Biology subjects

Hartmann, G.

Publications and source records attributed to Hartmann, G..

16 recordsLinked to original sources

bioRxiv2026

Mechanical stress-induced release of mitochondrial double-stranded RNA activates RIG-I to drive osteogenic differentiation in aortic disease

Background: Gain-of-function mutations in RIG-I and MDA5 (RIG-I-like receptors, RLR) cause Singleton-Merten syndrome, an interferonopathy with early aortic calcification. Here we set out to study a possible involvement of RIG-I-like receptor signaling in the formation of aortic valve stenosis in general. Methods and results: We investigated whether mechanical stress-induced RLR activation promotes osteogenic differentiation and calcification of primary human aortic cells, whether such RLR activation drives the development of aortic valve stenosis in vivo, and whether inhibition of downstream JAK/STAT activation ameliorates aortic valve stenosis. We found that activation of primary human aortic interstitial cells by exogenous RIG-I- and MDA5 agonists induced a type I interferon response and an osteogenic program including increased expression of BMP-2 and BSP2, and promoted calcification. These effects were RIG-I/MDA5 or MAVS-dependent, as assessed by CRISPR/Cas9 knockouts. The stress-granule protein G3BP1 and the Wnt receptor FZD5 were induced downstream of RLR activation and were required for osteogenic gene expression and calcification. To assess a potential endogenous source of RIG-I activation, mechanical stretch mimicking valvular tissue stress was applied in cell cuture, which induced a significant RIG-I-dependent interferon response. Sequencing of highly purified preparations of double-stranded RNA from stretched cells demonstrated a predominant mitochondrial origin of double-stranded RNA, and depleting mitochondrial RNA abolished the stretch-dependent response. The JAK/STAT inhibitor ruxolitinib suppressed the RIG-I-induced response including the expression of osteogenic factors in vitro. In a murine wire-injury model of aortic stenosis, MAVS deficiency attenuated valvular morphological changes and improved hemodynamic parameters. Ruxolitinib attenuated hemodynamic progression, prevented aortic stenosis development, and improved survival. Conclusions: Altogether, our results demonstrate that the mechanical-stress-induced release of mitochondrial double-stranded RNA activates RIG-I signaling in aortic interstitial cells, thereby driving osteogenic differentiation and calcification via a MAVS- and G3BP1-dependent pathway. JAK/STAT inhibition with ruxolitinib mitigates this process in a mouse model of aortic valve stenosis, identifying a candidate therapeutic strategy.

cell biology↗

bioRxiv2025

RIG-I Stimulation Enhances Effector Function and Proliferation of Primary Human CD8 T Cells

Cytotoxic CD8 T lymphocytes (CTL) are crucial in antiviral immune responses. However, their recruitment to infection sites renders them at risk of viral infection that could modulate their effector activity. CTL express RIG-I that detects cytosolic viral RNA and subsequently induce antiviral gene expression. Here, we investigated how influenza A virus (IAV) infection influence TCR-dependent effector responses. IAV infection of CTL stimulated RIG-I, and activated downstream pathways including TBK1 and NF-B, resulting in type-I interferon secretion. Transfection of CTL with a pure RIG-I ligand, tri-phosphorylated double stranded RNA(3p-dsRNA), not only stimulated these pathways but also enhanced CTL proliferation in vitro and protected them from IAV infection. Analogous with a positive effect on CD8 effector function, both IAV infection and RIG-I ligand transfection enhanced CTL degranulation and cytokine secretion. Conversely, activation of CTL via CD3/CD28-crosslinking increased their susceptibility to IAV infection. Altogether, RIG-I stimulation either by IAV infection or 3p-dsRNA transfection promoted cell intrinsic antiviral pathways and enhanced CD8 effector functions. These findings suggest that RIG-I agonists could enhance and prolong CTL effector function in immunotherapy.

immunology↗

bioRxiv2024

PLA2G15 is a Lysosomal BMP Hydrolase with Ester Position Specificity and Its Targeting Ameliorates Lysosomal Disease

Lysosomes catabolize lipids and other biological molecules, a function essential for cellular and organismal homeostasis. Key to lipid catabolism in the lysosome is bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles and a stimulator of lipid-degrading enzymes. BMP levels are altered in a broad spectrum of human conditions, including neurodegenerative diseases. While a lysosomal BMP synthase was recently discovered, the enzymes that mediate BMP turnover has remained elusive. Here we show that the lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that BMPs resistance to hydrolysis in the lysosome is conferred by the combination of its unique sn2, sn2 esterification position and stereochemistry, as neither feature alone is sufficient to provide this resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes under acidic conditions. Furthermore, PLA2G15 catalytic activity against synthesized BMP stereoisomers with primary esters was comparable to its canonical substrates challenging the long-held thought that BMPs unique stereochemistry is sufficient to confer resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is intrinsically stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate multiple BMP species, a phenotype reversible by supplementing wildtype PLA2G15 but not its catalytically dead mutant. In addition, targeting PLA2G15 to increase BMP reverses the cholesterol phenotype in Niemann Pick Disease Type C (NPC1) patient fibroblasts and significantly ameliorates disease pathologies in NPC1-deficient mice leading to extended lifespan. Our findings establish the rules that govern the stability of BMP in the lysosome and identify PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases.

cell biology↗

bioRxiv2023

mRNA N1-2'O-methylation by CMTR1 affects NVL2 mRNA splicing

Cap0-mRNA is characterized by a 5-5triphosphate-linked N7-methylated guanosine(m7G). In higher eukaryotes, the methyltransferase CMTR1 additionally methylates the 2O-position of the penultimate mRNA nucleotide(N1) ribose (cap1-mRNA). While the m7G cap is essential for mRNA export and translation initiation by the eIF4F complex, the N1-2O-methylation prevents recognition of cap1-mRNA by the antiviral RNA receptors RIG-I and IFIT1, but a function beyond immunotolerance remained elusive. Here, we generated CMTR1-knockout(CMTR1-/-) cells and found that type-I-interferon(IFN-I) treatment resulted in IFIT1-mediated reduction of cell viability and broad mRNA translation. Consequently, stimulation of the antiviral receptor RIG-I in CMTR1-/- cells revealed an IFIT1 dependent dramatic reduction of IFN-I and chemokine protein induction, demonstrating the importance of N1-2O-methylation for antiviral responses. Additionally, IFN-I- and IFIT1-independent effects were observed: CMTR1-/- cells were smaller, divided slower, and exhibited a reduced transcription of mRNAs coding ribosomal proteins (RP), 5TOP-RNA and snoRNA host genes(SNHG). Additionally, proteome and transcriptome analysis revealed that expression of NVL2, an essential factor in ribosome biogenesis, is strongly suppressed by an alternative-splicing event of NVL2 mRNA in CMTR1-/- cells. This reduction could only be rescued by catalytically active CMTR1. Altogether, besides antiviral immunity N1-2O-methylation by CMTR1 has broad effects on cellular physiology and controls splicing of NVL2.

molecular biology↗

bioRxiv2023

Assessment of technical and clinical utility of a bead-based flow cytometry platform for multiparametric phenotyping of CNS-derived extracellular vesicles

Extracellular vesicles (EVs) derived from the CNS are potential liquid-biopsy markers for early detection and monitoring of neurodegenerative diseases and brain tumors. This study assessed the performance of a bead-based flow cytometry assay (EV Neuro) for multiparametric detection of CNS-derived EVs and identification of disease-specific markers. Different sample materials and EV isolation methods were compared. Glioblastoma- and primary human astrocyte-derived EVs exhibited distinct EV profiles, with signal intensities increasing with higher EV input. Analysis of serum or plasma from glioblastoma, multiple sclerosis, Alzheimers Disease patients and healthy controls showed varying marker signal intensities. Notably, data normalization improved marker identification. Specific EV populations, such as CD36+EVs in glioblastoma and GALC+EVs in multiple sclerosis, were significantly elevated in disease compared to controls. Clustering analysis techniques effectively differentiated glioblastoma patients from controls. A potential correlation between CD107a+EVs and neurofilament levels in the blood was identified in multiple sclerosis patients. Together, the semi-quantitative EV Neuro assay demonstrated its utility for EV profiling in complex samples. However, reliable statistical results in biomarker studies require large sample cohorts and high effect sizes. Nonetheless, this exploratory trial confirmed the feasibility of discovering EV-associated biomarkers and monitoring circulating EV profiles in CNS diseases using the EV Neuro assay.

neuroscience↗

bioRxiv2023

hnRNPM and ELAVL1 control type I interferon induction by promoting IRF3 phosphorylation downstream of both cGAS and RIG-I

RIG-I and cGAS are crucial sensors of viral nucleic acids and induce type I IFNs via TBK1/IKK and IRF3. Here, we have identified hnRNPM as a novel positive regulator of IRF3 phosphorylation and type I IFN induction downstream of both cGAS and RIG-I. Combining interactome analysis and genome editing, we further identified ELAVL1 as an immune-relevant interactor of hnRNPM. Depletion of hnRNPM or ELAVL1 impaired type I IFN induction by HSV-1 and SeV. In addition, we found that hnRNPM and ELAVL1 interact with TBK1 and NF-kB p65. Confocal microscopy revealed cytosolic and perinuclear interactions between hnRNPM, ELAVL1, and TBK1. To our knowledge, hnRNPM and ELAVL1 represent the first non-redundant signaling components merging the cGAS-STING and RIG-I-MAVS pathways, thus representing a novel platform that fuels antiviral defense.

immunology↗

bioRxiv2022

RIG-I activation primes and trains innate antiviral immune memory

Adaptive processes of the innate immune system, known as trained immunity (TI), are critical to human health and disease, yet they have not been systematically investigated downstream of antiviral sensing. Here, we elucidate the potential of the antiviral cytosolic RNA receptor retinoic acid-inducible gene I (RIG-I) to train, prime and tolerize the innate immune system. Using a specific RIG-I agonist, we observed that repetitive stimulation enhanced interferon-stimulated gene (ISG) and pro-inflammatory cytokine induction in human primary monocytes, epithelial cells and fibroblasts and afforded non-specific antiviral protection. RNA sequencing revealed broad, cell type-specific transcriptional changes, indicative of priming of ISGs and training of the NF{kappa}B pathway, without measurable tolerization, while ATAC sequencing in monocytes demonstrated chromatin remodeling and enhanced accessibility of key transcription factor-binding motifs such as STAT1. Moreover, while STAT1 signaling was critically required, it was not sufficient to recapitulate RIG-I induced TI. Altogether, our data demonstrate that RIG-I-mediated TI promotes an immunologically alert state with important implications for host defense and the application of RIG-I ligands in anti-infective and anti-tumoral therapies. One Sentence SummaryRIG-I activation trains and primes innate immune response at the cellular level, affording non-specific immune protection by immune and non-immune cells.

immunology↗

bioRxiv2022

A conserved isoleucine in the binding pocket of RIG-I controls immune tolerance to mitochondrial RNA

RIG-I is a cytosolic receptor of viral RNA essential for the immune response to numerous RNA viruses. Accordingly, RIG-I must sensitively detect viral RNA yet tolerate abundant self-RNA species. The basic binding cleft and an aromatic amino acid of the RIG-I C-terminal domain(CTD) mediate high-affinity recognition of 5triphosphorylated and 5base-paired RNA(dsRNA). Here, we found that, while 5unmodified hydroxyl(OH)-dsRNA demonstrated residual activation potential, 5-monophosphate(5p)-termini, present on most cellular RNAs, prevented RIG-I activation. Determination of CTD/dsRNA co-crystal structures and mutant activation studies revealed that the evolutionarily conserved I875 within the CTD sterically inhibits 5p-dsRNA binding. RIG-I(I875A) was activated by both synthetic 5p-dsRNA and endogenous long dsRNA within the polyA-rich fraction of total cellular RNA. RIG-I(I875A) specifically interacted with a long, highly structured, polyA-bearing, non-coding mitochondrial(mt) RNA, and depletion of mtRNA from total RNA abolished its activation. Altogether, our study demonstrates that avoidance of 5p-RNA recognition is crucial to preventing mtRNA-triggered RIG-I-mediated autoinflammation.

immunology↗

bioRxiv2022

SAMHD1 controls innate immunity by regulating condensation of immunogenic self RNA

Recognition of pathogen-derived foreign nucleic acids is central to innate immune defense. This requires discrimination between structurally highly similar self and nonself nucleic acids to avoid aberrant inflammatory responses as in the autoinflammatory disorder Aicardi-Goutieres syndrome (AGS). How vast amounts of self RNA are shielded from immune recognition to prevent autoinflammation is not fully understood. Here we show that SAM domain and HD domain-containing protein 1 (SAMHD1), one of the AGS-causing genes, functions as a single-stranded RNA (ssRNA) 3exonuclease, the lack of which causes cellular RNA accumulation. Increased ssRNA in cells leads to dissolution of RNA-protein condensates, which sequester immunogenic double-stranded RNA (dsRNA). Release of sequestered dsRNA from condensates triggers activation of antiviral type I interferon via retinoic acid-inducible gene I-like receptors. Our results establish SAMHD1 as a key regulator of cellular RNA homeostasis and demonstrate that buffering of immunogenic self RNA by condensates regulates innate immune responses.

immunology↗

bioRxiv2022

Nucleic acid receptor ligands improve vaccination efficacy against the filarial nematode Litomosoides sigmodontis

Infections with helminths affect more than one billion people worldwide. Despite an urgent need there is no vaccine available that would confer long lasting protection against helminth infections. Previous studies indicated that a vaccination with irradiated infective L3 reduces the worm load. This present study investigated whether the additional activation of cytosolic nucleic acid receptors as adjuvant improves the efficacy of a vaccination with irradiated L3 larvae of the rodent filaria Litomosoides sigmodontis. Subcutaneous injection of irradiated L3 larvae in combination with poly(I:C) or 3pRNA resulted in increased neutrophil recruitment to the skin, accompanied by higher IP-10/CXCL10 and IFN-{beta} RNA levels at the site of injection. To investigate the in vivo impact on parasite clearance, BALB/c mice received 3 subcutaneous injections in 2-week intervals with irradiated L3 larvae in combination with poly(I:C) or 3pRNA prior to the challenge infection. Serum analysis before the challenge infection confirmed the induction of L. sigmodontis-specific antibodies in response to the immunization and serum from immunized mice significantly reduced larval motility in vitro with naive cells. 63 days after the challenge infection, vaccination with irradiated L3 larvae in combination with poly(I:C) or 3pRNA led to a significantly greater reduction in adult worm counts by 73% and 57%, respectively, compared to the immunization with irradiated L3 larvae alone (45%). Further, the treatment of L. sigmodontis infection with 3pRNA alone, but not poly(I:C), resulted in a reduced worm burden, supporting the therapeutic potential for the activation of RIG-I with 3pRNA. In conclusion, our data demonstrate that the additional activation of nucleic acid sensing immune receptors boosts the immune response and provides better protection against L. sigmodontis. Thus, the use of nucleic acid receptor agonists as vaccine adjuvants represents a promising novel strategy to improve the efficacy of vaccines against filariae and potentially of other helminths. Author SummaryFilarial nematodes can cause debilitating diseases such as onchocerciasis and lymphatic filariasis that present a major public health burden in the tropics and subtropics, putting more than a billion people at risk of infection. Filarial diseases are transmitted to humans by insect vectors as they take a blood meal. The WHO classifies both filarial infections as neglected tropical diseases and aims to eliminate the transmission of onchocerciasis and eliminate lymphatic filariasis as public health problem by 2030. However, up to date there is no vaccination available that could support the efforts to eliminate filarial diseases and potentially helminth infections in general. Here, we used the well-established murine model for filarial infection, Litomosoides sigmodontis, to test the use of nucleic acid receptor agonists as vaccine adjuvants to enhance local immune responses. We found that infection with L. sigmodontis induces type I IFN and our vaccine strategy enhances the production of type I IFN resulting in increased parasite-specific immune responses and enhanced worm clearance. In summary, our study provides a promising novel approach for a vaccination strategy using cytosolic RNA receptor agonists.

immunology↗

bioRxiv2022

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

Autoimmune vasculitis is a group of life-threatening diseases, whose underlying pathogenic mechanisms are incompletely understood, hampering development of targeted therapies. Here, we demonstrate that patients suffering from anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) showed increased activity of the DNA sensor cGAS and enhanced IFN-I signature. To identify potential therapeutic targets, we developed a mouse model for pulmonary AAV that mimics severe disease in patients. Immunogenic DNA accumulated during disease onset, triggering cGAS/STING/IRF3-dependent IFN-I release that promoted endothelial damage, pulmonary hemorrhages, and lung dysfunction. Macrophage subsets played dichotomic roles in disease. While recruited monocyte-derived macrophages were major disease drivers by producing most IFN-{beta}, resident alveolar macrophages contributed to tissue homeostasis by clearing red blood cells and limiting infiltration of IFN-{beta}-producing macrophages. Moreover, pharmacological inhibition of STING, IFNAR-I or its downstream JAK/STAT signaling reduced disease severity and accelerated recovery. Our study unveils the importance of STING/IFN-I axis in promoting pulmonary AAV progression and identifies cellular and molecular targets to ameliorate disease outcome. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/493983v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@521964org.highwire.dtl.DTLVardef@13506org.highwire.dtl.DTLVardef@1403dbeorg.highwire.dtl.DTLVardef@958cc4_HPS_FORMAT_FIGEXP M_FIG C_FIG SummaryKessler et al. identify aberrant DNA recognition by cGAS/STING axis and IFN-I production by inflammatory macrophages as a major driver of severe ANCA-associated vasculitis (AAV). Pharmacological interventions blocking this pathway ameliorate disease and accelerate recovery, identifying potential targets for therapeutic intervention in patients.

immunology↗

bioRxiv2021

Ionizing radiation improves RIG-I mediated immunotherapy through enhanced p53 activation in malignant melanoma

Radiation therapy induces cytotoxic DNA damage, which results in cell-cycle arrest and activation of cell-intrinsic death pathways, but its application has been limited by the radioresistance of tumors, such as in malignant melanoma. RIG-I is a cytosolic immune receptor expressed in all somatic cells, including tumor cells, with a key role in sensing viral RNA. RIG-I specific oligonucleotide ligands elicit a robust cell-intrinsic antiviral response and immunogenic cell death in tumor cells and are being tested in clinical trials. Nonetheless, their potential to overcome radioresistance has not yet been explored. Here, we demonstrate that activation of RIG-I enhances the extent and immunogenicity of irradiation-induced tumor cell death in human and murine melanoma cell lines in vitro and improved survival in the murine B16 melanoma model. Pathway analysis of transcriptomic data revealed a central role for p53 downstream of the combination treatment, which was corroborated using p53-/- B16 cells. In vivo, the effect of irradiation on immune-cell activation and inhibition of tumor growth was absent in mice carrying p53-/- B16 tumors, while the response to RIG-I stimulation in those mice was maintained. Our results identify p53 as pivotal for the synergistic antitumoral effect of RIG-I and irradiation, resulting in potent induction of immunogenic tumor-cell death. Thus, the administration of RIG-I ligands in combination with radiotherapy is a promising therapeutic approach to treating radioresistant tumors with a functional p53 pathway, such as malignant melanoma.

immunology↗

bioRxiv2021

RIG-I-induced innate antiviral immunity protects mice from lethal SARS-CoV-2 infection

The SARS-CoV-2 pandemic has underscored the need for rapidly employable prophylactic and antiviral treatments against emerging viruses. Nucleic acid agonists of the innate immune system can be administered to activate an effective antiviral program for prophylaxis in exposed populations, a measure of particular relevance for SARS-CoV-2 infection due to its efficient evasion of the host antiviral response. In this study, we utilized the K18-hACE2 mouse model of COVID-19 to examine whether prophylactic activation of the antiviral receptor RIG-I protects mice from SARS-CoV-2 infection. Systemic treatment of mice with a specific RIG-I ligand one to seven days prior to infection with a lethal dose of SARS-CoV-2 improved their survival of by up to 50 %. Improved survival was associated with lower viral load in oropharyngeal swabs and in the lungs and brain of RIG-I-treated mice. Moreover, despite antiviral protection, the surviving mice that were treated with RIG-I ligand developed adaptive SARS-CoV-2-specific immunity. These results reveal that prophylactic RIG-I activation by synthetic RNA oligonucleotides is a promising strategy to convey short-term, unspecific antiviral protection against SARS-CoV-2 infection and may be a suitable broad-spectrum approach to constraining the spread of newly emerging viruses until virus-specific therapies and vaccines become available.

immunology↗

bioRxiv2020

Human IFITM3 restricts Chikungunya virus and Mayaro virus infection and is susceptible to virus-mediated counteraction

Interferon-induced transmembrane (IFITM) proteins restrict infection by enveloped viruses through interfering with membrane fusion and virion internalisation. The role of IFITM proteins during alphaviral infection of human cells and viral counteraction strategies remain largely unexplored. Here, we characterized the impact of IFITM proteins and variants on entry and spread of Chikungunya virus (CHIKV) and Mayaro virus (MAYV) in human cells, and provide first evidence for a CHIKV-mediated antagonism of IFITM proteins. IFITM1, 2 and 3 restricted infection at the level of alphavirus glycoprotein-mediated entry, both in the context of direct infection and during cell-to-cell transmission. Relocalization of normally endosomal IFITM3 to the plasma membrane resulted in the loss of its antiviral activity. rs12252-C, a naturally occurring variant of IFITM3 that has been proposed to associate with severe influenza in humans, restricted CHIKV, MAYV and influenza A virus infection as efficiently as wild-type IFITM3. Finally, all antivirally active IFITM variants displayed reduced cell surface levels in CHIKV-infected cells involving a posttranscriptional process mediated by one or several non-structural protein(s) of CHIKV.

microbiology↗

bioRxiv2020

Coordination of two enhancers drives expression of olfactory trace amine-associated receptors

Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find that mechanisms regulating Taar gene choice display many unique features. The epigenetic signature of Taar genes in TAAR OSNs is different from that in OR OSNs. We further identify that two TAAR enhancers conserved across placental mammals are absolutely required for expression of the entire Taar gene repertoire. Deletion of either enhancer dramatically decreases the expression probabilities of different Taar genes, while deletion of both enhancers completely eliminates the TAAR OSN populations. In addition, both of the enhancers are sufficient to drive transgene expression in the partially overlapped TAAR OSNs. We also show that the TAAR enhancers operate in cis to regulate Taar gene expression. Our findings reveal a coordinated control of Taar gene choice in OSNs by two remote enhancers, and provide an excellent model to study molecular mechanisms underlying formation of an olfactory subsystem.

neuroscience↗

bioRxiv2020

ADA2 is a lysosomal DNase regulating the type-I interferon response

Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations in ADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. Here, we show that monocyte-derived proteomes from DADA2 patients are highly enriched in interferon response proteins. Using immunohistochemistry and detailed glycan analysis we demonstrate that ADA2 is post-translationally modified for sorting to the lysosomes. At acidic, lysosomal pH, ADA2 acts as a novel DNase that degrades cGAS/Sting-activating ligands. Furthermore, we define a clear structure-function relationship for this acidic DNase activity. Deletion of ADA2 increased the production of cGAMP and type I interferons upon exposure to dsDNA, which was reverted by ADA2 overexpression or deletion of STING. Our results identify a new level of control in the nucleic acid sensing machinery and provide a mechanistic explanation for the pathophysiology of autoinflammation in DADA2. One Sentence SummaryADA2 is a lysosomal nuclease controlling nucleic acid sensing and type I interferon production.

immunology↗