that mimic the native...
There is currently no prophylactic vaccine available for human immunodeficiency virus (HIV). Research efforts have resulted in improved immunogens that mimic the native envelope (Env) glycoprotein structure. Recently, a novel triple tandem trimer (TTT) platform has been used to generate a plasmid encoding Env immunogen (pBG505-TTT) that expresses only as trimers, making it more suitable for nucleic acid vaccines. We have previously demonstrated that adenosine deaminase-1 (ADA-1) is critical to the T follicular helper (TFH) function and improves vaccine immune responses . In this study, we demonstrate that co-delivery of plasmid-encoded adenosine deaminase 1 (pADA) with pBG505-TTT enhances the magnitude, durability, isotype switching and functionality of HIV-specific antibodies in a dose-sparing manner. Co-delivery of the molecular immune modulator ADA-1 also enhances HIV-specific T cell polyfunctionality, activation, and degranulation as well as memory B cell responses. These data demonstrate that pADA enhances HIV-specific cellular and humoral immunity, making ADA-1 a promising immune modulator for HIV-targeting vaccines.
PubMed: 38746176
DOI: 10.21203/rs.3.rs-4139764/v1 -
Respiratory Research Jan 2024Adenosine deaminase (ADA) is a useful biomarker for the diagnosis of tuberculous pleurisy (TBP). However, pleural effusions with high ADA can also be caused by other... (Observational Study)
Observational Study
BACKGROUND
Adenosine deaminase (ADA) is a useful biomarker for the diagnosis of tuberculous pleurisy (TBP). However, pleural effusions with high ADA can also be caused by other diseases, particularly hematologic malignant pleural effusion (hMPE). This study aimed to investigate the features that could differentiate TBP and hMPE in patients with pleural effusion ADA ≥ 40 IU/L.
METHODS
This was a retrospective observational study of patients with pleural effusion ADA ≥ 40 IU/L, conducted at a Korean tertiary referral hospital with an intermediate tuberculosis burden between January 2010 and December 2017. Multivariable logistic regression analyses were performed to investigate the features associated with TBP and hMPE, respectively.
RESULTS
Among 1134 patients with ADA ≥ 40 IU/L, 375 (33.1%) and 85 (7.5%) were diagnosed with TBP and hMPE, respectively. TBP and hMPE accounted for 59% (257/433) and 6% (27/433) in patients with ADA between 70 and 150 IU/L, respectively. However, in patients with ADA ≥ 150 IU/L, they accounted for 7% (9/123) and 19% (23/123), respectively. When ADA between 40 and 70 IU/L was the reference category, ADA between 70 and 150 IU/L was independently associated with TBP (adjusted odds ratio [aOR], 3.11; 95% confidence interval [CI], 1.95-4.95; P < 0.001). ADA ≥ 150 IU/L was negatively associated with TBP (aOR, 0.35; 95% CI, 0.14-0.90; P = 0.029) and positively associated with hMPE (aOR, 13.21; 95% CI, 5.67-30.79; P < 0.001). In addition, TBP was independently associated with lymphocytes ≥ 35% and a lactate dehydrogenase (LD)/ADA ratio < 18 in pleural effusion. hMPE was independently associated with pleural polymorphonuclear neutrophils < 50%, thrombocytopenia, and higher serum LD. A combination of lymphocytes ≥ 35%, LD/ADA < 18, and ADA < 150 IU/L demonstrated a sensitivity of 0.824 and specificity of 0.937 for predicting TBP.
CONCLUSION
In patients with very high levels of pleural effusion ADA, hMPE should be considered. Several features in pleural effusion and serum may help to more effectively differentiate TBP from hMPE.
Topics: Humans; Adenosine Deaminase; Tuberculosis, Pleural; Pleural Effusion; Pleural Effusion, Malignant; Hematologic Neoplasms
PubMed: 38178065
DOI: 10.1186/s12931-023-02645-6 -
Journal of Clinical Immunology Jul 2023Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)-deficient severe combined...
PURPOSE
Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID). Elapegademase is a PEGylated recombinant bovine ADA ERT developed to replace the now-discontinued bovine-derived pegademase. This study was a 1-way crossover from pegademase to elapegademase in 7 patients with ADA-SCID to assess efficacy and safety outcomes for elapegademase.
METHODS
After once-weekly pegademase dosage was adjusted to achieve therapeutic metabolic detoxification and trough ADA activity, patients transitioned to a bioequivalent dose of elapegademase. Maintenance of metabolic detoxification and adequate ADA activity were evaluated periodically.
RESULTS
One patient withdrew after 2 doses of an early elapegademase formulation due to injection-site pain caused by EDTA. The 6 remaining patients completed 71-216 weeks of elapegademase therapy with a formulation that did not contain EDTA. In these patients, elapegademase improved ADA activity compared with pegademase and maintained metabolic detoxification. Total lymphocyte counts increased for all completer patients from between 1.2- and 2.1-fold at the end of study compared with baseline. Elapegademase had a comparable safety profile to pegademase; no patient developed a severe infectious complication. Three patients had transient, non-neutralizing antibodies to pegademase, elapegademase, and/or polyethylene glycol ≤ 47 weeks of treatment without effect on trough plasma ADA activity or trough erythrocyte deoxyadenosine nucleotide levels.
CONCLUSION
Elapegademase was safe, well tolerated, achieved stable trough plasma ADA activity with weekly dosing, was effective in maintaining metabolic detoxification, and was associated with maintenance or improvements in lymphocyte counts compared with pegademase therapy in patients with ADA-SCID.
Topics: Humans; Animals; Cattle; Adenosine Deaminase; Edetic Acid; Severe Combined Immunodeficiency; Lymphocyte Count; Polyethylene Glycols
PubMed: 36840835
DOI: 10.1007/s10875-022-01426-y -
BMC Biology Nov 2023RNA editing by adenosine deaminase acting on RNA (ADAR) occurs in all metazoans and fulfils several functions. Here, we examined effects of acclimation temperature...
BACKGROUND
RNA editing by adenosine deaminase acting on RNA (ADAR) occurs in all metazoans and fulfils several functions. Here, we examined effects of acclimation temperature (27 °C, 18 °C,13 °C) on editing patterns in six tissues of zebrafish (Danio rerio).
RESULTS
Sites and total amounts of editing differed among tissues. Brain showed the highest levels, followed by gill and skin. In these highly edited tissues, decreases in temperatures led to large increases in total amounts of editing and changes in specific edited sites. Gene ontology analysis showed both similarities (e.g., endoplasmic reticulum stress response) and differences in editing among tissues. The majority of edited sites were in transcripts of transposable elements and the 3'UTR regions of protein coding genes. By experimental validation, translation efficiency was directly related to extent of editing of the 3'UTR region of an mRNA.
CONCLUSIONS
RNA editing increases 3'UTR polymorphism and affects efficiency of translation. Such editing may lead to temperature-adaptive changes in the proteome through altering relative amounts of synthesis of different proteins.
Topics: Animals; Zebrafish; 3' Untranslated Regions; RNA Editing; Temperature; Acclimatization
PubMed: 37981664
DOI: 10.1186/s12915-023-01738-4