The role of microRNAs in atopic dermatitis.

Atopic dermatitis (AD), known as eczema, is a chronic inflammatory skin condition affecting millions worldwide. This abstract provides an overview of the clinical features and underlying pathogenesis of AD, highlighting the role of specific microRNAs (miRNAs) in its development and progression. AD presents with distinct clinical manifestations that evolve with age, starting in infancy with dry, itchy skin and red patches, which can lead to sleep disturbances. In childhood, the rash spreads to flexural areas, resulting in lichenification. In adulthood, lesions may localize to specific areas, including the hands and eyelids. Pruritus (itchiness) is a hallmark symptom, often leading to excoriations and increased vulnerability to skin infections. The pathogenesis of AD is multifaceted, involving genetic, immunological, and environmental factors. Skin barrier dysfunction, immune dysregulation, genetic predisposition, microbiome alterations, and environmental triggers contribute to its development. Recent research has uncovered the role of miRNAs, such as miR-10a-5p, miR-29b, miR-124, miR-143, miR-146a-5p, miR-151a, miR-155, and miR-223, in AD pathogenesis. These microRNAs play crucial roles in regulating various aspects of immune responses, keratinocyte dynamics, and inflammation. MicroRNA-10a-5p orchestrates keratinocyte proliferation and differentiation, while miR-29b regulates keratinocyte apoptosis and barrier integrity. MicroRNA-124 exhibits anti-inflammatory effects by targeting the NF-κB signaling pathway. MicroRNANA-143 counters allergic inflammation by modulating IL-13 signaling. MicroRNA-146a-5p regulates immune responses and correlates with IgE levels in AD. MicroRNA-151a shows diagnostic potential and modulates IL-12 receptor ß2. MicroRNA-155 plays a central role in immune responses and Th17 cell differentiation, offering diagnostic and therapeutic potential. MicroRNA-223 is linked to prenatal smoke exposure and immune modulation in AD. Understanding these microRNAs' intricate roles in AD pathogenesis promises more effective treatments, personalized approaches, and enhanced diagnostic tools. Further research into these molecular orchestrators may transform the landscape of AD management, improving the quality of life for affected individuals.

Clinical heterogeneity in families with multiple cases of inborn errors of immunity.

BACKGROUND: Inborn errors of immunity (IEI) are a diverse range of genetic immune system illnesses affecting the innate and/or adaptive immune systems. Variable expressivity and incomplete penetrance have been reported in IEI patients with similar clinical diagnoses or even the same genetic mutation. METHODS: Among all recorded patients in the national IEI registry, 193 families with multiple cases have been recognized. Clinical, laboratory and genetic variability were compared between 451 patients with different IEI entities. RESULTS: The diagnosis of the first children led to the earlier diagnosis, lower diagnostic delay, timely treatment and improved survival in the second children in the majority of IEI. The highest discordance in familial lymphoproliferation, autoimmunity and malignancy were respectively observed in STK4 deficiency, DNMT3B deficiency and ATM deficiency. Regarding immunological heterogeneity within a unique family with multiple cases of IEI, the highest discordance in CD3+, CD4+, CD19+, IgM and IgA levels was observed in syndromic combined immunodeficiencies (CID), while non-syndromic CID particularly severe combined immunodeficiency (SCID) manifested the highest discordance in IgG levels. Identification of the first ATM-deficient patient can lead to improved care and better survival in the next IEI children from the same family. CONCLUSION: Intrafamilial heterogeneity in immunological and/or clinical features could be observed in families with multiple cases of IEI indicating the indisputable role of appropriate treatment and preventive environmental factors besides specific gene mutations in the variable observed penetrance or expressivity of the disease. This also emphasizes the importance of implementing genetic evaluation in all members of a family with a history of IEI even if there is no suspicion of an underlying IEI as other factors besides the underlying genetic defects might cause a milder phenotype or delay in presentation of clinical features. Thus, affected patients could be timely diagnosed and treated, and their quality of life and survival would improve.

The clinical relationship between histamine-1 receptor antagonists and risk of cancer: a systematic review and meta-analysis.

BACKGROUND: A systematic research was performed to review the relationship between use of histamine-1 receptor antagonists and cancer risk. METHOD: Databases were searched up to December 2021. Case-control and cohort studies evaluating the relationship between use of histamine-1 receptor antagonists and risk of cancer were selected. The major outcome was cancer risk. Odds ratio (OR) with 95% confidence intervals (CIs) was calculated. Subgroup, cumulative, and sensitivity analysis and Egger test were performed. RESULTS: Five case-controls and one cohort study were included. According to cohort study, use of antihistamines were not associated with cancer risk (RR = 0.92, 95% CI = (0.78-1.07). In case-controls, the frequency of antihistamine use in cases and controls was 11.28% and 14.82% respectively which was associated with decreased cancer risk (p value = 0.02, OR = 0.93, 95%CI = (0.87, 0.99)). Sensitivity analysis showed a change in direction of pooled OR by omitting some studies. Sub-group analysis according to type of cancer showed a decrease in cancer risk in antihistamine users in glioma (p value = 0.03). CONCLUSION: Antihistamines might reduce the risk of certain cancers. More studies with defined background of allergy are needed which can clarify the relevancy of different types of cancer with anti-H1 receptors.

Diversity of malignancies in patients with different types of inborn errors of immunity.

Genetic defects in the development, maturation, and/or function of the immune cells can lead to Inborn errors of immunity (IEI) which may predispose patients to malignancies. The overall risk for cancer in children with IEI ranges from 4 to 25% and the type of malignancy is highly dependent on the specific mutant gene underlying IEI. We investigated 3056 IEI patients registered in the Iranian national registry between the years 1999 and 2020 in this retrospective cohort study. The frequency of malignancy and its association with the type of IEI in these patients were evaluated. A total of 82 IEI patients with malignancy were enrolled in this study. Among them, predominantly lymphoma was the most common type of malignancy (67.1%), followed by leukemia (11%), and cancers of the head and neck (7.3%). Among identified lymphoma cancers, non-Hodgkin's lymphomas were the most frequent type (43.9%) followed by different subtypes of Hodgkin's lymphoma (23.2%). Solid tumors (18.3%) appeared to be very heterogeneous by type and localization. The correlation between the type of malignancy and survival status and the association between the type of malignancy and IEI entities were unremarkable. The awareness of the association between the presence of IEI and cancer highlights the importance of a synergistic effort by oncologists and immunologists in the early diagnosis of malignancy and personalized therapeutic strategies in IEI patients.

The effect of 3-year parental smoking on asthma status of their children.

OBJECTIVE: Whilst the prevalence and severity of asthma influenced by environmental factors, the effect of parental smoking on asthma status of their children was examined. PATIENTS AND METHODS: Ninety asthmatic children, 32 with smoker and 58 with non-smoker parents (baseline age, 8.5 ± 3.5 and 8.2 ± 3.3 respectively) were studies in two sessions 3 years apart by evaluating respiratory symptoms (RS) prevalence and severity, various drugs used, and pulmonary function tests (PFT) including forced vital capacity; forced volume in the first second, peak expiratory flow; and maximum expiratory low at 75, 50 and 25% of vital capacity (FVC, FEV1, PEF, MEF75, MEF50 and MEF25, respectively). RESULTS: The prevalence and severity of all RS were significantly increased in asthmatic children with smoking parents after 3 years except prevalence and severity of night wheeze and the prevalence of chest wheeze (p < 0.05 to p < 0.001), but the PFT values were non-significantly reduced. In asthmatic children with non-smoking parents, the prevalence and severity of RS were decreased after 3 years, which was significant for night and chest wheeze for prevalence and night cough and chest wheeze for severity (all, p < 0.05), and the PFT values were increased, which were statistically significant for FVC, FEV1, MEF50 and MEF25 (p < 0.05 to p < 0.01). Drugs used by the group with smoking parents were increased and were significantly higher than their reduction in the groups with non-smoking parents at the end of the study (p < 0.05 for fluticasone propionate 125/salmeterol and budesonide160/formoterol). CONCLUSION: Long-term parental smoking increased prevalence and severity of RS and drug used but decreased PFT values of their asthmatic children.

The Potential of Probiotics for Treating Skin Disorders: A Concise Review.

Probiotics are defined as "live microorganisms that confer a health benefit on the host when administered adequately." In recent years, the cosmetic industry has tried to develop many products classified as probiotics. They can exert their benefits at the skin level because of their favorite properties, and they could prevent and treat skin diseases and represent an emerging area for skin health. The antibacterial and immunomodulatory properties make them promising candidates to target skin disorders including acne, psoriasis, and atopic dermatitis and aid wound healing. The scientific reports show that specific probiotic strains can modulate cutaneous microflora, skin immune system, lipid barrier, and skin health preservation. This review summarizes the most relevant evidence from scientific literature concerning potential topical applications of probiotics in dermatology. Altogether, the evidence reported here affords the possibility of designing new strategies based on a topical approach to prevent and treat cutaneous disorders.

COVID-19 in children with inborn errors of immunity: clinical scenarios.

The new emerging virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes a huge burden of morbidity and mortality worldwide. One of the predisposing factors which might increase the infection susceptibility and its complications can be the Inborn Errors of Immunity (IEI). One hundred and seventeen primary immunodeficient (PID) pediatric patients were monitored from March to December 2020 for any signs and symptoms of SARS-CoV-2 infection. Among them twenty-eight children were symptomatic and nineteen out of the twenty-eight patients took the coronavirus PCR test. Out of them, the PCR test results of 9 patients were positive. Herein, we report the nine cases of pediatric patients with IEI who were also infected with SARS-CoV-2 with a positive PCR test. We observed a variation in clinical manifestations, clinical courses, and outcomes among IEI pediatric patients affected with COVID-19. In our survey, prompt diagnosis and appropriate monitoring for possible complications were shown to be effective in reducing the mortality rate of the SARS-CoV-2 affected patients with IEI. Although there is no approved treatment for SARS-CoV-2 infection, supportive treatment might reduce the complications and lead to better outcomes. This study received approval from the Research Ethics Committee of Mashhad University of Medical Science with the ethics code of IR.MUMS.REC.1399.155. (https://ethics.research.ac.ir/EthicsProposalViewEn.php?id=129963).

Adverse reactions in a large cohort of patients with inborn errors of immunity receiving intravenous immunoglobulin.

BACKGROUND: Intravenous immunoglobulins (IVIg) are the major treatment in inborn errors of immunity (IEI) disorders; However, IVIg infusions show some adverse effects. We aimed to assess the adverse reactions of IVIg infusions. METHODS: Data of IVIg infusions in IEI patients were collected from 2011 to 2021. Totally, 363 IEI patients received IVIg regularly in Iran entered the study. The adverse reactions are classified regarding their severity and chronicity. RESULTS: 22,667 IVIg infusions were performed in the study. 157 patients (43.2%) and 1349 (5.9%) infusions were associated with at least one type of adverse reaction. The highest rates of adverse reactions were seen in severe combined immunodeficiency. Myalgia, chills, headache, fever, and hypotension were the most frequent adverse effects of IVIg. CONCLUSION: The reactions affect almost half of the patients mainly in the first infusions which necessitate the close observation of IEI patients receiving IVIg.

Epidermal growth factor receptor inhibitor in advanced basal cell carcinoma.

Cetuximab can be used for the treatment of advanced basal cell carcinoma, especially when the patient cannot tolerate routine chemotherapy. Future studies are needed to confirm it.

Autoimmune manifestations among 461 patients with monogenic inborn errors of immunity.

BACKGROUND: The inborn errors of immunity (IEIs) are a group of heterogeneous disorders mainly characterized by severe and recurrent infections besides other complications including autoimmune and inflammatory diseases. In this study, we aim to evaluate clinical, immunologic, and molecular data of monogenic IEI patients with and without autoimmune manifestations. METHODS: We have retrospectively screened cases of monogenic IEI in the Iranian PID registry for the occurrence of autoimmunity and immune dysregulation. A questionnaire was filled for all qualified patients with monogenic defects to evaluate demographic, laboratory, clinical, and molecular data. RESULTS: A total of 461 monogenic IEI patients (290 male and 171 female) with a median (IQR) age of 11.0 (6.0-20.0) years were enrolled in this study. Overall, 331 patients (72.1%) were born to consanguineous parents. At the time of the study, 330 individuals (75.7%) were alive and 106 (24.3%) were deceased. Autoimmunity was reported in 92 (20.0%) patients with a median (IQR) age at autoimmune diagnosis of 4.0 (2.0-7.0) years. Sixteen patients (3.5%) showed autoimmune complications (mostly autoimmune cytopenia) as the first presentation of the disease. Most of the patients with autoimmunity were diagnosed clinically with common variable immunodeficiency (42.4%). The frequency of sinusitis and splenomegaly was significantly higher in patients with autoimmunity than patients without autoimmunity. In patients with autoimmunity, the most common pathogenic variants were identified in LRBA (in 21 patients, 23.0%), ATM (in 13 patients, 14.0%), and BTK (in 9 patients, 10.0%) genes. In the evaluation of autoimmunity by different genes, 4 of 4 IL10RB (100%), 3 of 3 AIRE (100%), and 21 of 30 LRBA (70.0%) mutated genes had the highest prevalence of autoimmunity. CONCLUSIONS: Autoimmune phenomena are common features among patients with monogenic IEI and are associated with a more complicated course of the disease. Therefore, when encountering autoimmune disorders, especially in the setting of dysgammaglobulinemia, it would be appropriate to conduct next-generation sequencing to discover responsible genes for the immune dysregulation at an early stage of the disease.

COVID-19 in a child with primary antibody deficiency.

Although presentation of COVID-19 in patients with immunodeficiency could be mild, it should not be missed, while early diagnosis and appropriate treatment can survive infected patients. Because even severe infections in PID patients may be presented with few symptoms and signs, this diagnosis should be considered in those immunocompromised patients who have exacerbating preexisting symptoms.

Prevalence of IgE-Mediated Food Hypersensitivity to Cereals and Beans Based on Skin Prick Test in Children with Celiac Disease.

BACKGROUND Celiac disease is a non-IgE mediated food allergy, which can cause extensive villus atrophy. Because of increased food allergen absorption, there are elevated IgA and IgG antibodies in these patients, so there is a concern about IgE antibody production against wheat and other cereals. METHODS In this study, we evaluated IgE-mediated hypersensitivity to wheat, rice, and other cereals in children with celiac disease. RESULTS 22 patients (50%) had at least one positive skin prick test to food allergens. The most frequent food allergen was peanut (31.8%), followed by wheat (18.2%), corn (9.1%), and rice (4.5%). The results revealed no significant correlation between age, sex, and the results of the skin prick test (p >0.05). The correlation between diagnosis time of celiac disease and results of skin prick test was also not significant statistically (p >0.05). CONCLUSION Because of the high prevalence of IgE mediated hypersensitivity to cereals and beans in children with celiac disease, a skin prick test might be considered in these patients, especially in refractory cases.

Death Due to COVID-19 in an Infant with Combined Immunodeficiencies.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 has affected millions of people, and especially in adult patients with underlying diseases lead to death. Meanwhile pediatric patients with inherited defects of T cell should be prone to viral diseases. CASE PRESENTATION: Herein, we report an infant with severe combined immunodeficiencies, who were affected and died because of COVID-19. CONCLUSION: Considering the importance of finding how immune system can affect the viral infection, presentation of COVID-19 in immune deficient patients can be valuable.

Impact of SARS-CoV-2 Pandemic on Patients with Primary Immunodeficiency.

Although it is estimated that COVID-19 life-threatening conditions may be diagnosed in less than 1:1000 infected individuals below the age of 50, but the real impact of this pandemic on pediatric patients with different types of primary immunodeficiency (PID) is not elucidated. The current prospective study on a national registry of PID patients showed that with only 1.23 folds higher incidence of infections, these patients present a 10-folds higher mortality rate compared to population mainly in patients with combined immunodeficiency and immune dysregulation. Therefore, further management modalities against COVID-19 should be considered to improve the survival rate in these two PID entities using hematopoietic stem cell transplantation and immunomodulatory agents.

How to Boost our Immune System Against Coronavirus Infection?

New emerging viruses like coronavirus 2019 (COVID-19) infections are always frightening. We know little about their transmission, behaviors, clinical manifestations, and outcomes. There is no vaccine or therapeutic strategies to deal with these infections yet. In this situation, preventive measures may be promising. Hand hygiene is a very important issue in preventing viral infection; however, there are other entities that can enhance the immune response and help in infection prevention. Herein we review some measures for boosting the immune system.

Monogenic Primary Immunodeficiency Disorder Associated with Common Variable Immunodeficiency and Autoimmunity.

BACKGROUND: Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency disorder mainly characterized by recurrent bacterial infections besides other immunological defects including loss of or dysfunction of B cells and decreased immunoglobulin levels. In this study, our aim is to evaluate clinical, immunological, and molecular data of patients with a primary clinical diagnosis of CVID and autoimmune phenotype with a confirmed genetic diagnosis. METHODS: Among 297 patients with CVID, who were registered in the Iranian Primary Immunodeficiency Registry at Children's Medical Center Hospital in Iran, 83 patients have been genetically examined and 27 patients with autoimmunity and confirmed genetic mutations were selected for analysis. Whole-exome sequencing and confirmatory Sanger sequencing methods were used for the study population. A questionnaire was retrospectively filled for all patients to evaluate demographic, laboratory, clinical, and genetic data. RESULTS: In the 27 studied patients, 11 different genetic defects were identified, and the most common mutated gene was LRBA, reported in 17 (63.0%) patients. Two patients (7.7%) showed autoimmune complications as the first presentation of immunodeficiency. Eleven patients (40.7%) developed one type of autoimmunity, and 16 patients (59.3%) progressed to poly-autoimmunity. Most of the patients with mono-autoimmunity (n = 9, 90.0%) primarily developed infectious complications, while in patients with poly-autoimmunity, the most common first presentation was enteropathy (n = 6, 37.6%). In 13 patients (61.9%), the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency. The most frequent autoimmune manifestations were hematologic (40.7%), gastrointestinal (48.1%), rheumatologic (25.9%), and dermatologic (22.2%) disorders. Patients with poly-autoimmunity had lower regulatory T cells than patients with mono-autoimmunity. CONCLUSION: In our cohort, the diagnosis of autoimmune disorders preceded the diagnosis of primary immunodeficiency in most patients. This association highlights the fact that patients referring with autoimmune manifestations should be evaluated for humoral immunity.

Global systematic review of primary immunodeficiency registries.

INTRODUCTION: During the last 4 decades, registration of patients with primary immunodeficiencies (PID) has played an essential role in different aspects of these diseases worldwide including epidemiological indexes, policymaking, quality controls of care/life, facilitation of genetic studies and clinical trials as well as improving our understanding about the natural history of the disease and the immune system function. However, due to the limitation of sustainable resources supporting these registries, inconsistency in diagnostic criteria and lack of molecular diagnosis as well as difficulties in the documentation and designing any universal platform, the global perspective of these diseases remains unclear. AREAS COVERED: Published and unpublished studies from January 1981 to June 2020 were systematically reviewed on PubMed, Web of Science and Scopus. Additionally, the reference list of all studies was hand-searched for additional studies. This effort identified a total of 104614 registered patients and suggests identification of at least 10590 additional PID patients, mainly from countries located in Asia and Africa. Molecular defects in genes known to cause PID were identified and reported in 13852 (13.2% of all registered) patients. EXPERT OPINION: Although these data suggest some progress in the identification and documentation of PID patients worldwide, achieving the basic requirement for the global PID burden estimation and registration of undiagnosed patients will require more reinforcement of the progress, involving both improved diagnostic facilities and neonatal screening.

Evaluation of Serum Substance P Level in Chronic Urticaria and Correlation with Disease Severity.

Substance P (SP) is a neurotransmitter emitted from neurons that plays a role in the pathogenesis of itching conditions including chronic urticarial (CU). The present research aims to investigate the serum level of S.P among CU patients and compare them with healthy subjects and explore how it correlates with the severity of urticaria. The present research was conducted on 87 CU patients who visited the allergy clinic of Ghaem Hospital, Mashhad, Iran from October 2017 to June 2018. Besides, 86 healthy subjects were recruited as the control group. Background information of patient was collected including age, sex, duration of the disease and the co-occurrence of angioedema. S.P serum level was measured in two groups by ELISA method. In the patients group, the autologous serum skin test (ASST) was performed along with the urticaria evaluation questionnaire include Urticaria Activity Score 7 (UAS7), Urticaria Control Test (UCT) and Chronic Urticaria Quality of Life (CU-Q2OL). Among the patients, the SP serum level showed to be about two times higher than the healthy subjects (p˂0.001). SP showed to be increased as patients' age grew (p=0.010). In patients with a positive ASST, SP level was higher (p=0.012). No correlation was found between SP and the presence of angioedema among patients. There was no correlation between the SP serum level and the scores obtained from urticaria evaluation questionnaires. SP among CU patients was higher than healthy subjects. SP was also higher among female, older and positive ASST patients. The SP value was not correlated with the severity of urticaria, angioedema. In conclusion, Using SP antagonist drugs could be a potential treatment for chronic urticaria.

Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran.

BACKGROUND: Severe combined immunodeficiency (SCID) is the most severe form of primary immunodeficiency disorders that is characterized by impaired early T lymphocyte differentiation and is variably associated with abnormal development of other lymphocyte lineages. SCID can be caused by mutations in more than 20 different genes. Molecular diagnosis in SCID patients contributes to genetic counseling, prenatal diagnosis, treatment modalities, and overall prognosis. In this cohort, the clinical, laboratory and genetic data related to Iranian SCID patients were comprehensively evaluated and efficiency of stepwise sequencing methods approach based on immunophenotype grouping was investigated METHODS: Clinical and laboratory data from 242 patients with SCID phenotype were evaluated. Molecular genetic analysis methods including Sanger sequencing, targeted gene panel and whole exome sequencing were performed on 62 patients. RESULTS: Mortality rate was 78.9% in the cohort with a median follow-up of four months. The majority of the patients had a phenotype of T-NK-B+ (34.3%) and the most severe clinical manifestation and highest mortality rate were observed in T-NK-B- SCID cases. Genetic mutations were confirmed in 50 patients (80.6%), of which defects in recombination-activating genes (RAG1 and RAG2) were found in 16 patients (32.0%). The lowest level of CD4+ and CD8+ cells were observed in patients with ADA deficiency (p = 0.026) and IL2RG deficiency (p = 0.019), respectively. CONCLUSION: Current findings suggest that candidate gene approach based on patient's immunophenotype might accelerate molecular diagnosis of SCID patients. Candidate gene selection should be done according to the frequency of disease-causing genes in different populations. Targeted gene panel, WES and WGS methods can be used for the cases which are not diagnosed using this method.

Investigation of the relationship between atopy and psoriasis.

INTRODUCTION: The relationship between allergic and autoimmune diseases is an important issue, which has recently attracted the researchers' interest. AIM: To determine the relationship between atopy and psoriasis. MATERIAL AND METHODS: This case-control study was conducted on 102 patients referred to the Ghaem Hospital, Mashhad, Iran, in 2016. The participants were assigned into two groups: experimental and control groups, including the patients suffering from psoriasis and those with no history of cutaneous or other systemic diseases, respectively. Both groups filled in the ISAAC questionnaire and had skin prick tests. In addition, the serum levels of immunoglobulin E (IgE) and blood eosinophil cell count were measured. The data were analysed using the regression test through SPSS version 16. RESULTS: According to the results of the ISAAC questionnaire, there was a significant difference between the control and experimental groups in terms of asthma (p = 0.04). The mean serum concentrations of IgE and eosinophil cell count were not significantly different between the experimental (153.93 IU/ml and 187.77 cells/µl, respectively) and control groups (152.19 IU/ml and 187.68 cells/µl, respectively) (p = 0.057 and p = 0.886, respectively). In addition, there was an indirect correlation between the eosinophil cell count and psoriasis severity (p = 0.032, r = -0.297). Furthermore, the comparison of the skin prick test results revealed no significant difference between the two groups regarding the number of positive and negative cases (p = 0.436). CONCLUSIONS: The findings suggested that atopy was not common in the patients with psoriasis and supported the concept that atopy protects against such autoimmune diseases such as psoriasis.