Etoposide Therapy of Cytokine Storm Syndromes.

Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.

SARS-CoV-2 infection of endothelial cells, dependent on flow-induced ACE2 expression, drives hypercytokinemia in a vascularized microphysiological system.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, has caused nearly 7 million deaths worldwide. Severe cases are marked by an aggressive inflammatory response known as hypercytokinemia, contributing to endothelial damage. Although vaccination has reduced hospitalizations, hypercytokinemia persists in breakthrough infections, emphasizing the need for disease models mimicking this response. Using a 3D microphysiological system (MPS), we explored the vascular role in SARS-CoV-2-induced hypercytokinemia. Methods: The vascularized micro-organ (VMO) MPS, consisting of human-derived primary endothelial cells (ECs) and stromal cells within an extracellular matrix, was used to model SARS-CoV-2 infection. A non-replicative pseudotyped virus fused to GFP was employed, allowing visualization of viral entry into human ECs under physiologic flow conditions. Expression of ACE2, TMPRSS2, and AGTR1 was analyzed, and the impact of viral infection on ACE2 expression, vascular inflammation, and vascular morphology was assessed. Results: The VMO platform facilitated the study of COVID-19 vasculature infection, revealing that ACE2 expression increased significantly in direct response to shear stress, thereby enhancing susceptibility to infection by pseudotyped SARS-CoV-2. Infected ECs secreted pro-inflammatory cytokines, including IL-6 along with coagulation factors. Cytokines released by infected cells were able to activate downstream, non-infected EC, providing an amplification mechanism for inflammation and coagulopathy. Discussion: Our findings highlight the crucial role of vasculature in COVID-19 pathogenesis, emphasizing the significance of flow-induced ACE2 expression and subsequent inflammatory responses. The VMO provides a valuable tool for studying SARS-CoV-2 infection dynamics and evaluating potential therapeutics.

The central role of natural killer cells in mediating acute myocarditis after mRNA COVID-19 vaccination.

BACKGROUND: Vaccine-related acute myocarditis is recognized as a rare and specific vaccine complication following mRNA-based COVID-19 vaccinations. The precise mechanisms remain unclear. We hypothesized that natural killer (NK) cells play a central role in its pathogenesis. METHODS: Samples from 60 adolescents with vaccine-related myocarditis were analyzed, including pro-inflammatory cytokines, cardiac troponin T, genotyping, and immunophenotyping of the corresponding activation subsets of NK cells, monocytes, and T cells. Results were compared with samples from 10 vaccinated individuals without myocarditis and 10 healthy controls. FINDINGS: Phenotypically, high levels of serum cytokines pivotal for NK cells, including interleukin-1ß (IL-1ß), interferon α2 (IFN-α2), IL-12, and IFN-γ, were observed in post-vaccination patients with myocarditis, who also had high percentage of CD57+ NK cells in blood, which in turn correlated positively with elevated levels of cardiac troponin T. Abundance of the CD57+ NK subset was particularly prominent in males and in those after the second dose of vaccination. Genotypically, killer cell immunoglobulin-like receptor (KIR) KIR2DL5B(-)/KIR2DS3(+)/KIR2DS5(-)/KIR2DS4del(+) was a risk haplotype, in addition to single-nucleotide polymorphisms related to the NK cell-specific expression quantitative trait loci DNAM-1 and FuT11, which also correlated with cardiac troponin T levels in post-vaccination patients with myocarditis. CONCLUSION: Collectively, these data suggest that NK cell activation by mRNA COVID-19 vaccine contributed to the pathogenesis of acute myocarditis in genetically and epidemiologically vulnerable subjects. FUNDING: This work was funded by the Hong Kong Collaborative Research Fund (CRF) 2020/21 and the CRF Coronavirus and Novel Infectious Diseases Research Exercises (reference no. C7149-20G).

Biparatopic Nanobody-Based Immunosorbent for the Highly Selective Elimination of Tumor Necrosis Factor-α.

Removing the overexpressed TNF-α by hemoperfusion positively affects clinical treatments for diseases such as autoimmune disease and sepsis. However, clearance ratios of adsorbents targeting TNF-α were limited by the extremely low concentration of TNF-α (mostly <1000 ng/L in sepsis) and hydrophobic interactions. In this work, biparatopic nanobodies (NbC21) with a high affinity of 19.9 pM, which bind to two distinct sites of TNF-α, were constructed as high-affinity ligands for the immunosorbent. The theoretical maximum adsorption capacity estimated from the Langmuir isotherm was up to 18.22 mg/g gel. The prepared immunosorbent (NbC21-sorbent) had an outstanding TNF-α clearance ratio of approximately 96% during the dynamic adsorption test, with a sorbent-to-serum ratio of 1:1000. Additionally, it demonstrated favorable hemocompatibility and a prolonged storage capability. The results indicated that the biparatopic nanobody immunosorbent exhibited significant potential for clinical applications as it met the stringent criteria for both efficacy and safety.

Highly secreted tryptophanyl tRNA synthetase 1 as a potential theranostic target for hypercytokinemic severe sepsis.

Despite intensive clinical and scientific efforts, the mortality rate of sepsis remains high due to the lack of precise biomarkers for patient stratification and therapeutic guidance. Secreted human tryptophanyl-tRNA synthetase 1 (WARS1), an endogenous ligand for Toll-like receptor (TLR) 2 and TLR4 against infection, activates the genes that signify the hyperinflammatory sepsis phenotype. High plasma WARS1 levels stratified the early death of critically ill patients with sepsis, along with elevated levels of cytokines, chemokines, and lactate, as well as increased numbers of absolute neutrophils and monocytes, and higher Sequential Organ Failure Assessment (SOFA) scores. These symptoms were recapitulated in severely ill septic mice with hypercytokinemia. Further, injection of WARS1 into mildly septic mice worsened morbidity and mortality. We created an anti-human WARS1-neutralizing antibody that suppresses proinflammatory cytokine expression in marmosets with endotoxemia. Administration of this antibody into severe septic mice attenuated cytokine storm, organ failure, and early mortality. With antibiotics, the antibody almost completely prevented fatalities. These data imply that blood-circulating WARS1-guided anti-WARS1 therapy may provide a novel theranostic strategy for life-threatening systemic hyperinflammatory sepsis.

Nanobody-functionalized conduit with built-in static mixer for specific elimination of cytokines in hemoperfusion.

Removing excessively produced cytokines is of paramount significance in blood purification therapy for hypercytokinemia-associated diseases. In this study, we devised a conduit that is modified with nanobodies (Nb) and incorporates static mixers (Nb-SMC) to eliminate surplus cytokines from the bloodstream. The low-pressure-drop (LPD) static mixer, with each unit featuring two 90°-crossed blades, was strategically arranged in a tessellated pattern on the inner wall of the conduit to induce turbulent mixing effects during the flow of blood. This arrangement enhances mass transfer and molecular diffusion, thereby assisting in the identification and elimination of cytokines. By utilizing computational fluid dynamics (CFD) studies, the Nb-SMC was rationally designed and prepared, ensuring an optimal interval between two mixer units (H/G = 2.5). The resulting Nb-SMC exhibited a remarkable selective clearance of IL-17A, reaching up to 85 %. Additionally, the process of Nb immobilization could be adjusted to achieve the simultaneous removal of multiple cytokines from the bloodstream. Notably, our Nb-SMC displayed good blood compatibility without potential adverse effects on the composition of human blood. As the sole documented static mixer-integrated conduit capable of selectively eliminating cytokines at their physiological concentrations, it holds promise in the clinical potential for hypercytokinemia in high-risk patients. STATEMENT OF SIGNIFICANCE: High-efficient cytokines removal in critical care still remains a challenge. The conduit technique we proposed here is a brand-new strategy for cytokines removal in blood purification therapy. On the one hand, nanobody endows the conduit with specific recognition of cytokine, on the other hand, the build-in static mixer enhances the diffusion of antigenic cytokine to the ligand. The combination of these two has jointly achieved the efficient and specific removal of cytokine. This innovative material is the only reported artificial biomaterial capable of selectively eliminating multiple cytokines under conditions close to clinical practice. It has the potential to improve outcomes for patients with hypercytokinemia and reduce the risk of adverse events associated with current treatment modalities.

Retrospective observational study of changes in serum cytokines and adiponectin with continuous plasma exchange with dialysis therapy for severe COVID-19.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is associated with a marked increase in the inflammatory cytokines, IL-6 and IL-18. Blood purification therapy aimed at controlling cytokines is one treatment option; however, evidence of its effectiveness is needed. Plasma exchange with dialysis (PED) is a blood purification method involving selective plasma exchange with dialysate flowing through the outer hollow fiber of the plasma separator. In this retrospective study, we investigated the efficacy of continuous PED (cPED) over 48 h in five patients with severe COVID-19. METHODS: We assessed changes in IL-6 and IL-18, as well as adiponectin (APN). RESULTS: There were no significant differences in changes in IL-6 and IL-18, but there was a marked improvement in cases with abnormally high IL-6 and IL-18 levels at baseline. APN, which inhibits inflammatory cytokines, was significantly elevated post-cPED. CONCLUSION: Our results suggest that cPED therapy is an effective treatment for COVID-19.

Serum levels of type I interferon (IFN-I) is associated with the severity of COVID-19.

Introduction. Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, coronavirus disease 2019 (COVID-19) has threatened global public health. Immune damage mechanisms are essential guidelines for clinical treatment and immune prevention.Hypothesis. The dysregulated type I interferon (IFN-I) responses, lymphocytopenia and hypercytokinemia during SARS-CoV-2 infection have been reported. However, whether there is a correlation between levels of IFN-I and the severity of COVID-19 has not been reported yet.Aim. To investigate the source of IFN-I and detect the exact roles of them in the pathogenesis of COVID-19.Methodology. Here ELISA was used to detect serum IFN-I (IFN-α and IFN-ß) for 137 cases with laboratory-confirmed COVID-19 admitted into one hospital in Wuhan from December 2019 to March 2020, and the relationships between IFN-α/ß concentrations and patients' clinical parameters were conducted by statistical analysis.Results. Both IFN-α and IFN-ß concentrations dramatically increased in COVID-19 patients, especially in old patients (>80 years) and severe cases. Statistical analysis demonstrated that serum IFN-α/ß concentrations were negatively correlated with the counts of total CD3+T, CD4+ and CD8+T cells, especially in critically ill cases. Moreover, serum IFN-α levels were positively correlated to IL-6 and TNF-α. Finally, immunofluorescent double staining showed that IFN-α and IFN-ß are major secretions from macrophages and dendritic cells (DCs) in lymph nodes from COVID-19 autopsies.Conclusion. These results demonstrate that macrophages and DCs are the main origination of IFN-I, and serum levels of IFN-I are positively associated with lymphopenia and cytokine storm, suggesting that IFN-α/ß deteriorated the severity of COVID-19. Anti-interferon or IFN-I signalling block drugs are needed to treat ICU patients.

[Research Progress on Capillary Leak Syndrome Associated with Hematopoietic Stem Cell Transplantation--Review].

Capillary leak syndrome (CLS) is a clinical syndrome characterized by impairment of vascular endothelial barrier function, increased vascular permeability, and reversible systemic edema. It is one of the early fatal complications after hematopoietic stem cell transplantation. So far, the exact pathogenesis of CLS has not been elucidated, and the diagnostic criteria and treatment methods have not been unified. At present, it is believed that the fundamental cause of CLS is hypercytokinemia, and the core factor is high permeability of vascular endothelial cells. According to the clinical manifestations, the natural course of CLS can be divided into prodrome, leakage and recovery stages. As far as treatment is concerned, symptomatic and supportive treatment is dominant according to different characteristics of each stage. In this review, the pathogenesis, clinical manifestations, diagnosis and treatment of hematopoietic stem cell transplant-associated CLS were briefly summarized.

Comparisons of lymphocytes profiles and inflammatory cytokines levels in blood of patients with differed severity of infection by human adenovirus type 7.

BACKGROUND: Human adenovirus (HAdV) infection outbreak causes community-acquired pneumonia. Cellular immune dysfunction and hypercytokinemia play important roles in the pathogenesis of adenovirus respiratory infection. Some soluble factors in peripheral blood can assist in judging the virus-induced disease severity. The expression levels of inflammatory cytokines differ among patients with different disease severity. However, whether and how HAdV-7 infection influences the composition of blood immune cells and serum cytokine levels in patients at different disease stages, as well as the diagnosis values of these parameters, have rarely been intensively studied. We aimed to investigate lymphocytes profiles and cytokines levels in blood of patients at different disease stages upon human adenovirus type 7 (HAdV-7) infections, and explored the diagnosis values of the investigated parameters. METHODS: Patients from two outbreaks of HAdV-7 in military of China were categorized into upper respiratory infection (URI) group, common pneumonia (CP) group and severe pneumonia (SP) group according to disease severity. Peripheral blood samples were subjected to routine laboratory tests, while flow cytometry and ELISA were used to measure the lymphocyte subsets and cytokines in blood, respectively. The receiver operating characteristic (ROC) curves were performed to examine the diagnostic of these blood parameters. RESULTS: Signs of imbalanced lymphocytes composition and hypercytokinemia were observed in HAdV-7-infected patients. The percentages of CD3+ T cells and NK cells were significantly decreased along with the aggravation of the disease, particularly for NK cells and CD4+ T cells. The neutrophil to lymphocyte ratio (NLR) increased significantly in patients with more severe disease. In addition, the levels of serum CXCL10, IL-2 and TNF-α were positively correlated with disease severity, while reduced levels of IFN-γ and IL-10 were found in SP patients. Furthermore, analysis of ROC showed that multiple parameters including the percentage of blood CD3+ cells and serum CXCL10 level could predict the progression of HAdV-7 infection. CONCLUSION: Imbalance of immune state with hypercytokinemia occurred during HAdV-7 infection. The percentages of blood immune cells such as CD3+ T cells and the levels of serum cytokines such as CXCL10 showed potential diagnosis values in HAdV-7 infection.

Inducible generalized activation of hSTING-N154S expression in mice leads to lethal hypercytokinemia: a model for "cytokine storm".

Excessive levels of circulating proinflammatory mediators, known as "hypercytokinemia," that are generated by overwhelming immune system activation can lead to death due to critical organ failure and thrombotic events. Hypercytokinemia has been frequently associated with a variety of infectious and autoimmune diseases, with severe acute respiratory syndrome coronavirus 2 infection currently being the commonest cause, of what has been termed the cytokine storm. Among its various functions within the host, STING (stimulator of interferon genes) is critical in the defense against certain viruses and other pathogens. STING activation, particularly within cells of the innate immune system, triggers potent type I interferon and proinflammatory cytokine production. We thus hypothesized that generalized expression of a constitutively active STING mutant in mice would lead to hypercytokinemia. To test this, a Cre-loxP-based system was used to cause the inducible expression of a constitutively active hSTING mutant (hSTING-N154S) in any tissue or cell type. Herein, we employed a tamoxifen-inducible ubiquitin C-CreERT2 transgenic to obtain generalized expression of the hSTING-N154S protein, thereby triggering the production of IFN-ß and multiple proinflammatory cytokines. This required euthanizing the mice within 3 to 4 d after tamoxifen administration. This preclinical model will allow for the rapid identification of compounds aimed at either preventing or ameliorating the lethal effects of hypercytokinemia.

Interferon signaling and hypercytokinemia-related gene expression in the blood of antidepressant non-responders.

Only 50% of patients with depression respond to the first antidepressant drug administered. Thus, biomarkers for prediction of antidepressant responses are needed, as predicting which patients will not respond to antidepressants can optimize selection of alternative therapies. We aimed to identify biomarkers that could predict antidepressant responsiveness using a novel data-driven approach based on statistical pattern recognition. We retrospectively divided patients with major depressive disorder into antidepressant responder and non-responder groups. Comprehensive gene expression analysis was performed using peripheral blood without narrowing the genes. We designed a classifier according to our own discrete Bayes decision rule that can handle categorical data. Nineteen genes showed differential expression in the antidepressant non-responder group (n = 15) compared to the antidepressant responder group (n = 15). In the training sample of 30 individuals, eight candidate genes had significantly altered expression according to quantitative real-time polymerase chain reaction. The expression of these genes was examined in an independent test sample of antidepressant responders (n = 22) and non-responders (n = 12). Using the discrete Bayes classifier with the HERC5, IFI6, and IFI44 genes identified in the training set yielded 85% discrimination accuracy for antidepressant responsiveness in the 34 test samples. Pathway analysis of the RNA sequencing data for antidepressant responsiveness identified that hypercytokinemia- and interferon-related genes were increased in non-responders. Disease and biofunction analysis identified changes in genes related to inflammatory and infectious diseases, including coronavirus disease. These results strongly suggest an association between antidepressant responsiveness and inflammation, which may be useful for future treatment strategies for depression.

Fatal Fulminant Cerebral Edema in Six Children With SARS-CoV-2 Omicron BA.2 Infection in Taiwan.

Acute fulminant cerebral edema in children following SARS-CoV-2 infection has been rarely reported. Such patients frequently demonstrate rapid progression and are usually fatal. In this retrospective study, we describe the detailed clinical, laboratory, and neuroimaging features of six fatal cases in Taiwan. All patients had shock initially, five showed rapid progression to multiorgan failure and disseminated intravascular coagulation, and three developed acute respiratory distress syndromes. The inflammatory biomarkers in the first 3 days, including interleukin 6, ferritin, lactate dehydrogenase, and D-dimer, showed significant elevation in all cases. The hyperinflammatory response may play a role in the pathophysiology.

Research Progress on Capillary Leak Syndrome Associated with Hematopoietic Stem Cell Transplantation--Review / 中国实验血液学杂志

Capillary leak syndrome (CLS) is a clinical syndrome characterized by impairment of vascular endothelial barrier function, increased vascular permeability, and reversible systemic edema. It is one of the early fatal complications after hematopoietic stem cell transplantation. So far, the exact pathogenesis of CLS has not been elucidated, and the diagnostic criteria and treatment methods have not been unified. At present, it is believed that the fundamental cause of CLS is hypercytokinemia, and the core factor is high permeability of vascular endothelial cells. According to the clinical manifestations, the natural course of CLS can be divided into prodrome, leakage and recovery stages. As far as treatment is concerned, symptomatic and supportive treatment is dominant according to different characteristics of each stage. In this review, the pathogenesis, clinical manifestations, diagnosis and treatment of hematopoietic stem cell transplant-associated CLS were briefly summarized.

Capillary leak syndrome following COVID-19 vaccination: Data from the European pharmacovigilance database Eudravigilance.

Capillary leak syndrome (CLS) emerged as new adverse event after immunization (AEFI) associated to COVID-19 vaccination. CLS is a rare condition characterized by increased capillary permeability, resulting in hypoalbuminemia, hypotension, and edema mainly in the upper and lower limbs. Our pharmacovigilance study aims to evaluate the CLS onset following receipt of COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) compared to viral vector vaccines (Ad26.COV2-S and ChAdOx1-SARS-COV-2). We carried a cross-sectional study using all Individual Case Safety Reports (ICSRs) reporting a COVID-19 vaccine as suspected drug and CLS as AEFI, which were collected in the pharmacovigilance database EudraVigilance from January 1st, 2021, to January 14th, 2022. We applied the Reporting Odds Ratio (ROR) 95% CI for the disproportionality analysis. During our study period, CLS was described as AEFI in 84 out of 1,357,962 ICRs reporting a vaccine COVID-19 as suspected drug and collected in the EV database. Overall, the ICSR reported by CLS were mainly related to the viral vector COVID-19(ChAdOx1-SARS-COV-2 = 36; Ad26.COV2-S = 9). The mRNA COVID-19 vaccines were reported in 39 ICSRs (BNT162b2 =33; mRNA-1273 =6). Majority of ICSRs were reported by healthcare professionals (71.4%). Majority of the patients were adult (58.3%) and the female gender accounted in more than 65% of ICSRs referred both to classes vaccines. In particular, women were more represented in ICSRs referred to mRNA-1273 (83.3%) and to ChAdOx1-SARS-COV-2 (72.2%). The CLS outcome was more frequently favorable in mRNA ICSRs (33,3%) than the viral vector ones (13.3%). Among the ICSRs reporting CLS with unfavorable outcome, we found also 9 fatal cases (BNT162b2 = 1; ChAdOx1-SARS-COV-2 = 4; Ad26.COV2-S = 4). From disproportionality analysis emerged a lower CLS reporting probability after vaccination with mRNA vaccines compared to viral vector-based ones (ROR 0.5, 95% CI 0.3-0.7; p <0.001).Our findings, even if subject to the limitations of spontaneous reporting systems, suggest a small but statistically significant safety concern for CLS following receipt of COVID-19 viral vector vaccines, in particular with Ad26.COV2-S. Cytokine-release following T-cell activation could be involved in CLS occurrence, but a precise mechanism has been not yet identified. COVID-19 vaccines remain attentive as possible triggers of CLS.

An autopsy case of fulminant myocarditis after severe acute respiratory syndrome coronavirus 2 vaccine inoculation.

A 61-year-old woman without significant medical history developed fever 3 days after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and went into shock the next day. She was negative for SARS-CoV-2 mRNA in real-time polymerase chain reaction (PCR). Finally, she died 10 days after vaccination. At autopsy, the heart showed moderate dilatation of both ventricles, and the myocardium showed an uneven color change and decreased elasticity. Histologically, severe myocarditis with extensive myocytolysis was observed. The myocarditis showed severe inflammatory cell infiltration with T-lymphocyte and macrophage predominance, and in addition to the inflammatory cells described above, vast nuclear dust accompanying neutrophilic infiltration was observed. In the bone marrow and lymph nodes, hemophagocytosis was observed. In postmortem examination, nucleic acids of any cardiotropic viruses including SARS-CoV-2 were not detected using multivirus real-time PCR system. We discussed the relationship between the possible immune reaction after vaccination and the myocarditis observed in this case from immunopathological viewpoints. This mRNA vaccine is the first applied nucleic acid vaccine for humans, and its mechanism of efficacy and immune acquisition remain unclear. We hope the accumulation of more detailed analyses of the similar cases to reveal the mechanism of this kind of adverse reaction.

RNF213-associated urticarial lesions with hypercytokinemia.

BACKGROUND: Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic autoinflammatory diseases. OBJECTIVE: We sought to investigate a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia. METHODS: We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling, and transcriptomic analyses on samples from 2 patients. The identified candidate protein was studied after in vitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was used to unveil the associated protein network. RESULTS: The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of proinflammatory (IL-1ß, IL-6, and TNF-α) and anti-inflammatory (IL-10 and IL-1 receptor antagonist [IL-1RA]) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever, and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. The affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein with a poorly known physiologic role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213. CONCLUSION: We identified a new entity characterized by chronic urticarial lesions associated with a clinically blunted hypercytokinemia. This disease, which is due to loss of function of RNF213, reveals mysterin's key role in the complex molecular network of innate immunity.

Can smoking prevalence explain COVID-19 indicators (cases, mortality, and recovery)? A comparative study in OECD countries.

There are many risk factors associated with the spread of the COVID-19 pandemic, including low wind speed, fossil fuel energy production, air pollution, and smoking. Several studies argue that smoking is not a risk factor for COVID-19 morbidity among males or any other sub-group. The study aims to analyze the following research questions: (1) can smoking prevalence explain COVID-19 indicators (cases, mortality, and recovery)? Are these relationships monotonically increasing or decreasing? In an attempt to test the counter-intuitive possibility of a non-linear relationship, the proposed empirical model relaxes the assumption of monotonic change by applying the quadratic design and testing which one of the two competing models (quadratic or linear) better fits the data. Findings suggest more complex relationships between corona indices and prevalence of smoking than previously thought. These patterns might be explained by several conditions such as the attenuation of hypercytokinemia for mild levels of smoking prevalence compared with non-smokers, elevated social distancing of smokers in countries with lower smoking prevalence, and unidentified factors that should be examined in future research.

Cleavage-Responsive Biofactory T Cells Suppress Infectious Diseases-Associated Hypercytokinemia.

Severe infectious diseases, such as coronavirus disease 2019 (COVID-19), can induce hypercytokinemia and multiple organ failure. In spite of the growing demand for peptide therapeutics against infectious diseases, current small molecule-based strategies still require frequent administration due to limited half-life and enzymatic digestion in blood. To overcome this challenge, a strategy to continuously express multi-level therapeutic peptide drugs on the surface of immune cells, is established. Here, chimeric T cells stably expressing therapeutic peptides are presented for treatment of severe infectious diseases. Using lentiviral system, T cells are engineered to express multi-level therapeutic peptides with matrix metallopeptidases- (MMP-) and tumor necrosis factor alpha converting enzyme- (TACE-) responsive cleavage sites on the surface. The enzymatic cleavage releases γ-carboxyglutamic acid of protein C (PC-Gla) domain and thrombin receptor agonist peptide (TRAP), which activate endothelial protein C receptor (EPCR) and protease-activated receptor-1 (PAR-1), respectively. These chimeric T cells prevent vascular damage in tissue-engineered blood vessel and suppress hypercytokinemia and lung tissue damages in vivo, demonstrating promise for use of engineered T cells against sepsis and other infectious-related diseases.