Elevated Serum IgE Levels Research Articles

Can We Better Understand, Diagnose, and Treat Ketamine‐Induced Uropathy, and Can It Be Reversed? ICI‐RS 2024

ABSTRACTIntroductionKetamine, a versatile anesthetic, has seen increased recreational use, leading to significant health issues, including ketamine‐induced uropathy (KIU). KIU manifests with lower urinary tract symptoms (LUTS) and can involve the upper urinary tract. This study aims to provide a comprehensive overview of KIU, addressing its pathophysiology, diagnostic strategies, and treatment options; and to define/identify future research priorities.MethodsDuring the 2024 meeting of the International Consultation on Incontinence Research Society (ICI‐RS) in Bristol, a dedicated Proposal (P) convened to explore KIU. This initiative involved a thorough review of existing literature, expert presentations, and consensus‐driven discussions. The methodology ensured a comprehensive exploration of KIU from both clinical and pre‐clinical perspectives, leading to actionable research recommendations.ResultsUnderstanding the mechanisms of KIU is crucial for developing effective treatment options targeting specific pathophysiological pathways. Key findings include bladder fibrosis driven by transforming growth factor‐β1 (TGF‐β1), elevated purinergic responses and upregulated P2X1 purinoceptor expression, decreased barrier function due to increased expression of antiproliferative factor (APF), and functional loss of the bladder through Cav1.2 channel blockade. Research indicates that fibrosis, typically considered irreversible, may be mitigated. However, the exact timing and extent of fibrosis initiation and its impact on long‐term outcomes require further research. LUTS typically improve after ketamine cessation but relapse upon resumption, indicating a hypersensitivity mechanism involving elevated serum IgE levels. Advanced stages of KIU do not always correlate with LUTS severity, shedding light on potential systemic effects and the need for evaluating liver enzymes. Furthermore, psychological dependency on ketamine, due to its positive perceptive and mood‐altering effects, complicates cessation efforts. Long‐term management requires a holistic approach, integrating medical treatments and supportive measures to help patients navigate life with potentially irreversible complications.ConclusionThis comprehensive review spans from fundamental pathology to practical clinical management, addressing both urological and systemic complications, and bridging insights from animal models to human applications. Developing effective treatment strategies necessitates addressing both the physical and psychological aspects of ketamine dependency.

Pathophysiology of Congenital High Production of IgE and Its Consequences: A Narrative Review Uncovering a Neglected Setting of Disorders.

Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.

Unraveling the unphosphorylated STAT3-unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome.

Patients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES. This study aims to elucidate the role of unphosphorylated STAT3-unphosphorylated NF-κB (uSTAT3-uNF-κB) activation pathway in LOF STAT3 HIES patients. The mRNA expression of downstream molecules of unphosphorylated STAT3-unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter. A reduced expression of the downstream signaling molecules of the uSTAT3-uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients. The reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3-uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

Hyper IgE Syndromes.

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a geneticmolecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Kimura’s disease: rare inflammatory condition mimicing as soft tissue neoplasm

Kimura’s disease is rare benign chronic inflammatory condition of unknown etiology involving head and neck region. The characteristic features of this condition are elevated serum IGE levels and microscopic picture reveals lymphoid proliferation with eosinophilic infiltration. It is commonly misdiagnosed as soft tissue neoplasm. Surgical wide local excision is the main stay of treatment. Sometimes combined therapy (excision and postoperative radiotherapy) is needed. Here we are presenting one interesting rare case, 32-year-old male with post auricular swelling, diagnosed as soft tissue tumor preoperatively, after excision came out as kimura’s disease.

Impact of fucosyltransferase 1-mediated epidermal blood group antigen H on anti-inflammatory response in atopic dermatitis.

The presence of the blood group H2 antigen on the membrane of red blood cells determines blood type O in individuals and this H2 antigen serves as a precursor to the A and B antigens expressed in blood types A and B, respectively. However, the specific involvement of ABH antigens in skin diseases is unknown. Therefore, we aim to investigate the expression of ABH antigens in skin tissue of patients with atopic dermatitis (AD) and MC903-induced AD-like mice. We demonstrated that the expression of ABH antigen is primarily located in the granular and horny layers of the skin in healthy control individuals. However, in patients with AD, the expression of the ABH antigen was absent or diminished in these layers, while the H2 antigen expression increased in the spinous layers of the affected skin lesions. Then, we investigated the biological function of blood group H antigen mediated by fucosyltransferase 1 (Fut1) in the skin, utilizing an AD mouse model induced by MC903 in wild-type (WT) and Fut1-knockout mice. After the application of MC903, Fut1-deficient mice, with no H2 antigen expression on their skin, exhibited more severe clinical signs, increased ear swelling, and elevated serum IgE levels compared with those of WT mice. Additionally, the MC903-induced thickening of both the epidermis and dermis was more pronounced in Fut1-deficient mice than that in WT mice. Furthermore, Fut1-deficient mice showed a significantly higher production of interleukin-4 (IL-4) and IL-6 in skin lesions compared with that of their WT counterparts. The expression of chemokines, particularly Ccl2 and Ccl8, was notably higher in Fut1-deficient mice compared with those of WT mice. The infiltration of CD4+ T cells, eosinophils, and mast cells into the lesional skin was significantly elevated in Fut1-deficient mice compared with that in WT mice. These findings demonstrate the protective role of H2 antigen expression against AD-like inflammation and highlight its potential therapeutic impact on AD through the regulation of blood group antigens.

Kimura Disease: A Detailed Analysis of Clinical and Radiological Manifestations in a Retrospective Case Series.

Kimura disease (KD) is a rare chronic inflammatory disease that affects mainly young Asian men and is characterized by painless subcutaneous masses, lymphadenopathy, and elevated serum IgE levels. Despite its benign nature, KD poses a diagnostic and therapeutic challenge due to its rarity and clinical variability. This study aimed to provide a comprehensive analysis of the clinical and radiological features of KD in a retrospective case series, to assess treatment outcomes, and to discuss the implications for diagnosis and management. We retrospectively analyzed four histologically confirmed cases of KD admitted to Zhejiang Provincial People's Hospital from January 2018 to October 2023. Clinical and radiological data were retrospectively analyzed, and imaging findings were analyzed by two neuroradiologists to determine lesion characteristics and contrast enhancement patterns. Our findings showed that the patients were predominantly male, with a mean age of 43 years and an age range of 13-71 years. All patients presented with painless subcutaneous masses and three of them had peripheral blood eosinophilia and elevated serum IgE levels. Radiographically, the lesions were predominantly ill-defined with heterogeneous enhancement, accompanied by subcutaneous fat atrophy. Complete surgical excision and oral corticosteroids were effective treatments, and no recurrence was noted during follow-up. KD should be considered in the differential diagnosis of painless subcutaneous masses in the head and neck region, especially in the presence of eosinophilia and elevated IgE levels. Our findings contribute to the understanding of KD's clinical and radiological spectrum and highlight the need for long-term follow-up due to the risk of recurrence.

MicroRNA-29 regulates IgE class-switching in B cells and susceptibility to skin inflammation

Abstract MicroRNA (miRNA) gene regulation is vital for the development of B cells. Our group established that the miR-29 family is a regulator of B cell survival and B cell receptor (BCR) signaling. Specifically, we identified PTEN as a direct target of miR-29. Conditional knockout of miR-29 in B cells diminishes cell viability, which is compensated by normalizing Pten expression. In our latest observations, mice with a B-cell-specific miR-29 deletion exhibited an inflammatory skin phenotype, characterized by cutaneous lesions, continuous itching and a 50% survival rate. Pten ablation fails to improve their lifespan. These findings indicate that miR-29 targets other transcripts in B cells apart from Pten. Notable features such as epidermal proliferation and elevated serum IgE levels. We hypothesize the absence of miR-29 in B cells may lead to to atopic dermatitis. Computational analysis predicts miR-29 likely regulates Il4Ra transcript levels, and qPCR supports this prediction. Our in vitro assays demonstrate that B cells deficient in miR-29 exhibit greater IgE class switching when stimulated with IL-4, compared to wild-type counterparts. Additionally, we observed that mice developing inflammatory skin conditions harbor an increased Staphylococcus burden. Therefore, we propose that miR-29 plays a role in the co-regulation of Pten and Il4ra to influence the survival and function of mature B cells and may alter how these cells respond to environmental/microbial antigens.

THE INFLUENCE OF ATOPY ON CYSTIC FIBROSIS COURSE IN CHILDREN

The relevance of research. The course of cystic fibrosis (CF) depends on the influence of different modifying factors. One of these factors is atopy. The role of atopy in CF course is incompletely determined today and requires further study. The purpose of the study: to improve medical care for patients with CF by clarifying the pathogenetic role of atopy in the disease course. Materials and methods. Analysis of data from a clinical and paraclinical examination of 42 children with CF in the Kharkiv region. Patients were divided into two groups: with an elevated level of total immunoglobulin E (n=19) and with a normal level of this indicator (n=23) to determine the features of CF course depending on the atopy presence. Results and discussion. In the group with elevated and normal levels of total serum IgE, boys were predominant, as in the general population, and accounted for 73.6% and 60.8%, respectively. The first manifestations of CF were represented mainly by intestinal signs in both groups at 68.4% and 73.9% of cases, respectively. Data analysis of the clinical features of CF course in children with elevated level of IgE (severity of lung and liver lesions) revealed results without significant differences between groups. High level of sensitivity to ordinary domestic, food and pollen allergens was not detected in children of group with elevated level of IgE. Patients with CF and atopy were found to have a probable increase in the levels of CD3, IgM, spontaneous NBT; phagocytosis of latex; decreasing in the levels of CD4, IgA compared to the group with a normal level of total IgE. Conclusion. Features of the CF phenotype associated with the atopy were analyzed. The received data can be used when determining the treatment algorithm, taking into account the individual characteristics of the disease course.

Evaluation of Artemisia dubia folium extract-mediated immune efficacy through developing a murine model for acute and chronic stages of atopic dermatitis

BackgroundAtopic dermatitis (AD) is a biphasic type of skin inflammation characterized by a predominance of type-2 (TH2) and type-1 (TH1) helper T cell-biased immune responses at the acute and persistent chronic phases, respectively. The present study was aimed to evaluate the efficacy of Artemisia dubia folium extract (ADFE) on AD-like skin lesions through developing a murine model for acute and chronic stages of AD. To induce acute phase AD, the dorsal skin of BALB/c mice was sensitized twice a week with 1% 2, 4-dinitrochlorobenzene (DNCB), followed by challenge (twice) in the following week with 0.2% DNCB. To induce persistent chronic AD, some mice were challenged twice a week for 4 more weeks. After the second challenge, the dorsal skin was exposed to 3% ADFE (five times per week) for 2 weeks (acute phase) or 4 weeks (persistent chronic phase).ResultsThe paradigm of TH2 or TH1 predominance at the acute and chronic phase, respectively, was observed in this mouse model. During the acute phase, we observed an increased IL-4/IFN-γ ratio in splenic culture supernatants, an increased IgG1/IgG2a ratio in serum, and elevated serum IgE levels; however, the skew toward TH2 responses was diminished during the chronic stage. Compared with vehicle controls, ADFE reduced the IL-4/IFN-γ and IgG1/IgG2a ratios in acute AD, but both ratios increased during the chronic stage.ConclusionsOur results suggest that ADFE concomitantly suppresses the TH2 predominant response in acute AD, as well as the TH1 predominant response in chronic AD. Thus, ADFE is a candidate therapeutic for AD.

Dendritic cells under allergic condition enhance the activation of pruritogen-responsive neurons via inducing itch receptors in a co-culture study

BackgroundItch sensitization has been reported in patients with chronic allergic skin diseases and observed in a mouse model of allergic contact dermatitis (ACD). There is evidence suggesting that neuroimmune interactions may contribute to itch sensitization, as an increase in dendritic cells (DCs) within ganglia has been observed during allergic conditions. However, how DCs interact with sensory neurons in ganglia during allergic conditions is still not known. This study aims to investigate the role of DCs in dorsal root ganglion (DRG) under ACD conditions, specifically focusing on itch sensitization within the DRG. The tolylene-2,4-diisocyanate (TDI) mouse model for ACD and the co-culture model of DCs and DRG neurons was employed in this study.ResultsWe successfully induced ACD by TDI, as evidenced by the development of edema, elevated total serum IgE levels, and an observed itch reaction in TDI-sensitized mice. Calcium imaging and RT-qPCR analysis revealed that TDI-sensitized mice exhibited signs of peripheral sensitization, including a higher percentage of neurons responding to pruritogens and increased activation and expression of itch receptors in excised DRG of TDI-sensitized mice. Immunofluorescence and flow cytometric analysis displayed an increase of MHCII+ cells, which serves as a marker for DCs, within DRG during ACD. The co-culture study revealed that when DRG neurons were cultured with DCs, there was an increase in the number of neurons responsive to pruritogens and activation of itch receptors such as TRPA1, TRPV1, H1R, and TRPV4. In addition, the immunofluorescence and RT-qPCR study confirmed an upregulation of TRPV4.ConclusionsOur findings indicate that there is an increase of MHCII+ cells and itch peripheral sensitization in DRG under TDI-induced ACD condition. It has been found that MHCII+ cells in DRG might contribute to the itch peripheral sensitization by activating itch receptors, as shown through co-culture studies between DRG neurons and DCs. Further studies are required to identify the specific mediator(s) responsible for peripheral sensitization induced by activated DCs.

Hyper-IgE syndrome: a case report

Introduction and importance: Hyper-IgE syndrome (HIES), also known as Job syndrome, is a rare primary immunodeficiency disorder characterized by elevated serum IgE levels, recurrent infections, and various clinical features. Early diagnosis, prompt management of infections, and supportive care are essential in improving outcomes for individuals with HIES. Genetic testing, including STAT3 gene sequencing, plays a crucial role in confirming the diagnosis. Further research is needed to enhance our understanding of HIES and develop targeted therapies to improve the quality of life for affected individuals. Case presentation: This case report presents the clinical features and management of a 37-year-old male with HIES, diagnosed at the age of 2 due to recurrent cold abscesses caused by Staphylococcal infections. Clinical discussion: The patient exhibited typical symptoms of HIES, including recurrent eczema, frequent bacterial infections, mucocutaneous candidiasis, and various physical abnormalities. Diagnostic markers such as elevated IgE levels and eosinophilia supported the HIES diagnosis, which was further confirmed by the identification of a STAT3 gene mutation. Treatment primarily involved supportive measures and antibiotics for infections. The patient’s blood test results and imaging findings revealed abnormalities such as low red blood cell count, elevated erythrocyte sedimentation rate, and pulmonary nodules. Conclusion: This case report highlights the importance of early diagnosis, prompt management of infections, and the need for ongoing research to improve our understanding and treatment of HIES.

Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency

Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD). We sought to understand the mechanisms of eczema in DOCK8 deficiency. Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus. Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8-/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells. Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency.

Oral administration of egg ovalbumin allergen induces dysregulation of tryptophan metabolism in sensitized BALB/c mice.

Food allergy (FA), triggered by specific dietary allergens, has emerged as a substantial global concern for food safety and public health. While studies have elucidated changes in immune cells and cytokines associated with allergen exposure, a comprehensive analysis of the host's metabolic features and the interaction between metabolites and the gut microbiota has not been conducted. In this study, egg allergen ovalbumin (OVA) was administered by the oral route to sensitized BALB/c mice to faithfully replicate key aspects of human FA, including severe allergic diarrhea, mast cell infiltration, and elevated levels of serum IgE, mMCPT-1, and Th2 cell hallmark cytokines (such as IL-4, IL-5, and IL-13). Furthermore, the untargeted and targeted metabolomic analyses indicated that FA in mice precipitated a substantial decrease in the tryptophan metabolites indole-3-acrylic acid (IA) and indole-3-lactic acid (ILA). The integration of shotgun metagenome and metabolome data further unveiled that the dysregulation of indole metabolism is related to a decline in the abundance of beneficial bacteria such as Lactobacillus and Bifidobacterium. Additionally, disruption of the tryptophan indole derivative pathway compromises the maintenance of intestinal mucosal function through the AHR signaling pathway, manifested by decreased expression of Reg3g and IL22. Taken together, this study demonstrated that the anaphylaxis triggered by oral ingestion of food allergens can lead to disruptions in tryptophan metabolism, consequently impairing intestinal immune homeostasis.

The effectiveness of Omalizumab in the treatment of Hyper-IgE syndrome: A case report

BACKGROUND - Hyper-immunoglobulin E (IgE) syndrome (HIES) is a rare primary multisystem immunodeficiency disorder with an incidence of one case per million population. It is characterized by elevated serum IgE levels, dermatitis, recurrent skin and lung infections, skeletal abnormalities such as scoliosis, and distinctive facial features. Moreover, the clinical manifestations may include vascular, dental, joint, and brain abnormalities. Treatment for HIES predominantly targets symptom relief. Omalizumab, a monoclonal antibody, works by inhibiting the binding of free IgE to receptors on effector cells, consequently reducing the release of inflammatory mediators and alleviating some cutaneous and respiratory symptoms of HIES. To date, according to our understanding, no treatment protocol for HIES patients exists in Jordan. To fill this gap, we report our experience using omalizumab and intravenous immunoglobulin (IVIG) in treating the first documented case of HIES in Jordan. CASE PRESENTATION - We present the case of an 18-year-old male patient who had been diagnosed with HIES since infancy. The patient had been subjected to multiple treatment trials, but none proved effective. In our treatment protocol, 150 mg of omalizumab was administered subcutaneously every 2 weeks, later increasing to 300 mg. Following this treatment, the eczema symptoms and eosinophil count showed a marked reduction. The patient’s IgE level decreased from 21,800 IU/ml in 2011 and 2,039 IU/ml in 2019 to 764 IU/ml in 2022, with treatment commencing in the latter year. CONCLUSION - The combined use of omalizumab and IVIG therapies demonstrated efficacy in reducing the elevated IgE levels and symptom severity in our patient. There is a need for more case studies to report clinical findings in the management of HIES

Interventional pulmonary procedures and their outcomes in patients with STAT3 hyper IgE syndrome

BackgroundSTAT3 hyperimmunoglobulin E syndrome (STAT3-HIES) also referred to as autosomal dominant HIES (AD-HIES) is an inborn error of immunity characterized by the classic triad of eczema, frequent opportunistic infections, and elevated serum IgE levels. As a consequence of lung sequels due to repeated infections and impaired tissue healing, patients may require interventional pulmonary procedures.MethodFour patients with dominant-negative STAT3 mutations who had received interventional pulmonary procedures were enrolled. The demographic, clinical, and molecular characteristics were gathered through a medical record search. All reported STAT3-HIES patients in the literature requiring pulmonary procedures as part of their treatment were reviewed.ResultRecurrent episodes of pneumonia and lung abscess were the most prevalent symptoms. The most common non-immunological features were scoliosis, failure to thrive, and dental problems such as primary teeth retention and disseminated decays. Bronchiectasis, lung abscess, pneumatocele, and cavitary lesion were the most prevalent finding on high-resolution computed tomography at the earliest recording. All patients underwent pulmonary surgery and two of them experienced complications.ConclusionPatients with STAT3-HIES have marked pulmonary infection susceptibility which may necessitate thoracic surgeries. Since surgical procedures involve a high risk of complication, surgical options are recommended to be utilized only in cases of drug resistance or emergencies.

Low CCL2 and CXCL8 Production and High Prevalence of Allergies in Children with Microcephaly Due to Congenital Zika Syndrome.

Congenital Zika Syndrome (CZS) is associated with an increased risk of microcephaly in affected children. This study investigated the peripheral dysregulation of immune mediators in children with microcephaly due to CZS. Gene expression quantified by qPCR in whole blood samples showed an increase in IFNγ and IL-13 transcripts in children affected with microcephaly compared to the control group. The microcephaly group exhibited significantly decreased CCL2 and CXCL8 levels in serum, quantified by CBA assay. An allergic profile questionnaire revealed a high prevalence of allergies in the microcephaly group. In accordance, elevated serum IgE level measured by the Proquantum Immunoassay was observed in children affected with microcephaly compared to the control group. Altogether, these findings show a persistent systemic inflammation in children with microcephaly due to CZS and suggest a possible impairment in leukocyte migration caused by low production of CCL2 and CXCL8, in addition to high levels of IgE associated with high prevalence of allergies. The dysregulation of inflammatory genes and chemokines underscores the importance of understanding the immunological characteristics of CZS. Further investigation into the long-term consequences of systemic inflammation in these children is crucial for developing appropriate therapeutic strategies and tailored vaccination protocols.

A CCR4 antagonist attenuates atopic dermatitis-like skin inflammation by inhibiting the recruitment and expansion of Th2 cells and Th17 cells.

CCR4 is a major trafficking receptor for T-helper (Th) 2 cells and Th17 cells and is considered as a potential therapeutic target for atopic dermatitis (AD). The CCR4 ligands CCL17 and CCL22 have been reported to be upregulated in the skin lesions of AD patients. Of note, thymic stromal lymphopoietin (TSLP), a master regulator of the Th2 immune response, promotes the expression of CCL17 and CCL22 in AD skin lesions. Here, we investigated the role of CCR4 in an AD mouse model induced by MC903, a TSLP inducer. Topical application of MC903 to ear skin increased the expression of not only TSLP but also CCL17, CCL22, the Th2 cytokine IL-4, and the Th17 cytokine IL-17A. Consistently, MC903 induced AD-like skin lesions as shown by increased epidermal thickness; increased infiltration of eosinophils, mast cells, type 2 innate lymphoid cells, Th2 cells, and Th17 cells; and elevated serum levels of total IgE. We also found increased expansion of Th2 cells and Th17 cells in the regional lymph nodes (LNs) of AD mice. Compound 22, a CCR4 inhibitor, ameliorated AD-like skin lesions with reduction of Th2 cells and Th17 cells in the skin lesions and regional LNs. We further confirmed that compound 22 diminished the expansion of Th2 cells and Th17 cells in the coculture of CD11c+ dendritic cells (DCs) and CD4+ T cells derived from the regional LNs of AD mice. Collectively, CCR4 antagonists may exhibit anti-allergic effects by inhibiting both the recruitment and expansion of Th2 cells and Th17 cells in AD.

CORRELATION BETWEEN TOTAL SERUM IgE LEVELS AND SOME CHARACTERISTICS IN VIETNAMESE PEMPHIGOID PATIENTS

Objectives: To determine the correlation between total serum IgE levels and some clinical and subclinical characteristics in pemphigoid patients.Methods: A cross-sectional study on 42 pemphigoid patients, all of which were newly diagnosed. Information was collected from patient interviews and medical records. Total serum IgE levels were determined using a total IgE ELISA following the manufacturer’s instructions. Eosinophil counts were analyzed on the same day when serum samples were taken. For IgE DIF staining of perilesional skin, IgE Goat anti-Human, FITC was used, incubation was performed overnight at 4oC.Results: Among 42 pemphigoid patients, the average age was 73.2 ± 15.5 years old. 60% of pemphigoid patients had elevated total serum IgE levels, the mean value was 121.6 ± 101.8 UI/mL. Total serum IgE levels were significantly correlated with eosinophil counts (r = 0.61; p < 0.05) and the BPDAI urticaria/erythema (U/E) score (r = 0.50; p < 0.05). However, total circulating IgE levels were not significantly associated with total BPDAI score (p > 0.05). DIF IgE staining on perilesional skin of pemphigoid patients had a positive rate of 14.3%.Conclusion: Total serum IgE values correlated with some clinical and subclinical characteristics in pemphigoid patients. IgE autoantibodies were present in the skin of pemphigoid patients, supporting the hypothesis that IgE potentially modulates pruritus associated with pemphigoid.

Unveiling the TGF- β1 paradox: Significant implication of TGF- β1 promoter variants and its mRNA and protein expression in atopic dermatitis

BackgroundAtopic Dermatitis (AD) is a chronic inflammatory skin disorder with evidence of lichenification in later stages. There is mounting evidence supporting the role of TGF- β1 in mediating inflammation as well as subsequent tissue remodeling, often resulting in fibrosis. Given the role of genetic variants in the differential expression of TGF-β1 in various diseases, this study seeks to ascertain the role of TGF-β1 promoter variants (rs1800469 and rs1800468) in AD susceptibility, as well as their association with TGF- β1 mRNA expression, TGF- β1 serum levels and skin prick test positivity in Atopic Dermatitis patients. MethodsAn aggregate of 246 subjects including 134 AD cases and 112 matched healthy controls were genotyped for TGF-β1 promoter polymorphisms by PCR-RFLP. TGF- β1 mRNA was quantified by quantitative Real-Time PCR (qRT-PCR), Vitamin-D levels by chemiluminescence, and serum TGF- β1, and total IgE levels were determined by ELISA. In-vivo allergy testing was performed for the evaluation of allergic reactions to house dust mites and food allergens. ResultsA higher frequency of TT genotypes of rs1800469 (OR = 7.7, p = 0.0001) and GA+AA genotypes of rs1800468 (OR-4.4, p < 0.0001) were observed in AD cases than those in controls. Haplotype analysis demonstrated that TG haplotype carriers had an increased risk of AD (p = 0.013). Quantitative analysis revealed a significant upregulation of both mRNA (p = 0.0002) and serum levels (p < 0.0001) of TGF- β1 with a substantial positive correlation between them (Correlation coefficient=0.504; p = 0.01). Moreover, serum TGF-β1 levels were associated with quality of life (p = 0.03), the severity of the disease (p = 0.03), and House dust mite allergy (p = 0.01) whereas TGF-β1 mRNA levels positively correlated with disease severity(p = 0.02). Stratification analysis revealed that the TT genotype of rs1800469 was associated with higher IgE levels (p = 0.01) and eosinophil percentage(p = 0.007) whereas the AA genotype of rs1800468 correlated with elevated serum IgE levels (p = 0.01). Besides, no significant association of genotypes with mRNA and serum expression of TGF-β1 was observed. ConclusionOur study indicates that TGF-β1 promoter SNPs bear a significant risk of AD development. Moreover, upregulation of TGF-β1 mRNA and serum levels and their association with disease severity, quality of life, and HDM allergy suggests its role as a diagnostic/prognostic biomarker that could help in the development of new therapeutic and prevention strategies.