Inappropriate Immune Response Research Articles

Self-reported diagnoses of dietary allergens and fecundability in a North American cohort

Abstract STUDY QUESTION To what extent are self-reported diagnoses of food allergies associated with fecundability, the per-cycle probability of conception? SUMMARY ANSWER Fecundability was not appreciably associated with self-reported food allergy diagnoses, number of food allergies, age at first diagnosis, or time since last allergic reaction. WHAT IS KNOWN ALREADY Food allergies are atopic diseases that are characterized by an inappropriate immune response to a normally harmless dietary substance. While some studies have observed associations between atopic disorders and infertility, no study has examined the association between food allergies and fecundability, the per-cycle probability of conception. STUDY DESIGN, SIZE, DURATION A prospective cohort study including 7711 females trying to conceive without fertility treatment at enrollment (2018–2022) and followed for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS We analyzed data from an internet-based prospective cohort of pregnancy planners in North America. At baseline, female participants completed an online questionnaire on demographic, medical, and lifestyle factors that included questions on food allergy diagnoses, age at diagnosis, and time since last reaction. Participants completed bimonthly follow-up questionnaires for up to 12 months to ascertain pregnancy status. The analysis included 7711 PRESTO participants with ≤6 menstrual cycles of pregnancy attempt time at enrollment (2018–2022). We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusted for demographic, lifestyle, and behavioral characteristics. MAIN RESULTS AND THE ROLE OF CHANCE A total of 1028 (13%) participants reported a history of diagnosed food allergy, with the most commonly reported allergy being dairy or shellfish. A history of diagnosed food allergy (vs none) was not appreciably associated with fecundability (FR = 0.93, 95% CI: 0.86–1.02), though specific allergens were associated with fecundability in opposing directions (e.g. inverse association with egg and positive association with soy). We observed non-monotonic associations between fecundability and number of food allergies, age at first allergy diagnosis, and time since last allergic reaction. Inverse associations between self-reported diagnosed food allergens (all types combined) and reduced fecundability were slightly stronger among those with BMI ≥25 (FR = 0.90, 95% CI: 0.80–1.01) than those with BMI <25 (FR = 0.97, 95% CI: 0.86–1.10) and among those born ≥1990 (FR = 0.91, 95% CI: 0.80–1.03) compared with those born <1990 (FR = 0.96, 95% CI: 0.86–1.08). LIMITATIONS, REASONS FOR CAUTION Non-differential misclassification of food allergies was likely given that we relied on self-reported diagnoses. Confounding by unmeasured dietary factors may have influenced associations between specific food allergens and fecundability, if participants were deficient in specific nutrients because they excluded or substituted selected foods due to the allergy. Generalizability may be reduced given our study population was restricted to North American pregnancy planners. WIDER IMPLICATIONS OF THE FINDINGS Diagnoses of food allergies have substantially increased over the past several decades. Our findings indicate that self-reported diagnoses of food allergies were not meaningfully associated with subfertility. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by NIH/NICHD grant R01-HD086742. S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics and Kindara.com for primary data collection. L.A.W. is a paid consultant for AbbVie, Inc. and the Gates Foundation. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

Early subclinical stages of the inflammatory bowel diseases: insights from human and animal studies.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication, or prevention. Here, we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of patients with IBD and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

Mycoplasma pneumoniae: not a typical respiratory pathogen.

Mycoplasma pneumoniae is a leading cause of community-acquired pneumonia among school-aged children and young adults. Infections occur throughout the year but tend to surge during winter months across Europe. A characteristic epidemic cycle, where a substantial surge in the number of infections occurs, is seen approximately every 1-4 years and hypothesized to be driven by changes in immunity and a shift in circulating variants. Once thought to be an organism of low virulence, it has now been found to possess several virulence factors, including toxin production, biofilm formation and evasion of antibody-mediated immunity. The lack of a cell wall and reduced metabolic pathways limit the options for antibiotic treatment. Acquired macrolide resistance is a growing concern, with >80% of cases in China being macrolide-resistant. Although efforts have been made to develop a vaccine, there are still substantial hurdles to overcome in relation to vaccine-enhanced disease, which results from an inappropriate immune response among vaccinated individuals.

Sensory sentinels: Neuroimmune detection and food allergy.

Food allergy is classically characterized by an inappropriate type-2 immune response to allergenic food antigens. However, how allergens are detected and how that detection leads to the initiation of allergic immunity is poorly understood. In addition to the gastrointestinal tract, the barrier epithelium of the skin may also act as a site of food allergen sensitization. These barrier epithelia are densely innervated by sensory neurons, which respond to diverse physical environmental stimuli. Recent findings suggest that sensory neurons can directly detect a broad array of immunogens, including allergens, triggering sensory responses and the release of neuropeptides that influence immune cell function. Reciprocally, immune mediators modulate the activation or responsiveness of sensory neurons, forming neuroimmune feedback loops that may impact allergic immune responses. By utilizing cutaneous allergen exposure as a model, this review explores the pivotal role of sensory neurons in allergen detection and their dynamic bidirectional communication with the immune system, which ultimately orchestrates the type-2 immune response. Furthermore, it sheds light on how peripheral signals are integrated within the central nervous system to coordinate hallmark features of allergic reactions. Drawing from this emerging evidence, we propose that atopy arises from a dysregulated neuroimmune circuit.

Oral exposure to nano- and microplastics: Potential effects in food allergies?

BackgroundFood allergies (FA) is an inappropriate immune response to dietary antigens and ranks among the most common chronic diseases globally, with a rising incidence. Environmental exposure significantly influences the development of FA. In modern life, hundreds of thousands of novel environmental contaminants have been introduced, including nano- and microplastics (NMPs). The recently introduced ‘Epithelial Barrier Theory’ suggests that NMPs damage the epithelium of our skin, lungs and gastrointestinal system. And studies also have shown a correlation between NMPs exposure and allergic diseases, such as allergic asthma and rhinitis. However, the relationship between NMPs and FA remains unclear. There is a possibility that high concentrations of NMPs in the diet and environment could increase the prevalence or severity of FA. PurposeThis review aimed to provide relevant information on the possible effects of NMPs exposure on FA. Main findingsContaminating NMPs can interact with food allergens in the food matrix, potentially binding to and altering their structure. Moreover, NMPs might decrease the gastrointestinal digestibility of food allergens, increase intestinal permeability, promote an intestinal inflammatory environment in the intestines, cause intestinal dysbiosis or interfere with immune systems-all of which might enhance sensitivity to food allergens. Principal conclusionsGiven the limited information on the impacts of NMPs exposure regarding to the risk of FA development, further research is needed to determine whether NMPs could amplify the risk of allergic sensitization to food proteins.

The Microbiome in Inflammatory Bowel Disease.

The management of patients with inflammatory bowel disease (IBD) aims to control inflammation through the use of immunosuppressive treatments that target various points in the inflammatory cascade. However, the efficacy of these therapies in the long term is limited, and they often are associated with severe side effects. Although the pathophysiology of the disease is not completely understood, IBD is regarded as a multifactorial disease that occurs due to an inappropriate immune response in genetically susceptible individuals. The gut microbiome is considered one of the main actors in the development of IBD. Gut dysbiosis, characterised by significant changes in the composition and functionality of the gut microbiota, often leads to a reduction in bacterial diversity and anti-inflammatory anaerobic bacteria. At the same time, bacteria with pro-inflammatory potential increase. Although changes in microbiome composition upon biological agent usage have been observed, their role as biomarkers is still unclear. While most studies on IBD focus on the intestinal bacterial population, recent studies have highlighted the importance of other microbial populations, such as viruses and fungi, in gut dysbiosis. In order to modulate the aberrant immune response in patients with IBD, researchers have developed therapies that target different players in the gut microbiome. These innovative approaches hold promise for the future of IBD treatment, although safety concerns are the main limitations, as their effects on humans remain unknown.

AUTOIMMUNE ENCEPHALITIS: DIAGNOSTIC AND TREATMENT APPROACH

Autoimmune encephalitis is a type of brain inflammation induced by an inappropriate immune response to a neuronal antigen, resulting in the generation of autoantibodies. Autoimmunity as important cause of encephalitis in recent years has not been much reported in Indonesia. Increased familiarity with autoimmune encephalitis among physician, not only neurologist, is extremely important for early detection. Prompt diagnosis and early immunotherapy leads to better prognosis in this potentially treatable disease, despite a long disease course. Autoimmune encephalitis is characterized by acute-subacute progressive neuropsychiatric symptoms with associated cognitive dysfunction, encephalopathy, psychiatric disorders, movement disorders and seizures, with anti-N-methyl-D-aspartate (NMDA) receptors encephalitis as the most common type. In addition to clinical features, further diagnostic investigations needed are brain magnetic resonance imaging (MRI), electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, and autoantibody testing. Challenges in establishing diagnosis include wide range of clinical symptoms, absence of abnormalities in brain MRI, unspecified EEG findings, negative antibody testing, and limited availability of antibody testing in Indonesia. This literature review discusses the recognition, diagnosis and principle of treatment of autoimmune encephalitis.

N-ethyl-N-nitrosourea (ENU)-induced C-terminal truncation of Runx3 results in autoimmune colitis associated with Th17/Treg imbalance

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory intestinal disease that affects people around the world. The primary cause of IBD is an imbalance in the host immune response to intestinal flora. Several human genes, including IL10, STAT3, IRGM, ATG16L1, NOD2 and RUNX3, are associated with inappropriate immune responses in IBD. It has been reported that homozygous Runx3-knockout (ko) mice spontaneously develop colitis. However, the high mortality rate in these mice within the first two weeks makes it challenging to study the role of Runx3 in colitis. To address this issue, a spontaneous colitis (SC) mouse model carrying a C-terminal truncated form of Runx3 with Tyr319stop point mutation has been generated. After weaning, SC mice developed spontaneous diarrhea and exhibited prominent enlargement of the colon, accompanied by severe inflammatory cell infiltration. Results of immunofluorescence staining showed massive CD4+ T cell infiltration in the inflammatory colon of SC mice. Colonic IL-17A mRNA expression and serum IL-17A level were increased in SC mice. CD4+ T cells from SC mice produced stronger IL-17A than those from wildtype mice in Th17-skewing conditions in vitro. In addition, the percentages of Foxp3+ Treg cells as well as the RORγt+Foxp3+ Treg subset, known for its role in suppressing Th17 response in the gut, were notably lower in colon lamina propria of SC mice than those in WT mice. Furthermore, transfer of total CD4+ T cells from SC mice, but not from wildtype mice, into Rag1-ko host mice resulted in severe autoimmune colitis. In conclusion, the C-terminal truncated Runx3 caused autoimmune colitis associated with Th17/Treg imbalance. The SC mouse model is a feasible approach to investigate the effect of immune response on spontaneous colitis.

Role of Ayurvedic Herbs in the Management of Celiac Disease

Celiac disease or gluten-sensitive enteropathy is an autoimmune hypersensitivity disorder affecting the small intestine. It occurs due to an inappropriate immune reaction to gluten, which results in inflammation and damage to the small intestine. One of the most prevalent illnesses, celiac disease, is brought on by both environmental (gluten) and genetic causes of human leukocyte antigen (HLA) and non-HLA genes. The prevalence of celiac disease has been estimated to approximate 0.5%-1% in different parts of the world. Due to improved physician awareness and expertise, as well as the widespread use of extremely sensitive and precise diagnostic tests for celiac disease, the prevalence of celiac disease has considerably grown in the past 30 years. While older children have either limited or unusual symptoms, only a small percentage of celiac patients have the classic signs of the condition like chronic or intermittent diarrhea, failure to thrive, weight loss, delayed puberty, short stature, nausea, vomiting, chronic abdominal pain, abdominal distension, chronic constipation. Early detection of celiac disease is crucial to preventing long-term consequences. According to Ayurveda, some symptoms of celiac disease found in Grahani Dosha. Grahani is described as an Agni Adhisthana by most of Acharya. Mandagini is the root cause of Ama Dosha, and it is a crucial factor for the manifestation of most diseases. The treatment approach of celiac disease in Ayurveda medicinal science involves the intake of various preparations of some specific medicinal plants like Kutaja (Holarrhena antidysenterica) Pippali, (Piper longum Linn.), Chitraka, (Plumbago zeylanica) Guduchi, (Tinospora cordifolia) Ashwagandha, (Withania somnifera), Haridra (Curcuma longa Linn.), etc which have Agni Deepana and Ama Pachana properties. These illness-specific medicinal herbs help normalize digestive fire and evict "Ama" toxins from the body channels, which pacify the vitiated Agni and maintain homeostasis among vitiated Doshas.

A Comparative Study on Serum Levels of “Thymic Stromal Lymphopoietin” Between Patients with Psoriasis Vulgaris and Healthy Individuals: A Case-Control Study

Abstract Background: Thymic stromal lymphopoietin (TSLP) is a cytokine initially implicated to be associated with allergic disorders inducing Th2 response. Emerging studies have shown that TSLP is also involved in autoimmune diseases. In psoriasis, TSLP acts in synergy with T cell-derived CD40L to promote the release of IL-23 from dendritic cells. IL-23 is responsible for the inappropriate immune reaction and keratinocyte proliferation in psoriasis. Targeting TSLP could be a novel therapeutic approach in the treatment of psoriasis. Objective: To compare the serum levels of TSLP between patients with psoriasis and healthy individuals. Materials and Methods: A prospective hospital-based case-control study was carried out on 38 patients with psoriasis. The severity of psoriasis was graded into mild, moderate, and severe according to PASI. A total of 30 healthy individuals with matched age and sex were taken as controls. 5 ml of venous blood was collected, centrifuged, and the collected serum was stored at -80°C until quantitative assessment by sandwich enzyme-linked immunosorbent assay (ELISA) technique. Results: TSLP has been found to be significantly elevated in the sera of cases (0.1380178 pg/ml) than in controls (0.1125974 pg/ml). There was also a significant proportionate increase in the mean TSLP with the mean PASI score. Limitations: The sample size was small and we could not follow-up the cases to study the changes in TSLP levels with remission of the lesions. Conclusion: We found that serum TSLP was elevated in psoriasis patients and correlated with disease severity, indicating a possible pathogenetic role.

Impaired reprogramming of the autophagy flux in maturing dendritic cells from crohn disease patients with core autophagy gene-related polymorphisms

ABSTRACT Crohn disease (CD) is an inflammatory bowel disease whose pathogenesis involves inappropriate immune responses toward gut microbiota on genetically predisposed backgrounds. Notably, CD is associated with single-nucleotide polymorphisms affecting several genes involved in macroautophagy/autophagy, the catabolic process that ensures the degradation and recycling of cytosolic components and microorganisms. In a clinical translation perspective, monitoring the autophagic activity of CD patients will require some knowledge on the intrinsic functional status of autophagy. Here, we focused on monocyte-derived dendritic cells (DCs) to characterize the intrinsic quantitative features of the autophagy flux. Starting with DCs from healthy donors, we documented a reprogramming of the steady state flux during the transition from the immature to mature status: both the autophagosome pool size and the flux were diminished at the mature stage while the autophagosome turnover remained stable. At the cohort level, DCs from CD patients were comparable to control in term of autophagy flux reprogramming capacity. However, the homozygous presence of ATG16L1 rs2241880 A>G (T300A) and ULK1 rs12303764 (G/T) polymorphisms abolished the capacity of CD patient DCs to reprogram their autophagy flux during maturation. This effect was not seen in the case of CD patients heterozygous for these polymorphisms, revealing a gene dose dependency effect. In contrast, the NOD2 rs2066844 c.2104C>T (R702W) polymorphism did not alter the flux reprogramming capacity of DCs. The data, opening new clinical translation perspectives, indicate that polymorphisms affecting autophagy-related genes can differentially influence the capacity of DCs to reprogram their steady state autophagy flux when exposed to proinflammatory challenges. Abbreviation: BAFA1: bafilomycin A1, CD: Crohn disease; DC: dendritic cells; HD: healthy donor; iDCs: immature DCs; IL: interleukin; J: autophagosome flux; LPS: lipopolysaccharide; MHC: major histocompatibility complex; nA: autophagosome pool size; SNPs: single-nucleotide polymorphisms; PCA: principal component analysis; TLR: toll like receptor; τ: transition time; TNF: tumor necrosis factor.

Mechanisms underlying aryl hydrocarbon receptor-driven divergent macrophage function.

Macrophages play an essential role in the innate immune system by differentiating into functionally diverse subsets in order to fight infection, repair damaged tissues, and regulate inappropriate immune responses. This functional diversity stems from their ability to adapt and respond to signals in the environment, which is in part mediated through aryl hydrocarbon receptor (AHR)-signaling. AHR, an environmental sensor, can be activated by various ligands, ranging from environmental contaminants to microbially derived tryptophan metabolites. This review discusses what is currently known about how AHR-signaling influences macrophage differentiation, polarization, and function. By discussing studies that are both consistent and divergent, our goal is to highlight the need for future research on the mechanisms by which AHR acts as an immunological switch in macrophages. Ultimately, understanding the contexts in which AHR-signaling promotes and/or inhibits differentiation, proinflammatory functions, and immunoregulatory functions, will help uncover functional predictions of immunotoxicity following exposure to environmental chemicals as well as better design AHR-targeted immunotherapies.

Programmed cell death-1-modified pig developed using electroporation-mediated gene editing for in vitro fertilized zygotes.

Programmed cell death-1 (PD-1) is an immunoinhibitory receptor required to suppress inappropriate immune responses such as autoimmunity. Immune checkpoint antibodies that augment the PD-1 pathway lead to immune-related adverse events (irAEs), organ non-specific side effects due to autoimmune activation in humans. In this study, we generated a PD-1 mutant pig using electroporation-mediated introduction of the CRISPR/Cas9 system into porcine zygotes to evaluate the PD-1 gene deficiency phenotype. We optimized the efficient guide RNAs (gRNAs) targeting PD-1 in zygotes and transferred electroporated embryos with the optimized gRNAs and Cas9 into recipient gilts. One recipient gilt became pregnant and gave birth to two piglets. Sequencing analysis revealed that both piglets were biallelic mutants. At 18mo of age, one pig showed non-purulent arthritis of the left elbow/knee joint and oligozoospermia, presumably related to PD-1 modification. Although this study has a limitation because of the small number of cases, our phenotypic analysis of PD-1 modification in pigs will provide significant insight into human medicine and PD-1-deficient pigs can be beneficial models for studying human irAEs.

Immunosuppressants alter the immune response associated with Glucantime® treatment for Leishmania infantum infection in a mouse model.

Immunosuppression is a major risk factor for the development of visceral leishmaniasis (VL). The number of patients receiving immunosuppressant drugs such as TNF antagonist (anti-TNF) and methotrexate (MTX) is increasing. In these patients, VL is more severe, their response to treatment poorer, and they are at higher risk of relapse, a consequence (largely) of the poor and inappropriate immune response they develop. To examine the effect of immunosuppressive treatment on the host immune response and thus gain insight into the reduced efficacy of pentavalent antimonials in these patients. Experiments were performed using BALB/c mice immunosuppressed with anti-TNF or MTX, infected with Leishmania infantum promastigotes, and then treated with Glucantime® at clinical doses. Immunosuppression with both agents impeded parasite elimination from the spleen and bone marrow. Low pro-inflammatory cytokine production by CD4+ and CD8+ T cells was detected, along with an increase in PD-1 and IL-10 expression by B and T cells in the immunosuppressed groups after treatment. The immunosuppressed mice were unable to develop specific cellular immunity to the parasite, perhaps explaining the greater risk of VL relapse seen in pharmacologically immunosuppressed human patients.

Orally Administrated Inflamed Colon-Targeted Nanotherapeutics for Inflammatory Bowel Disease Treatment by Oxidative Stress Level Modulation in Colitis.

Inflammatory bowel disease (IBD) is characterized by an inappropriate and persistent inflammatory immune response and is often accompanied by excessive reactive oxygen species (ROS) production. For effective IBD treatment, there is a high demand for safe and targeted therapy that can be orally administered. In this study, we aimed to propose the use of inflamed colon-targeted antioxidant nanotherapeutics (ICANs) for in situ oxidative stress level modulation in colitis. ICANs consist of mesoporous silica nanoparticles (MSNs) with surface-attached ROS-scavenging ceria nanoparticles (CeNPs), which are further coated with poly(acrylic acid) (PAA) to facilitate preferential adherence to inflamed colon tissues through electrostatic interaction. We achieved a high ROS-scavenging property that remained effective even after artificial gastrointestinal fluid incubation by optimization of the molecular weight and PAA-coating pH. The orally administered ICANs demonstrated enhanced adherence to inflamed colon tissues in an acute inflammation mouse model of IBD induced by dextran sulfate sodium. This targeted delivery resulted in gut microenvironment modulation by regulating redox balance and reducing inflammatory cell infiltration, thereby suppressing the colitis-associated immune response. These findings highlight the potential of noninvasive ICANs as a promising candidate for treating inflammatory intestinal diseases by oxidative stress level modulation in colitis.

Diacylglycerol kinase zeta deficiency attenuates papain-induced type 2 airway inflammation

Allergic airway diseases are caused by inappropriate immune responses directed against inhaled environmental antigens. We previously reported that the inhibition of diacylglycerol (DAG) kinaseζ (DGKζ),an enzyme that terminates DAG-mediated signaling,protects against T cell-mediated allergic airway inflammation by blocking Th2 cell differentiation.In this study, we tested whether DGKζ deficiency also affects allergic airway disease mediated by type 2 innate lymphoid cells (ILC2)s. DGKζ-deficient mice displayed diminished ILC2 function and reduced papain-induced airway inflammation compared to wildtype mice. Unexpectedly, however, mice with hematopoietic cell-specific deletion ofDGKζ displayed intact airway inflammation upon papain challenge. Rather, bone marrow chimera studies revealed thatDGKζ deficiency in the non-hematopoietic compartment was responsible for the reduction in papain-induced airway inflammation. These data suggest that DGK might represent a novel therapeutic target not only for T cell-dependent but also ILC2-dependent allergic airway inflammation by affecting non-hematopoietic cells.

Innate Immunity in Autoimmune Thyroid Disease during Pregnancy.

Autoimmune thyroid disease (AITD) is the most common organ-specific autoimmune disorder clinically presented as Hashimoto thyroiditis (HT) and Graves' disease (GD). The pathogenesis of AITD is caused by an inappropriate immune response related to genetic, non-genetic, and environmental factors. Pregnancy is one of the factors that have a great influence on the function of the thyroid gland because of the increased metabolic demand and the effects of hormones related to pregnancy. During pregnancy, an adaptation of the maternal immune system occurs, especially of the innate immune system engaged in maintaining adaptive immunity in the tolerant state, preventing the rejection of the fetus. Pregnancy-related hormonal changes (estrogen, progesterone, hCG) may modulate the activity of innate immune cells, potentially worsening the course of AITD during pregnancy. This especially applies to NK cells, which are associated with exacerbation of HD and GD. On the other hand, previous thyroid disorders can affect fertility and cause adverse outcomes of pregnancy, such as placental abruption, spontaneous abortion, and premature delivery. Additionally, it can cause fetal growth retardation and may contribute to impaired neuropsychological development of the fetus. Therefore, maintaining the thyroid equilibrium in women of reproductive age and in pregnant women is of the highest importance.

EVIDENCE FROM FATAL COVID-19 FOR TARGETING THE BRADYKININ METABOLISM-A SINGLE-CENTER COHORT STUDY.

Background: Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called bradykinin storm. However, clinical investigations of bradykinin, its metabolite des-Arg 9 -bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients. A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020-02/2021, prevalent wildtype SARS-CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg 9 -bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and nonsurvivors (n = 23) of COVID-19 from admission until discharge or death. Results: We found significantly higher plasma levels of des-Arg 9 -bradykinin in survivors and nonsurvivors of COVID-19 compared with healthy controls. In addition, plasma des-Arg 9 -bradykinin levels were higher ( P < 0.001, effect size = 0.79) in nonsurvivors compared with survivors of COVID-19 and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or lactate dehydrogenase, and outcome. Consequently, compared with healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and nonsurvivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced ( P < 0.001, effect size = 0.7) in nonsurvivors compared with survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and nonsurvivors of COVID-19. Conclusion: Our data demonstrates that des-Arg 9 -bradykinin is significantly elevated in COVID-19 intensive care unit patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg 9 -bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg 9 -bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.

Camellia sinensis (L.) Kuntze Extract Attenuates Ovalbumin-Induced Allergic Asthma by Regulating Airway Inflammation and Mucus Hypersecretion.

Asthma is a pulmonary disease induced by the inhalation of aeroallergens and subsequent inappropriate immune responses. Camellia sinensis (L.) Kuntze has been evaluated as an effective antioxidant supplement produced from bioactive compounds, including flavonoids. In this study, we aimed to determine the effects of Camellia sinensis (L.) Kuntze extract (CE) on ovalbumin-induced allergic asthma. The components of CE were analyzed using high-performance liquid chromatography (HPLC) chromatogram patterns, and asthmatic animal models were induced via ovalbumin treatment. The antioxidant and anti-inflammatory effects of CE were evaluated using 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS), and nitric oxide (NO) assays. Seven compounds were detected in the CE chromatogram. In the ovalbumin-induced mouse model, CE treatment significantly decreased the inflammation index in the lung tissue. CE also significantly decreased eosinophilia and the production of inflammatory cytokines and OVA-specific IgE in animals with asthma. Collectively, our results indicate that CE has anti-inflammatory and antioxidant activities, and that CE treatment suppresses asthmatic progression, including mucin accumulation, inflammation, and OVA-specific IgE production.

Cationic brush hybrid nanoparticles scavenge cell-free DNA to enhance rheumatoid arthritis treatment

Abnormally high level of cell-free DNA (cfDNA) is one of the important causes of autoimmune diseases, which aggravate the symptoms of rheumatoid arthritis (RA). Recently, the utilization of cationic polymeric nanoparticles for scavenging cfDNA has emerged as a promising therapeutic strategy for the treatment of RA. However, the intravenous introduction of cationic polymeric nanoparticles into the circulation carries a risk of dissociation, causing toxicity. To realize the potential clinical translation, we employed a series of silica particles grafted with poly(2-(dimethylamino) ethyl methacrylate) (PDMA) (SiNP@PDMA) brush, which possess adjustable PDMA content (100, 200, and 300 degree of polymerization (DP)) and particle size (50, 100, and 200 nm diameter), to selectively scavenge cfDNA in inflamed joint cavity. We demonstrate that the binding affinity for cfDNA, cytotoxicity, circulation time in vivo and retention in the inflamed joint cavity are influenced by the core-shell structure of SiNP@PDMA, ultimately impacting therapeutic efficacy. Among them, SiNP@PDMA with 100 nm size and 200 DP of PDMA exhibit enhanced accumulation and prolonged retention time in inflammatory joint cavity, resulting in superior therapeutic effect. Therefore, in this study, applying the precisely tuning size and cation content of SiNP@PDMA, we demonstrated the factors to matter the therapeutic effect of cationic nanoparticles, which deepened the understanding of the anti-inflammatory therapies based on cfDNA scavenger for RA. Statement of significanceInspired by the discovery that cfDNA would induce inappropriate immune responses to exacerbate the progress of RA, we innovatively employed SiNP@PDMA as a cfDNA scavenger to inhibit cfDNA-induced inflammation in RA. Increase in the cation content efficiently strengthened the binding between SiNP@PDMA and cfDNA, leading to an improvement in inhibitory effect of inflammation. In addition, we compared the behaviors of 50, 100 and 200 nm SiNP@PDMA in RA symptom suppression, local cfDNA scavenging and inflammation inhibition. The results demonstrated that SiNP100-PDMA200 outperformed other analogues, corresponding to their more favorable distribution in inflammatory articular cavity. Together, this study revealed the structure-property relationship of cfDNA scavengers for further development of safe and effective cfDNA scavenging system.