Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis.

In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells (NFKB1) in affected patients. In patients' macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1ß secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-ß (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1ß and/or IFN-I signaling could represent a therapeutic approach for these patients.

Newborn Screening Today and Tomorrow: A Brief Report from the International Primary Immunodeficiencies Congress.

This article presents the report of the session on "Newborn Screening for Primary Immunodeficiencies-Now What?" organised during the International Primary Immunodeficiency Congress (IPIC) held in November 2023. This clinical conference was organised by the International Patient Organisation for Primary Immunodeficiencies (IPOPI), the global patient organisation advocating for primary immunodeficiencies (PIDs) in patients. The session aimed at exploring the advances in newborn screening (NBS) for severe combined immunodeficiency, starting with the common practice and inserting the discussion into the wider perspective of genomics whilst taking into consideration the ethical aspects of screening as well as incorporating families and the public into the discussions, so as to ensure that NBS for treatable rare disorders continues to be one of the major public health advances of the 20th century.

Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity.

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 (Tregs) in patients with type I interferonopathies caused by mutations in ADAR1 or IFIH1 (encoding MDA5). We analyzed the underlying mechanisms using murine models and found that Treg-specific deletion of Adar1 caused peripheral Treg loss and scurfy-like lethal autoimmune disorders. Similarly, knock-in mice with Treg-specific expression of an MDA5 gain-of-function mutant caused apoptosis of peripheral Tregs and severe autoimmunity. Moreover, the impact of ADAR1 deficiency on Tregs is multifaceted, involving both MDA5 and PKR sensing. Together, our results highlight the dysregulation of Treg homeostasis by intrinsic aberrant RNA sensing as a potential determinant for type I interferonopathies.

Clinical and functional spectrum of RAC2-related immunodeficiency.

ABSTRACT: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Multilayer concept of autoimmune mechanisms and manifestations in inborn errors of immunity: Relevance for precision therapy.

Autoimmunity in inborn errors of immunity (IEIs) has a multifactorial pathogenesis and develops subsequent to a genetic predisposition in conjunction with gene regulation, environmental modifiers, and infectious triggers. On the basis of incremental data availability owing to upfront application of omics technologies, a more granular and dynamic view of mechanisms and manifestations is warranted. Here, we present a comprehensive novel concept of autoimmunity in IEIs that considers multiple layers of interdependent elements and connects 101 causative genes or deletions according to the quality of the allelic variants with 47 molecular pathways and 22 immune effector mechanisms. Furthermore, we list 50 resulting manifestations together with the corresponding Human Phenotype Ontology terms and review the types and frequencies of the most relevant clinical presentations. When all of its elements are taken together, this concept (1) extends the historical anatomic view of central versus peripheral tolerance toward multiple interdependent mechanisms of immune tolerance, (2) delineates the mechanisms underlying the protean clinical manifestations, and thereby, (3) points toward the most suitable precision therapy for autoimmunity in IEIs. The multilayer concept of autoimmune mechanisms and manifestations in IEIs will facilitate research design and provide clinical guidance on the use of precision medicine irrespective of the data depth available in each health care scenario.

Disrupted degradative sorting of TLR7 is associated with human lupus.

Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.

JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study.

BACKGROUND: Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling present with variable manifestations of immune dysregulation and infections. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but initially reported outcomes were poor. JAK inhibitors (JAKi) offer a targeted treatment option that may be an alternative or bridge to HSCT. However, data on their current use, treatment efficacy and adverse events are limited. OBJECTIVE: We evaluated the current off-label JAKi treatment experience for JAK/STAT inborn errors of immunity (IEI) among European Society for Immunodeficiencies (ESID)/European Society for Blood and Marrow Transplantation (EBMT) Inborn Errors Working Party (IEWP) centers. METHODS: We conducted a multicenter retrospective study on patients with a genetic disorder of hyperactive JAK/STAT signaling who received JAKi treatment for at least 3 months. RESULTS: Sixty-nine patients (72% children) were evaluated (45 STAT1 gain of function [GOF], 21 STAT3-GOF, 1 STAT5B-GOF, 1 suppressor of cytokine signaling 1 [aka SOCS1] loss of function, 1 JAK1-GOF). Ruxolitinib was the predominantly prescribed JAKi (80%). Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients. We documented highly heterogeneous dosing and monitoring regimens. The response rate and time to response varied across different diseases and manifestations. Adverse events including infection and weight gain were frequent (38% of patients) but were mild (grade I-II) and transient in most patients. At last follow-up, 52 (74%) of 69 patients were still receiving JAKi treatment, and 11 patients eventually underwent HSCT after receipt of previous JAKi bridging therapy, with 91% overall survival. CONCLUSIONS: Our study suggests that JAKi may be highly effective to treat symptomatic JAK/STAT IEI patients. Prospective studies to define optimal JAKi dosing for the variable clinical presentations and age ranges should be pursued.

Impact of newborn screening for SCID on the management of congenital athymia.

BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.

A Novel Biallelic LCK Variant Resulting in Profound T-Cell Immune Deficiency and Review of the Literature.

Lymphocyte-specific protein tyrosine kinase (LCK) is an SRC-family kinase critical for initiation and propagation of T-cell antigen receptor (TCR) signaling through phosphorylation of TCR-associated CD3 chains and recruited downstream molecules. Until now, only one case of profound T-cell immune deficiency with complete LCK deficiency [1] caused by a biallelic missense mutation (c.1022T>C, p.L341P) and three cases of incomplete LCK deficiency [2] caused by a biallelic splice site mutation (c.188-2A>G) have been described. Additionally, deregulated LCK expression has been associated with genetically undefined immune deficiencies and hematological malignancies. Here, we describe the second case of complete LCK deficiency in a 6-month-old girl born to consanguineous parents presenting with profound T-cell immune deficiency. Whole exome sequencing (WES) revealed a novel pathogenic biallelic missense mutation in LCK (c.1393T>C, p.C465R), which led to the absence of LCK protein expression and phosphorylation, and a consecutive decrease in proximal TCR signaling. Loss of conventional CD4+ and CD8+ αßT-cells and homeostatic T-cell expansion was accompanied by increased γδT-cell and Treg percentages. Surface CD4 and CD8 co-receptor expression was reduced in the patient T-cells, while the heterozygous mother had impaired CD4 and CD8 surface expression to a lesser extent. We conclude that complete LCK deficiency is characterized by profound T-cell immune deficiency, reduced CD4 and CD8 surface expression, and a characteristic TCR signaling disorder. CD4 and CD8 surface expression may be of value for early detection of mono- and/or biallelic LCK deficiency.

Future Directions in the Diagnosis and Treatment of APDS and IEI: a Survey of German IEI Centers.

Introduction: The diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000. We conducted surveys by questionnaire and interviewed physicians at different IEI centers in Germany. Methods: We queried structural aspects of IEI care in Germany, diagnostic procedures in IEI care (including molecular diagnostics), distribution of APDS patients, APDS symptoms and severity, treatment algorithms in APDS, the role of stem cell transplantation and targeted therapies in IEI with focus on APDS. We were especially interested in how genetic diagnostics may influence treatment decisions, e.g. with regard to targeted therapies. Results/discussion: Most centers care for both pediatric and adult patients. A total of 28 APDS patients are currently being treated at the centers we surveyed. Patient journeys vary considerably, as does severity of disease. Genetic diagnosis continues to gain importance - whole genome sequencing is likely to become routine in IEI in the next few years. According to the experts interviewed, stem cell transplantation and - with new molecules being approved - targeted therapies, will gain in importance for the treatment of APDS and IEI in general.

C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib.

C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH.

[Newborn screening for severe combined immunodeficiencies (SCID) in Germany]. / Neugeborenenscreening auf schwere kombinierte Immundefekte (SCID) in Deutschland.

Patients with a severe combined immunodeficiency (SCID) harbor genetic mutations disrupting T cell immunity and hence suffer severe, life-threatening infections or manifestations of immune dysregulation within the first months of their life. The only cure is to correct their immune system, usually by means of hematopoietic stem cell transplantation (HSCT). Pilot studies and national programs in the United States and in European countries have shown that patients can be identified at an early asymptomatic stage through newborn screening. This allows treatment before the occurrence of severe complications, which improves the outcome of curative strategies like HSCT.After assessment by the Federal Joint Committee (G-BA), the SCID screening was implemented into newborn screening in Germany in 2019. The first results of the screening (dry blood spot cards from around 2 million newborns between August 2019 and February 2022) were recently published. As expected, in addition to classic SCID diseases (incidence 1:54,000), infants with syndromic disorders and T cell lymphopenia were also identified. All patients with classic SCID were scheduled for curative treatment. Of the 25 patients with classic SCID, 21 were already transplanted at the time of data analysis. Only one of 21 transplanted patients died due to pre-existing infections. A comparison of the recent screening data with historical data suggests that SCID newborn screening has been successfully implemented in Germany. Patients with SCID are routinely identified very early and scheduled for curative therapy.

Allogeneic HSCT for Symptomatic Female X-linked Chronic Granulomatous Disease Carriers.

X-linked chronic granulomatous disease (XL-CGD) is an inherited disorder of superoxide production, causing failure to generate the oxidative burst in phagocytes. It is characterized by invasive bacterial and fungal infections, inflammation, and chronic autoimmune disease. While XL-CGD carriers were previously assumed to be healthy, a range of clinical manifestations with significant morbidity have recently been described in a subgroup of carriers with impaired neutrophil oxidative burst due to skewed lyonization. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard curative treatment for CGD but has rarely been reported in individual symptomatic carriers to date. We undertook a retrospective international survey of outcome of HSCT for symptomatic XL-CGD carriers. Seven symptomatic female XL-CGD carriers aged 1-56 years underwent HSCT in four centers, indicated for severe and recurrent infection, colitis, and autoimmunity. Two patients died from transplant-related complications, following donor engraftment and restoration of oxidative burst. All surviving patients demonstrated resolution of their neutrophil oxidative burst defect with concordant reduction in infection and inflammatory symptoms and freedom from further immunosuppressive therapy. In conclusion, allogeneic HSCT may cure the phagocyte defect in symptomatic XL-CGD carriers and improve their recurrent and disabling infective and inflammatory symptoms but risks transplant-related complications.

An International Survey of Allogeneic Hematopoietic Cell Transplantation for X-Linked Agammaglobulinemia.

PURPOSE: X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton's tyrosine kinase (BTK). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients. METHODS: XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes. RESULTS: In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50-95%), and the 1-year discontinuation rate of IgRT was 89%. CONCLUSION: Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage.

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.

BACKGROUND: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. OBJECTIVES: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS. METHODS: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. RESULTS: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. CONCLUSIONS: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients.

The GAIN Registry - a New Prospective Study for Patients with Multi-organ Autoimmunity and Autoinflammation.

Patient registries are a very important and essential tool for investigating rare diseases, as most physicians only see a limited number of cases during their career. Diseases of multi-organ autoimmunity and autoinflammation are especially challenging, as they are characterized by diverse clinical phenotypes and highly variable expressivity. The GAIN consortium (German multi-organ Auto Immunity Network) developed a dataset addressing these challenges. ICD-11, HPO, and ATC codes were incorporated to document various clinical manifestations and medications with a defined terminology. The GAIN dataset comprises detailed information on genetics, phenotypes, medication, and laboratory values. Between November 2019 and July 2022, twelve centers from Europe have registered 419 patients with multi-organ autoimmunity or autoinflammation. The median age at onset of symptoms was 13 years (IQR 3-28) and the median delay from onset to diagnosis was 5 years (IQR 1-14). Of 354 (84.5%) patients who were genetically tested, 248 (59.2%) had a defined monogenetic cause. For 87 (20.8%) patients, no mutation was found and for 19 (4.5%), the result was pending. The most common gene affected was NFkB1 (48, 11.5%), and the second common was CTLA4 (40, 9.5%), both genetic patient groups being fostered by specific research projects within GAIN. The GAIN registry may serve as a valuable resource for research in the inborn error of immunity community by providing a platform for etiological and diagnostic research projects, as well as observational trials on treatment options.

Transition for adolescents with a rare disease: results of a nationwide German project.

PURPOSE: The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs. METHODS: The transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients' disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process. RESULTS: Of a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients. CONCLUSION: The described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

DNA sensing via the cGAS/STING pathway activates the immunoproteasome and adaptive T-cell immunity.

The immunoproteasome is a specialized type of proteasome involved in MHC class I antigen presentation, antiviral adaptive immunity, autoimmunity, and is also part of a broader response to stress. Whether the immunoproteasome is regulated by DNA stress, however, is not known. We here demonstrate that mitochondrial DNA stress upregulates the immunoproteasome and MHC class I antigen presentation pathway via cGAS/STING/type I interferon signaling resulting in cell autonomous activation of CD8+ T cells. The cGAS/STING-induced adaptive immune response is also observed in response to genomic DNA and is conserved in epithelial and mesenchymal cells of mice and men. In patients with idiopathic pulmonary fibrosis, chronic activation of the cGAS/STING-induced adaptive immune response in aberrant lung epithelial cells concurs with CD8+ T-cell activation in diseased lungs. Genetic depletion of the immunoproteasome and specific immunoproteasome inhibitors counteract DNA stress induced cytotoxic CD8+ T-cell activation. Our data thus unravel cytoplasmic DNA sensing via the cGAS/STING pathway as an activator of the immunoproteasome and CD8+ T cells. This represents a novel potential pathomechanism for pulmonary fibrosis that opens new therapeutic perspectives.

Humans with inherited MyD88 and IRAK-4 deficiencies are predisposed to hypoxemic COVID-19 pneumonia.

X-linked recessive deficiency of TLR7, a MyD88- and IRAK-4-dependent endosomal ssRNA sensor, impairs SARS-CoV-2 recognition and type I IFN production in plasmacytoid dendritic cells (pDCs), thereby underlying hypoxemic COVID-19 pneumonia with high penetrance. We report 22 unvaccinated patients with autosomal recessive MyD88 or IRAK-4 deficiency infected with SARS-CoV-2 (mean age: 10.9 yr; 2 mo to 24 yr), originating from 17 kindreds from eight countries on three continents. 16 patients were hospitalized: six with moderate, four with severe, and six with critical pneumonia, one of whom died. The risk of hypoxemic pneumonia increased with age. The risk of invasive mechanical ventilation was also much greater than in age-matched controls from the general population (OR: 74.7, 95% CI: 26.8-207.8, P < 0.001). The patients' susceptibility to SARS-CoV-2 can be attributed to impaired TLR7-dependent type I IFN production by pDCs, which do not sense SARS-CoV-2 correctly. Patients with inherited MyD88 or IRAK-4 deficiency were long thought to be selectively vulnerable to pyogenic bacteria, but also have a high risk of hypoxemic COVID-19 pneumonia.