Clinical implication of detecting sensitization to iodinated radiocontrast media in the basophil activation test by flow cytometry

The use of iodinated radiocontrast media is necessary for visualization. A number of patients have adverse effects of various nature and severity when these drugs are administered. Routine allergy tests do not provide adequate diagnosis of reactions to drugs in this group. The aim of this work is to assess the capabilities of the basophil activation test to confirm sensitization to non-ionic iodinated radiocontrast media, as well as to select a safe alternative drug in patients with a burdened history. Basophil activation test by flow cytometry was performed in 184 patients The Nikiforov Russian Centre of Emergency and Radiation Medicine» EMERCOM of Russia and 32 volunteers using ultravist, omnipack, and optiray. The presence of sensitization was assessed based on the basophil activation index, as well as spontaneous and anti-IgE antibody-induced activation of basophils and the population of T-lymphocytes type 2 immune response. The volunteers showed no sensitization to iodinated radiocontrast media. In patients with a medium degree of hypersensitivity reaction in vivo, in vitro sensitization to drugs was detected 4 times more often than in patients with a mild degree (51% versus 13.5%). In patients with systemic reactions to the administration of a known drug, in vitro sensitization was confirmed in 86% of cases, while the frequency of detection of sensitization to drugs did not differ. Spontaneous activation of basophils in patients and type 2 T-lymphocytes were 2 times higher than in volunteers. Patients were more likely to have low (less than 30%) activation of basophils for anti-IgE antibodies. The specificity of the basophil activation test with iodinated radiocontrast media was 100% with a sensitivity of 94.1%. Most patients were able to select a non-sensitizing contrast. Inclusion in the algorithm of spontaneous and anti-IgE antibody-induced activation of basophils and a population of T-lymphocytes type 2 immune response will allow the doctor to carry out a personalized approach to the management of patients with a burdened history.

Higher exhaled nitric oxide at 6 weeks of age is associated with less bronchiolitis and wheeze in the first 12 months of age

BackgroundNitric oxide in exhaled air (eNO) is used as a marker of type 2 immune response-induced airway inflammation. We aimed to investigate the association between eNO and bronchiolitis incidence and respiratory symptoms in infancy, and its correlation with eosinophil protein X (EPX).MethodsWe followed up infants at 6 weeks of age born to mothers with asthma in pregnancy and measured eNO during natural sleep using a rapid response chemiluminescense analyser (CLD88; EcoMedics), collecting at least 100 breaths, interpolated for an expiratory flow of 50 mL/s. EPX normalised to creatinine was measured in urine samples (uEPX/c). A standardised questionnaire was used to measure symptoms in first year of life. Associations were investigated using multiple linear regression and robust Poisson regression models.ResultseNO levels were obtained in 184 infants, of whom 125/184 (68%) had 12 months questionnaire data available and 51/184 (28%) had uEPX/c measured. Higher eNO was associated with less respiratory symptoms during the first 6 weeks of life (n=184, ß-coefficient: –0.49, 95% CI –0.95 to –0.04, p=0.035). eNO was negatively associated with uEPX/c (ß-coefficient: –0.004, 95% CI –0.008 to –0.001, p=0.021). Risk incidence of bronchiolitis, wheeze, cold or influenza illness and short-acting beta-agonist use significantly decreased by 18%–24% for every unit increase in eNO ppb.ConclusionHigher eNO levels at 6 weeks of age may be a surrogate for an altered immune response that is associated with less respiratory symptoms in the first year of life.

IL-33 genetics and epigenetics in immune-related diseases

Interleukin-33 (IL-33) is a 30KDa protein, which belongs to the Interleukin-1 cytokine family. It is a crucial regulator of innate and adaptive immune responses. This interleukin is additionally involved in the inflammatory reaction versus helminthic infections. Interleukin 33 acts on group 2 innate lymphoid cells and mast cells macrophages, dendritic cells and CD4 + Th2 cells eliciting a type 2 immune response. Moreover, the cytokine can activate the ST2 of Tregs, demonstrating its ability to downregulate inflammation. IL-33 has also an intracellular function by regulating transcription. The active IL-33 doesn’t have a signal peptide, so it’s not released across a normal secretory pathway; the interleukin is released when the cells are damages and acts like an “alarmin”. Its influence on immune activation could be slightly adjusted via fine epigenetic interactions involving cascade pathways and immune genes. Due to the diverse data emerged from different experimental research, we decided span literature to clarify, as much as possible, how IL-33 is influenced by and influence gene expression. The authors reported how its balance is influenced, according to the tissue considered. Fundamental for immune-related diseases, IL-33 has a key role in controlling inflammation. The understanding of the cytokine switch will be fundamental in a near future in order to block or activate some immune pathways. In fact, we could control interleukins effects not only by monoclonal antibodies but also by using siRNA or miRNAs for silencing or expressing key genes.

The discovery of group 2 innate lymphoid cells has changed the concept of type 2 immune diseases

Group 2 innate lymphoid cells (ILC2s), discovered in 2010, have been recognized as immune cells with unique functions and their involvement in various diseases has been clarified. Before 2010, the antigen-specific response was a primary focus of immunology research, and immune responses were considered almost equivalent to biological responses to foreign antigens. However, with the emergence of ILC2s, the importance of ‘antigen-independent responses’ was confirmed, and this concept has permeated basic and clinical research as well as drug development. When ILC2s were discovered, their function in the acute phase of diseases garnered attention because of their rapid and potent type 2 immune response. However, several studies have revealed that the main role of ILC2s is more closely related to the chronicity of diseases, such as allergy and fibrosis, than to the induction of diseases. In this review, we discuss how ILC2 research has affected the concept of ‘Taishitsu’, a Japanese term describing the overall nature of an individual as determined by the interaction of genetic and acquired predisposition.

Huangbai Liniment Ameliorates Skin Inflammation in Atopic Dermatitis

Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3–4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1β, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.

Platelets, Not an Insignificant Player in Development of Allergic Asthma

Allergic asthma is a chronic and heterogeneous pulmonary disease in which platelets can be activated in an IgE-mediated pathway and migrate to the airways via CCR3-dependent mechanism. Activated platelets secrete IL-33, Dkk-1, and 5-HT or overexpress CD40L on the cell surfaces to induce Type 2 immune response or interact with TSLP-stimulated myeloid DCs through the RANK-RANKL-dependent manner to tune the sensitization stage of allergic asthma. Additionally, platelets can mediate leukocyte infiltration into the lungs through P-selectin-mediated interaction with PSGL-1 and upregulate integrin expression in activated leukocytes. Platelets release myl9/12 protein to recruit CD4+CD69+ T cells to the inflammatory sites. Bronchoactive mediators, enzymes, and ROS released by platelets also contribute to the pathogenesis of allergic asthma. GM-CSF from platelets inhibits the eosinophil apoptosis, thus enhancing the chronic inflammatory response and tissue damage. Functional alterations in the mitochondria of platelets in allergic asthmatic lungs further confirm the role of platelets in the inflammation response. Given the extensive roles of platelets in allergic asthma, antiplatelet drugs have been tested in some allergic asthma patients. Therefore, elucidating the role of platelets in the pathogenesis of allergic asthma will provide us with new insights and lead to novel approaches in the treatment of this disease.

Immune system challenge improves recognition memory and reverses malaria-induced cognitive impairment in mice

The immune system plays a role in the maintenance of healthy neurocognitive function. Different patterns of immune response triggered by distinct stimuli may affect nervous functions through regulatory or deregulatory signals, depending on the properties of the exogenous immunogens. Here, we investigate the effect of immune stimulation on cognitive-behavioural parameters in healthy mice and its impact on cognitive sequelae resulting from non-severe experimental malaria. We show that immune modulation induced by a specific combination of immune stimuli that induce a type 2 immune response can enhance long-term recognition memory in healthy adult mice subjected to novel object recognition task (NORT) and reverse a lack of recognition ability in NORT and anxiety-like behaviour in a light/dark task that result from a single episode of mild Plasmodium berghei ANKA malaria. Our findings suggest a potential use of immunogens for boosting and recovering recognition memory that may be impaired by chronic and infectious diseases and by the effects of ageing.

In chronic pancreatitis CD25+/Foxp3+ regulatory T-cells control pancreatic fibrosis by suppression of the type 2 immune response

Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identified Tregs as central regulators of the fibroinflammatory reaction by a selective depletion of Foxp3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP resulted in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, Foxp3+/CD25+ Tregs suppress the type-2 immune response by a repression of Gata3+ T-helper cells (Th2), Gata3+ innate lymphoid cells type 2 (ILC2) and CD206+ M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator Follistatin. Our study identified Tregs as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg-triggered immune response could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.