Autoinflammatory Process Research Articles

Migraine-like headache due to frontal osteitis and meningitis in a delayed diagnosis of SAPHO syndrome: A case report and literature review

Synovitis, acne, pustulosis, hyperostosis, and osteomyelitis (SAPHO) syndrome is a rare polygenic autoinflammatory disorder that is associated with headaches of different etiological origins. Herein we report the case of a patient with SAPHO syndrome and provide a literature review. The patient was a 64-year-old female who complained of a recurrent headache, which had persisted for several years, and diffuse arthralgias. A computed tomography-angiogram demonstrated the narrowing of the left carotid canal. The patient had an erythrocyte sedimentation rate of 19 mm/s, and her cerebrospinal fluid contained 20 leukocytes/μL (13 mononuclear) and 0.43 g/L of proteins. Bone scintigraphy showed radiotracer uptake in the frontal bones and spine. The patient’s son had previously been diagnosed with SAPHO syndrome; therefore, the possibility of a disorder in the same spectrum was considered. Corticotherapy followed by sulphasalazine resolved the symptoms. This case illustrates an atypical cranial and meningeal involvement of the SAPHO autoinflammatory process. Our findings underscore the importance of considering immune-mediated disorders in the differential diagnosis of headaches.

The prototypical interferonopathy: Aicardi-Goutières syndrome from bedside to bench.

Aicardi-Goutières syndrome (AGS) is a progressive genetic encephalopathy caused by pathogenic mutations in genes controlling cellular anti-viral responses and nucleic acid metabolism. The mutations initiate autoinflammatory processes in the brain and systemically that are triggered by chronic overproduction of type I interferon (IFN), including IFN-alpha. Emerging disease-directed therapies aim to dampen autoinflammation and block cellular responses to IFN production, creating an urgent and unmet need to understand better which cells, compartments, and mechanisms underlying disease pathogenesis. In this review, we highlight existing pre-clinical models of AGS and our current understanding of how causative genetic mutations promote disease in AGS, to promote new model development and a continued focus on improving and directing future therapies.

Changes in the levels of cytokines IL-1β, IL-4, IL-8, and IL-10 in dental orthopedic fixed prosthetics

Despite significant advances in materials science, introduction of new methods and principles of prosthetic treatment into the practice of dentists, complications after prosthetics with fixed structures are encountered. The result of dental prosthetics of patients with defects of hard tissues of teeth depends not only on the chosen construction and materials from which they are made, but is closely connected with the functional activity of the immune system. Cytokines are an important factor of mucosal immunity. The cytokine system represents one of the key components of mucosal immunity. It regulates normal physiological functions, restoration of haemostasis in the interaction of physical, chemical and biological factors on the body and participates in the pathogenesis of allergic, autoimmune, and autoinflammatory processes. The aim of the study is to compare the content of IL-1â, IL-8, IL-10, and IL-4 in unstimulated saliva and gingival fluid in patients during adaptation to metal-ceramic and oxide ceramic tooth-supported constructions. In the period from 2021-2024, we examined 3 groups of patients aged 46±2 years: group 1 – comparison group, patients without dental constructions in the oral cavity (25 people); group 2 – patients treated with tooth-supported metal-ceramic (MC) crowns (25 people); and group 3 – patients treated with tooth-supported zirconium dioxide (ZrO2) crowns (25 people). On the basis of IL-1â, IL-8, IL-10, and IL-4 we concluded that the mucosal immunity of oral mucous membranes is less affected by the structures made of oxide ceramics compared to the crowns made of metal-ceramics. Similar patterns of changes in the levels of IL-1â, IL-8, and IL-4 in saliva and gingival fluid in patients who underwent dental rehabilitation were found, which allows us to use only saliva in order to eliminate the complexity and specificity of gingival fluid sampling. Also, changes in cytokine indices in saliva and gingival fluid at different stages of prosthodontics reflect the level of reaction of oral mucosal immunity, which can serve as a criterion of the quality of the performed dental treatment.

Multimorbid pathology at psoriasis (scientific review)

Chronic auto-inflammatory process in psoriasis is associated with the involvement of internal organs and systems, as well as the development of several systemic disorders: heart failure, psoriatic arthritis, diabetes, obesity, etc. In this regard, the purpose of our study is to integrate information about comorbid and concomitant pathology in patients with psoriasis. Data on the biological aspects of the increased risk of occurrence and adverse cardiovascular outcome of myocardial infarction, stroke and cardiovascular mortality in patients with psoriasis are supported by clinical observations on the relationship of the course of coronary heart disease with the area of skin lesion. The association between the presence of obesity and an increased level of proinflammatory cytokines has been confirmed, which may be one of the triggers for the development of psoriatic arthritis associated with early disability of patients with psoriasis. There was a greater incidence of non-response to psoriasis treatment among obese patients. Cardiovascular complications are the most common cause of death for patients with psoriasis. Identifying common combinations of comorbid and concomitant diseases in the main chronic disease can serve as a basis for the development of tactics and criteria for patient management in order to optimize treatment.

ОЦЕНКА ОСОБЕННОСТЕЙ ПРОЯВЛЕНИЙ ЗАБОЛЕВАНИЯ У ПАЦИЕНТОВ С ВРОЖДЕННЫМИ ДЕФЕКТАМИ ИММУНИТЕТА, ПОЛУЧАЮЩИХ АЛЛОГЕННУЮ ТРАНСПЛАНТАЦИЮ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК

Congenital immunodeficiency disorders (CIDs) are a group of rare and diverse diseases that are based on dysfunction of the immune system. The only therapy that radically cures CIDs is allogeneic hematopoietic stem cell transplantation (HSCT). Despite the expansion of indications for HSCT in CIDs, making a decision on the need for HSCT in many diseases still remains a difficult task requiring an assessment of the risk for the life-threatening complications development in a patient. The purpose of this research was to assess the diseases developing in patients with CIDs who received allogeneic HSCT. Materials and methods used: the study included 312 patients with CIDs under the age of 18 y/o who had received allogeneic HSCT at the National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev (Moscow, Russia) in 2012-2020. The analysis was performed in 5 main groups of CIDs: immunodeficiencies with cellular and humoral defects (n=71), combined immune deficiency with associated or syndromic pathology (n=98), immune dysregulation defects (n=56), qualitative and quantitative defects of phagocytosis (n=57) and other CIDs nonmentioned above (n=30). Results: the presence of diseases uncontrolled by the therapy at the time of HSCT was noted in 160 (51%) patients. 73 (23%) had infection, 109 (35%) had autoimmune and/or autoinflammatory diseases, 15 (5%) showed absence of remission of an oncological disease. 33 patients had a combination of various diseases: 29 had infectious and autoinflammatory ones, two had infectious and tumor ones, another two had autoinflammatory and tumor. Active infections were observed in 48% of patients with immunodeficiencies with cellular and humoral defects and 33% of patients with other CIDs, active autoinflammatory processes in 43% of immune dysregulation defects and 63% of other CIDs, active tumors in 12% of patients with defects of phagocytosis. Conclusion: solutions have been proposed for assessing the pre-transplant status of patients with CIDs for the presence of infectious, autoimmune/autoinflammatory and oncological complications, age and nutritional status of the patient, which in tis turn underlie the choice for the optimal HSCT technique.

Recent advances and evolving concepts in Still's disease.

Still's disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still's disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still's disease and MAS. Pathological entities associated with Still's disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still's disease courses were recognized. Newer proposals of alternative Still's disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still's disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management.

488. Initial laboratory markers may help distinguish between Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Abstract Background In May of 2020, the Centers for Disease Control and Prevention defined a new diagnosis, Multisystem Inflammatory Syndrome in Children (MIS-C), described as a Kawasaki-like illness and related to the SARS-CoV-2 virus. Patients with this syndrome met criteria for inflammation, along with multiple organ system involvement. Clinically distinguishing between Kawasaki Disease (KD) and MIS-C is challenging due to significant overlap between the two disease entities. Furthermore, approximately 25-50% of MIS-C cases also meet criteria for KD. Currently there is very limited data describing specific differences in laboratory markers between KD and MIS-C to guide clinicians in diagnosis and management. This study aims to assess if quantitative laboratory data markers help distinguish between KD and MIS-C. Methods We conducted a retrospective study of patients hospitalized within two network pediatric hospitals with the diagnosis of MIS-C [M35.81] or Kawasaki Disease [M30.3] between January 1, 2019 and March 31, 2021. Children with an alternate diagnosis at discharge were excluded. Demographic characteristics and laboratory data were recorded and analyzed. Results A total of 91 pediatric patients were included in the study: 40 with MIS-C and 45 with KD. Patients with MIS-C were significantly older with a median age 5.3 years, compared to 2.4 years for KD (p=0.001). Patients with KD presented with higher median white blood cell (WBC) count, absolute lymphocyte count, and platelet count compared to those with MIS-C (p< 0.001). A higher alanine aminotransferase (ALT) was also noted (p=0.01). Patients with MIS-C were noted to have higher median ferritin levels and C-reactive protein (CRP) (p< 0.001) (Table 1). Conclusion Both MIS-C and KD are autoinflammatory disease processes that have significant overlap. Identifying differences in initial laboratory values upon presentation can lead to earlier diagnosis. A normal ferritin level may indicate KD. Disclosures All Authors: No reported disclosures

Evidence of autoinflammation as a principal mechanism of myocardial injury in SARS-CoV-2 PCR-positive medical examiner cases

BackgroundDisease from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains the seventh leading cause of death in the United States. Many patients infected with this virus develop later cardiovascular complications including myocardial infarctions, stroke, arrhythmia, heart failure, and sudden cardiac death (20–28%). The purpose of this study is to understand the primary mechanism of myocardial injury in patients infected with SARS-CoV-2.MethodsWe investigated a consecutive cohort of 48 medical examiner cases who died with PCR-positive SARS-CoV-2 (COVpos) infection in 2020. We compared them to a consecutive cohort of 46 age- and sex-matched controls who were PCR-negative for SARS-CoV-2 (COVneg). Clinical information available at postmortem examination was reviewed on each patient. Formalin-fixed sections were examined using antibodies directed against CD42 (platelets), CD15 (myeloid cells), CD68 (monocytes), C4d, fibrin, CD34 (stem cell antigen), CD56 (natural killer cells), and myeloperoxidase (MPO) (neutrophils and neutrophil extracellular traps(NETs)). We used a Welch 2-sample T-test to determine significance. A cluster analysis of marker distribution was also done.ResultsWe found a significant difference between COVpos and COVneg samples for CD42, CD15, CD68, C4d, fibrin, and MPO, all of which were significant at p < 0.001. The most prominent features were neutrophils (CD15, MPO) and MPO-positive debris suggestive of NETs. A similar distribution of platelets, monocytes, fibrin and C4d was seen in COVpos cases. Clinical features were similar in COVpos and COVneg cases for age, sex, and body mass index (BMI).ConclusionThese findings suggest an autoinflammatory process is likely involved in cardiac damage during SARS-CoV-2 infection. No information about clinical cardiac disease was available.

Sterile inflammation, cross-presentation, autophagy and adaptive immunity in immunoinflammatory rheumatic diseases

Proinflammatory extracellular and intracellular DAMPs are the dominant etiological factors of sterile inflammation in immuno-inflammatory rheumatic diseases. They are generated by systemic progressive disorganization of loose fibrous unformed connective tissue, programmed cell death and cell necrosis. Sterile inflammation is a multi-stage process which is induced by a sequence of reactions mediated by leukocytes and resident cells of the macrophage-monocyte series, aimed at cleansing the focus of inflammation from cellular and tissue detritus, followed by restoration of homeostasis of damaged tissue. An important role in this process belongs to the transendothelial migration of leukocytes to the focus of sterile inflammation and formation of cellular inflammatory infiltrate. The key feature of these events is the reactivity of PRR receptors followed by a cascade of PRR-DAMPs interactions with subsequent launch of molecular and cellular processes causing the local and/or systemic manifestations of sterile inflammation. Activation of innate immunity is the result of PRR-DAMPs interactions which launches the molecular and cellular reactions. Hence, it is possible to attribute the immunoinflammatory rheumatic diseases to the category of systemic sterile autoinflammatory processes. Generalization of the pathophysiological effects of pro-inflammatory DAMPs and, accordingly, the systemic and multi-organ nature of tissue and internal organ damage in immunoinflammatory rheumatic diseases is due to the wide occurrence of receptors for “danger signals”. The most important place in the development of DAMP-mediated sterile inflammation is occupied by the phenomenon of cross-presentation and autophagy. The cross-presentation causes exposition of extracellular DAMPs from internalized proteins with MHC class I molecules to autoreactive CD8+ cytotoxic T lymphocytes. Autophagy provides processsing of intracellular peptide DAMPs, their loading onto MHC class II molecules with subsequent induction of adaptive immune response in CD4+T cell populations. The innate lymphoid cells (ILC) make an important contribution to these processes. The model of functional coupling and complementarity between ILCs and Th-CD4+T cells has expanded our understanding of immune regulation by extending the activity of innate and adaptive immunity to the level of maintaining tissue homeostasis, morphogenesis, repair, regeneration and inflammation. Progression of systemic sterile inflammation may be a result of PRR-DAMP interactions of tissue ILCs followed by switching of ILC/Th-CD4+T cell partners. The data presented in this review define the promising molecular and cellular targets aiming for regulation and/or inhibition of sterile inflammation in immunoinflammatory rheumatic diseases.

Kisgyermekkori, erythrodermiával járó pustulosus psoriasis

Juvenile generalized pustular psoriasis is an extremely rare clinical variant of psoriasis, in which extensive skin symptoms, erythrodermia, subcorneal pustules are often accompanied by systemic symptoms, fever, arthritis and laboratory abnormalities. In severe cases, lifethreatening condition may develop. Recently, there is increasing evidence that von Zumbuch-type generalized pustulosus psoriasis (GPP) is associated with increased innate immune activity, and autoinflammatory processes dominate, whereas in plaque-type psoriasis (PV) the role of adaptive immunity is typically predominant. Currently, there is no standard therapeutic guideline for the treatment of childhood cases, which makes selecting and administering the appropriate therapy for pediatric patients challenging

Human peripheral blood age-associated (CD11c+Tbet+) B cells: No association with age.

Human peripheral blood age-associated (CD11c+Tbet+) B cells: No association with age.

An Update on Familial Mediterranean Fever.

(1) Background: Familial Mediterranean Fever (FMF) is the prototypal autoinflammatory disease, characterized by recurrent bursts of neutrophilic inflammation. (2) Methods: In this study we look at the most recent literature on this condition and integrate it with novel information on treatment resistance and compliance. (3) Results: The canonical clinical presentation of FMF is in children with self-limited episodes of fever and polyserositis, associated with severe long-term complications, such as renal amyloidosis. It has been described anecdotally since ancient times, however only recently it has been characterized more accurately. We propose an updated overview on the main aspects of pathophysiology, genetics, diagnosis and treatment of this intriguing disease. (4) Conclusions: Overall, this review presents the all the main aspects, including real life outcome of the latest recommendation on treatment resistance of FMF, a disease, that not only helped understanding the pathophysiology of the auto inflammatory process but also the functioning of the innate immune system itself.

Recurrent pericarditis.

Pericarditis is an important differential diagnosis in patients with chest pain. The two most common causes in the developed world are idiopathic pericarditis and inflammation following cardiac surgery or myocardial infarction. Recurrence of pericarditis affects up to 30% of patients, half of whom experience multiple episodes, and approximately 10% develop steroid-dependent and colchicine-refractory pericarditis. Recurrence is due to autoinflammatory processes in the pericardium. Advanced diagnostic imaging and treatment with colchicine and interleukin-1 inhibitors has helped reduce morbidity considerably in recent years. In this clinical review, we summarise up-to-date knowledge about the diagnostic evaluation and treatment of patients with recurrent primary pericarditis.

B-cell driven autoimmunity in two patients with monogenic autoinflammatory disorders

RationaleAutoimmunity and autoinflammation are classically recognized as two different disease processes. In this report, we present two patients with Behcet’s disease (BD)-like autoinflammation who subsequently developed lupus-like serology and B-cell phenotypes. MethodA retrospective review of medical records and research-based flow cytometry of two patients with the monogenetic autoinflammatory disease was performed. ResultsOur first patient had a history of multiple skin and genital lesions, as well as persistent cough with pulmonary nodules. Her immune evaluation demonstrated marked CD4 activation with decreased naïve CD4 cells. Throughout her disease course, she developed high titer ANA and dsDNA. Her genetic analysis revealed a heterozygous c.1039C>T (p. Gln347*) variant of the RELA gene, a truncation mutation. The downstream truncated variant of the RELA gene has been reported to be associated with BD-like autoinflammatory syndrome. Our second patient had a BD-like presentation with recurrent mouth and vaginal ulcers, Crohn’s disease-like GI inflammation, and periodic fevers. She also had features of autoimmune disease with Hashimoto thyroiditis. At disease onset, she was negative for ANA. However, over a period of eight years, her ANA titers increased to >1:2560, with high titer anti-chromatin antibody and new-onset bilateral sacroiliitis. Her genetic testing revealed a (p.Arg364Lysfs*25) variant of the TNFAIP3 gene associated with BD-like autoinflammatory syndrome. Research-based B-cell profiles in both patients revealed increased B-cell autoreactivity and B-cell dysregulation similar to classical lupus patients. ConclusionOur case report demonstrated that the monogenetic autoinflammatory disease process could evolve to develop autoimmunity, thus complicating clinical presentation and management.

What do we know about co-stimulatory and co-inhibitory immune checkpoint signals in ankylosing spondylitis?

Ankylosing Spondylitis is the main entity of a family of inflammatory diseases affecting many musculoskeletal (sacroiliac joints, spine, peripheral joints) and extra-musculoskeletal sites, termed spondyloarthritis. While it is debated whether disease onset is primarily driven by autoimmune or autoinflammatory processes, what is certain is that both innate and adaptive immune responses orchestrate local and systemic inflammation, which leads to chronic pain and immobility. Immune checkpoint signals are one key player for keeping the immune system in check and in balance, but their role in disease pathogenesis is still rather elusive. Therefore, we ran a MEDLINE search utilizing the PubMed platform for a variety of immune checkpoint signals in regard to ankylosing spondylitis. In this review, we summarise the experimental and genetic data available and evaluate the relevance of immune checkpoint signalling in the pathogenesis of ankylosing spondylitis. Markers such as PD-1 and CTLA-4 have been extensively studied and facilitate the concept of an impaired negative immune regulation in ankylosing spondylitis. Other markers are either neglected completely or insufficiently examined, and the data is conflicting. Still, some of those markers remain interesting targets to decipher the pathogenesis of ankylosing spondylitis and to develop new treatment strategies.

Time restricted feeding modifies leukocyte responsiveness and improves inflammation outcome.

Time restricted eating, the dietary approach limiting food intake to a maximal 10-hour period of daytime is considered beneficial in metabolic dysfunctions, such as obesity and diabetes. Rhythm of food intake and parallel changes in serum nutrient levels are also important entrainment signals for the circadian clock, particularly in tissues involved in metabolic regulation. As both the metabolic state and the circadian clock have large impact on immune functions, we investigated in mice whether time restricted feeding (TRF) affects systemic inflammatory potential. TRF slackened the symptoms in K/BxN serum-transfer arthritis, an experimental model of human autoimmune joint inflammation. Compared to ad libitum conditions TRF reduced the expression of inflammatory mediators in visceral adipose tissue, an integrator and coordinator of metabolic and inflammatory processes. Furthermore, TRF strengthened the oscillation of peripheral leukocyte counts and alongside decreased the pool of both marginated and tissue leukocytes. Our data suggest that the altered leukocyte distribution in TRF mice is related to the attenuated expression of adhesion molecules on the surface of neutrophils and monocytes. We propose that TRF modifies both rhythm and inflammatory potential of leukocytes which contribute to the milder reactivity of the immune system and therefore time-restricted eating could serve as an effective complementary tool in the therapy of autoinflammatory processes.

Autoimmune Pericarditis: Multimodality Imaging.

The purpose of this review is to understand the underlying mechanism that leads to pericarditis in systemic autoimmune and autoinflammatory diseases. The underlying mechanism plays a vital role in the appropriate management of patients. In addition, we will review the current landscape of available cardiac imaging modalities with emphasis on pericardial conditions as well as proposed treatment and management tailored toward pericardial autoimmune and autoinflammatory processes. Approximately 22% of all cases of pericarditis with a known etiology are caused by systemic autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and vasculitis. In recent years, there have been advancements of imaging modalities including cardiac MRI, cardiac CT scan, and PET scan and their respective nuances in regard to contrast use, technique, and views which clinicians may utilize to better understand the extent of a patient's pericardial pathology and the trajectory of his or her disease process. In this review, we will discuss systemic autoimmune and autoinflammatory diseases that involve the pericardium. We will also review different imaging modalities that are currently used to further characterize such conditions. Having a deeper understanding of such techniques will improve patient outcomes by helping clinicians tailor treatment plans according to the unique underlying condition.

Psoriasis, Is It a Microdamage of Our "Sixth Sense"? A Neurocentric View.

Psoriasis is considered a multifactorial and heterogeneous systemic disease with many underlying pathologic mechanisms having been elucidated; however, the pathomechanism is far from entirely known. This opinion article will demonstrate the potential relevance of the somatosensory Piezo2 microinjury-induced quad-phasic non-contact injury model in psoriasis through a multidisciplinary approach. The primary injury is suggested to be on the Piezo2-containing somatosensory afferent terminals in the Merkel cell–neurite complex, with the concomitant impairment of glutamate vesicular release machinery in Merkel cells. Part of the theory is that the Merkel cell–neurite complex contributes to proprioception; hence, to the stretch of the skin. Piezo2 channelopathy could result in the imbalanced control of Piezo1 on keratinocytes in a clustered manner, leading to dysregulated keratinocyte proliferation and differentiation. Furthermore, the author proposes the role of mtHsp70 leakage from damaged mitochondria through somatosensory terminals in the initiation of autoimmune and autoinflammatory processes in psoriasis. The secondary phase is harsher epidermal tissue damage due to the primary impaired proprioception. The third injury phase refers to re-injury and sensitization with the derailment of healing to a state when part of the wound healing is permanently kept alive due to genetical predisposition and environmental risk factors. Finally, the quadric damage phase is associated with the aging process and associated inflammaging. In summary, this opinion piece postulates that the primary microinjury of our “sixth sense”, or the Piezo2 channelopathy of the somatosensory terminals contributing to proprioception, could be the principal gateway to pathology due to the encroachment of our preprogrammed genetic encoding.

ADAR1 Prevents Autoinflammatory Processes in the Heart Mediated by IRF7.

ADAR1 (adenosine deaminase acting on RNA-1)-mediated adenosine to inosine (A-to-I) RNA editing plays an essential role for distinguishing endogenous from exogenous RNAs, preventing autoinflammatory ADAR1 also regulates cellular processes by recoding specific mRNAs, thereby altering protein functions, but may also act in an editing-independent manner. The specific role of ADAR1 in cardiomyocytes and its mode of action in the heart is not fully understood. To determine the role of ADAR1 in the heart, we used different mutant mouse strains, which allows to distinguish immunogenic, editing-dependent, and editing-independent functions of ADAR1. Different Adar1-mutant mouse strains were employed for gene deletion or specific inactivation of ADAR1 enzymatic activity in cardiomyocytes, either alone or in combination with Ifih1 (interferon induced with helicase C domain 1) or Irf7 (interferon regulatory factor 7) gene inactivation. Mutant mice were investigated by immunofluorescence, Western blot, RNAseq, proteomics, and functional MRI analysis. Inactivation of Adar1 in cardiomyocytes resulted in late-onset autoinflammatory myocarditis progressing into dilated cardiomyopathy and heart failure at 6 months of age. Adar1 depletion activated interferon signaling genes but not NFκB (nuclear factor kappa B) signaling or apoptosis and reduced cardiac hypertrophy during pressure overload via induction of Irf7. Additional inactivation of the cytosolic RNA sensor MDA5 (melanoma differentiation-associated gene 5; encoded by the Ifih1 gene) in Adar1 mutant mice prevented activation of interferon signaling gene and delayed heart failure but did not prevent lethality after 8.5 months. In contrast, compound mutants only expressing catalytically inactive ADAR1 in an Ifih1-mutant background were completely normal. Inactivation of Irf7 attenuated the phenotype of Adar1-deficient cardiomyocytes to a similar extent as Ifih1 depletion, identifying IRF7 as the main mediator of autoinflammatory responses caused by the absence of ADAR1 in cardiomyocytes. Enzymatically active ADAR1 prevents IRF7-mediated autoinflammatory reactions in the heart triggered by endogenous nonedited RNAs. In addition to RNA editing, ADAR1 also serves editing-independent roles in the heart required for long-term cardiac function and survival.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.

When All Is Not as It Seems: Recurrent Fever and New-onset Joint Pain in a 17-Month-old Girl.