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In newborn screening (NBS), it is important to consider the availability of multiplex assays or other tests that can be integrated into existing systems when attempting to implement NBS for new target diseases. Recent developments in innovative testing technology have made it possible to simultaneously screen for severe primary immunodeficiency (PID) and spinal muscular atrophy (SMA) using quantitative real-time polymerase chain reaction (qPCR) assays. We describe our experience of optional NBS for severe PID and SMA in Osaka, Japan. A multiplex TaqMan qPCR assay was used for the optional NBS program. The assay was able to quantify the levels of T-cell receptor excision circles and kappa-deleting recombination excision circles, which is useful for severe combined immunodeficiency and B-cell deficiency screening, and can simultaneously detect the homozygous deletion of SMN1 exon 7, which is useful for NBS for SMA. In total, 105,419 newborns were eligible for the optional NBS program between 1 August 2020 and 31 August 2023. A case each of X-linked agammaglobulinemia and SMA were diagnosed through the optional NBS and treated at early stages (before symptoms appeared). Our results show how multiplex PCR-based NBS can benefit large-scale NBS implementation projects for new target diseases. [ABSTRACT FROM AUTHOR]

Background Thalassemia patients are generally immunocompromised, making them susceptible to infection. A study at the Thalassemia Center at Dr. Cipto Mangunkusumo Hospital, Jakarta, showed that all thalassemia patients experienced zinc deficiency. Decreased cellular immune response has been associated with zinc deficiency, and splenectomy exacerbates the risk of infection. Objective To evaluate for improvement of cellular immune response in splenectomized thalassemia major patients after zinc supplementation. Methods This randomized, double-blind, controlled trial was conducted on splenectomized thalassemia major patients over a 12-week period. The inclusion criteria were splenectomized thalassemia major patients aged > 12 to 18 years with negative HIV test results. Patients receiving corticosteroids were excluded. Fifty-six subjects were randomly divided into two groups, the zinc group and the placebo group. Before and after the 12 -week treatment, we evaluated subjects' serum zinc, T lymphocyte count, CD4+ T lymphocyte count, CD8+ T lymphocyte count, and CD4+/CD8+ ratio and were analyzed with unpaired T-test, Mann Whitney test, and Wilcoxon Signed Rank test. Results After zinc supplementation, serum zinc serum levels in 18/28 subjects in the zinc group became normalized. None of the cellular immune response parameters were significantly different between the two groups after zinc supplementation (P > 0.05). This finding might have been due to the subjects' compliance which was lower in the zinc group (75.82%) than in the placebo group (83.19%). Conclusion Cellular immune response in splenectomized thalassemia major patients is not significantly changed after 12 weeks of zinc supplementation. [ABSTRACT FROM AUTHOR]

Flow cytometry plays is important in the diagnosis of acute lymphoblastic leukaemia (ALL) and when antigen-specific immunotherapy is indicated. We have investigated the effects of prednisolone, vincristine, daunorubicin, asparaginase and methotrexate on the antigen expression on blast cells that could influence the planning of antigen-specific therapy as well as risk-based treatment assignment. Patients aged ≤ 17 years with de novo B-cell ALL (B-ALL) were enrolled in the study. Blast cells were isolated and exposed in vitro to 5 individual cytotoxic drugs in logarithmically increasing concentrations. Then, the expression of CD10, CD19, CD20, CD27, CD34, CD45, CD58, CD66c and CD137 antigens was determined by quantitative flow cytometry. Cytotoxic drugs caused dose-dependent or dose-independent modulation of antigen expression. Daunorubicin caused a dose-dependent down-modulation of CD10, CD19, CD34, CD45 and CD58 and an up-modulation of CD137. Vincristine caused a dose-dependent down-modulation of CD19 and CD58 and an up-modulation of CD45. Daunorubicin also caused dose-independent down-modulation of CD27 and prednisolone down-modulation of CD10, CD19, CD27, CD34 and CD58. Down-modulation of CD20 was detected only in relation to the specific dose of daunorubicin. The results of the study have shown that cytotoxic drugs can alter the expression of antigens that are important for immunotherapy. Importantly, daunorubicin, prednisolone and vincristine caused down-modulation of CD19 and CD58, suggesting that these drugs are better avoided during bridging therapy prior to bispecific antibodies or CAR-T cell therapy. In addition, immunophenotypic changes on blast cells induced by different drugs could also influence risk-based treatment assignment. [ABSTRACT FROM AUTHOR]

Recurrent pericarditis is a problematic clinical condition that impairs the quality of life of the affected patients due to the need for repeated hospital admissions, emergency department visits, and complications from medications, especially glucocorticoids. Unfortunately, available treatments for recurrent pericarditis are very limited, including only a handful of medications such as aspirin/NSAIDs, glucocorticoids, colchicine, and immunosuppressants (such as interleukin-1 (IL-1) blockers, azathioprine, and intravenous human immunoglobulins). Until recently, the clinical experience with the latter class of medications was very limited. Nevertheless, in the last decade, experience with IL-1 blockers has consistently grown, and valid clinical data have emerged from randomized clinical trials. Accordingly, IL-1 blockers are a typical paradigm shift in the treatment of refractory recurrent pericarditis with a clearly positive cost/benefit ratio for those unfortunate patients with multiple recurrences. A drawback related to the above-mentioned medications is the absence of universally accepted and established treatment protocols regarding the full dose administration period and the need for a tapering protocol for individual medications. Another concern is the need for long-standing treatments, which should be discussed with the patients. The above-mentioned unmet needs are expected to be addressed in the near future, such as further insights into pathophysiology and an individualized approach to affected patients. [ABSTRACT FROM AUTHOR]

Background: Primary immune thrombocytopenia (pITP) in dogs presents a diagnostic challenge, and clinical markers of severity are lacking. Objectives: Identify clinicopathologic features that differentiate pITP from secondary ITP (sITP) and markers related to bleeding severity, transfusion, and survival of dogs with pITP. Animals: Ninety‐eight thrombocytopenic dogs (58 pITP and 40 sITP). Methods: Client‐owned dogs with platelet counts <50 000/μL were enrolled in a prospective, multi‐institution cohort study. History and treatment information, through a maximum of 7 days, was recorded on standard data forms. Bleeding severity was scored daily using a bleeding assessment tool (DOGiBAT). At‐admission blood samples were collected for CBC, biochemistry, C‐reactive protein concentration, and coagulation panels, and to measure platelet surface‐associated immunoglobulin G (PSAIg) and expression of platelet membrane proteins and phospholipids. Dogs with evidence of coincident disease were classified as sITP. Results: No definitive pITP diagnostic test was found. However, pITP cases were characterized by lower platelet counts, D dimer concentrations, and platelet membrane protein expression than sITP cases. Differentiation between pITP and sITP was further enhanced using logistic regression modeling combining patient sex, coagulation profile, platelet count, D dimer, and PSAIg. A second model of pITP severity indicated that low hematocrit and high BUN concentration were associated with non‐survival. Low hematocrit at admission, but not platelet count or DOGiBAT score, was associated with transfusion. Conclusions and Clinical Importance: Pending validation studies, models constructed from at‐admission clinicopathologic findings may improve differentiation of pITP from sITP and identify the most severe pITP cases at the time of presentation. [ABSTRACT FROM AUTHOR]

Pediatric inflammatory, multisystem syndrome temporally associated with SARS-CoV-2 infection (PIMS-TS), also known as a multisystem inflammatory syndrome in children (MIS-C), is diagnosed in children who develop an inadequate inflammatory response after exposure to the SARS-CoV-2 virus. The pathogenesis of the abnormal response of the immune system to a previous SARS-COV-2 infection has not been explained. Similarly, the safety and effectiveness of COVID-19 vaccinations in this group of patients have become the subject of clinical discussion. Presenting experiences from many centers aims to answer this question. We present 4 cases of patients who suffered from PIMS-TS. Three of them were safely vaccinated against COVID-19 after illness. One patient developed PIMS-TS temporarily associated with COVID-19 vaccination. We also collected and discussed data from other centers. [ABSTRACT FROM AUTHOR]

The diagnosis and treatment of patients with mendelian susceptibility to mycobacterial disease (MSMD) pose consistent challenges due to the diverse infection spectrum observed in this population. Common clinical manifestations include Bacillus Calmette-Guérin vaccine (BCG) complications in countries where routine BCG vaccination is practiced, while in non-BCG-vaccinating countries, Non-Tuberculous Mycobacteria (NTM) is prevalent. In tuberculosis-endemic regions, Mycobacterium tuberculosis (MTB) has a high prevalence, along with other intracellular organisms. Isolating these organisms presents a significant challenge, and treatment is often initiated without confirming the specific species. This review primarily focuses on the methods and challenges associated with diagnosing and treating MSMD patients. [ABSTRACT FROM AUTHOR]

The management of immune thrombocytopenia (ITP) and the prediction of patient response to therapy still represent a significant and constant challenge in hematology. ITP is a heterogeneous disease with an unpredictable evolution. Although the pathogenesis of ITP is currently better known and its etiology has been extensively studied, up to 75% of adult patients with ITP may develop chronicity, which represents a significant burden on patients' quality of life. A major risk of ITP is bleeding, but knowledge on the exact relationship between the degree of thrombocytopenia and bleeding symptoms, especially at a lower platelet count, is lacking. The actual management of ITP is based on immune suppression (corticosteroids and intravenous immunoglobulins), or the use of thrombopoietin receptor agonists (TPO-RAs), rituximab, or spleen tyrosine kinase (Syk) inhibitors. A better understanding of the underlying pathology has facilitated the development of a number of new targeted therapies (Bruton's tyrosine kinase inhibitors, neonatal Fc receptors, strategies targeting B and plasma cells, strategies targeting T cells, complement inhibitors, and newer TPO-RAs for improving megakaryopoiesis), which seem to be highly effective and well tolerated and result in a significant improvement in patients' quality of life. The disadvantage is that there is a lack of knowledge of the predictive factors of response to treatments, which would help in the development of an optimized treatment algorithm for selected patients. [ABSTRACT FROM AUTHOR]

Background: In this study, we aimed to report long-term follow-up of our pediatric and adult patients with DCLRE1C (DNA cross-link repair 1C) hypomorphic mutation who were diagnosed leaky severe combined immunodeficiency (SCID)., Methods: Eighteen patients (13 children and five adults), aged between 6 and 29 years were included. Clinical and immunological features, including immunoglobulin levels, T and B cells, natural killer cell subsets, regulator T (Treg) cell ratios/markers, and cytokines, were assessed before and after hematopoietic stem cell transplantation (HSCT) and compared with healthy controls., Results: Recurrent infections (78%) and skin manifestations (61%) such as granulomatous skin lesions, warts, and vitiligo were the most common clinical findings. Autoimmune diseases were observed in 33% and malignancy in 17%. Most patients had low serum IgA and B- and T-cell lymphopenia at the first admission. Recent thymic emigrants (RTE), T naive , B naive , CD56 dim CD16 + cell ratios were significantly lower in the patients than in control; however, follicular helper T T FH and Th1 [interferon gamma (IFN-γ)] cell ratios were significantly higher than the control. Although, Treg ratio and its functional receptors tend to be high but not significant. Eleven patients (61.1%) were treated with HSCT. Median follow-up times of transplant patients was 56 (9-67) months., Conclusion: Patients with hypomorphic DCLRE1C mutations may present with variable clinical and laboratory findings at different ages. Our study showed a helper T (Th)1-dominant immune response before and after HSCT. Increased IFN-γ and T FH cells ratio could be a reason of chronic inflammation and autoimmunity developing before and after HSCT. Long-term follow-up of these patients after HSCT will help to better understand the disease and its pathophysiology., (© 2024 The Author(s). Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Diseases of the pericardium encompass a spectrum of conditions, including acute and recurrent pericarditis, where inflammation plays a pivotal role in the pathogenesis and clinical manifestations. Anti-inflammatory therapy indeed forms the cornerstone of treating these conditions: NSAIDs, colchicine, and corticosteroids (as a second-line treatment) are recommended by current guidelines. However, these medications come with several contraindications and are not devoid of adverse effects. In recent years, there has been an increased focus on the role of the inflammasome and potential therapeutic targets. Recurrent pericarditis also shares numerous characteristics with other autoinflammatory diseases, in which interleukin-1 antagonists have already been employed with good efficacy and safety. The objective of this review is to summarize the available studies on the use of anti-IL-1 drugs both in acute and recurrent pericarditis. [ABSTRACT FROM AUTHOR]

Background and objective: Rasmussen's encephalitis (RE) is a rare chronic neurological disorder, characterized by unilateral inflammation of the cerebral cortex, refractory focal epilepsy or epilepsia partialis continua, hemiparesis, and progressive cognitive decline. Interleukin-1 (IL-1) plays an important role in neuroinflammation as a key element in the activation of the inflammatory IL-1β-IL-1 receptor type 1 (IL-1R1) axis. Anakinra, an IL-1 inhibitor, is successfully used in patients with new onset refractory status epilepticus and febrile infection-related epilepsy syndrome. Methods and results: We present 38-year-old male with RE having right-sided hemiparesis and continuous spasms being unresponsive to immune modulatory therapies like pulse steroid, intravenous immunoglobulin and anti-seizure drugs. After treatment with anakinra for three weeks, the continuous spasms almost completely subsided, and his muscle strength returned to normal. Discussion: Anakinra may be considered as a treatment option in patients with RE and refractory seizures. [ABSTRACT FROM AUTHOR]

Intelligent transfer of drugs to target cells is one of the important challenges in pharmaceuticals and disease treatment. Based on this, various investigations have been done on the interaction of drugs with different materials and compounds, among which nanomaterials have received more attention due to their wide active surface. In this context, the interaction of 5Fluorouracil (5FU) drug connected B12P12 and ScB11P12 nanocages with the adenine nucleobase is investigated. The results of this study could provide a new idea about the effect of nanocages on drug binding to nucleobase. The computational studied base on the density functional theory at the ωB97XD/6-31G (d, p) level of theory is fulfilled in presence of a static electric field (SEF) in the z-direction (z + 0.01, z + 0.02, z + 0.03, and z + 0.04 au). The outcomes of this study confirm that the interaction of 5FU&B12P12 and 5FU&ScB11P12 complexes with adenine is exothermic and favorable. The electron localized field (ELF) plots, quantum theory of atom in molecule (QTAIM) outputs, and reduced density gradient (RDG) scatter plots have been computed and results are analyzed. The output results demonstrated that the nature of bonding between 5FU&B12P12, and 5FU&ScB11P12 complexes with adenine is electrostatic type. The Eg of all studied complexes change in the range of 5.08 to 6.95 eV and the ∆Eg% is in the range of ‒5.84 to 12.51%. The results of this study recommended that the doping Sc atom and electrical field application increase the interaction of 5FU-drug&B12P12 nanocage with adenine and it is an efficient system for 5FU drug delivery toward target cells. [ABSTRACT FROM AUTHOR]

Introduction: Plasmacytoid dendritic cells (pDCs) infiltrate a large set of human cancers. Interferon alpha (IFN-a) produced by pDCs induces growth arrest and apoptosis in tumor cells and modulates innate and adaptive immune cells involved in anti-cancer immunity. Moreover, effector molecules exert tumor cell killing. However, the activation state and clinical relevance of pDCs infiltration in cancer is still largely controversial. In Primary Cutaneous Melanoma (PCM), pDCs density decreases over disease progression and collapses in metastatic melanoma (MM). Moreover, the residual circulating pDC compartment is defective in IFN-a production. Methods: The activation of tumor-associated pDCs was evaluated by in silico and microscopic analysis. The expression of human myxovirus resistant protein 1 (MxA), as surrogate of IFN-a production, and proximity ligation assay (PLA) to test dsDNA-cGAS activation were performed on human melanoma biopsies. Moreover, IFN-a and CXCL10 production by in vitro stimulated (i.e. with R848, CpG-A, ADU-S100) pDCs exposed to melanoma cell lines supernatants (SN-mel) was tested by intracellular flow cytometry and ELISA. We also performed a bulk RNA-sequencing on SN-mel-exposed pDCs, resting or stimulated with R848. Glycolytic rate assay was performed on SN-mel-exposed pDCs using the Seahorse XFe24 Extracellular Flux Analyzer. Results: Based on a set of microscopic, functional and in silico analyses, we demonstrated that the melanoma milieu directly impairs IFN-a and CXCL10 production by pDCs via TLR-7/9 and cGAS-STING signaling pathways. Melanoma-derived immunosuppressive cytokines and a metabolic drift represent relevant mechanisms enforcing pDC-mediated melanoma escape. Discussion: These findings propose a new window of intervention for novel immunotherapy approaches to amplify the antitumor innate immune response in cutaneous melanoma (CM). [ABSTRACT FROM AUTHOR]

Primary cell lines are invaluable for exploring cancer biology and investigating novel treatments. Despite their numerous advantages, primary cultures are laborious to obtain and maintain in culture. Hence, established cell lines are still more common. This study aimed to evaluate a range of techniques for isolating primary breast cancer cultures, employing distinct enzymatic compositions, incubation durations, and mechanical approaches, including filtration. Out of several protocols, we opted for a highly effective method (Method 5) that gave rise to a primary cell culture (BC160). This method combines mechanical disaggregation and enzymatic digestion with hyaluronidase and collagenase. Moreover, the paper addresses common issues in isolating primary cultures, shedding light on the struggle against fibroblasts overgrowing cancer cell populations. To make primary cell lines a preferred model, it is essential to elaborate and categorise isolation methods, develop approaches to separate heterogeneous cultures and investigate factors influencing the establishment of primary cell lines. [ABSTRACT FROM AUTHOR]

NPSLE diagnosis is still challenging because of many SLE-related and non-SLE-related processes that can be presented in patient. The report of NPSLE in Indonesia is still limited. This study aim to describe the clinical features, nutrition status, and laboratory characteristics of Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) and compared to non NPSLE case in Indonesian children. The study is a retrospective cohort study. Data were collected from the complete medical record of Juvenile Systemic lupus Erythematosus (jSLE) patients 2016 - 2020 at the Allergy Immunology Outpatient clinic at Dr. Soetomo General Academic Hospital. We include all patients with ages ranging from age 0-18 years old with a diagnosis of Systemic lupus Erythematosus (SLE). The diagnosis fo SLE based on American College of Rheumatology (ACR) criteria 1997 and Neuropsychiatric (NP) manifestations were classified using the standardized nomenclature and case definitions for the 19 NP manifestations linked to SLE developed in 1999 by the ACR ad hoc Committee. Disease activity SLE was defined according to the American Mexican-Systemic Lupus Erythematosus Disease Activity Index (Mex-SLEDAI) criteria. Statistical analysis conducted in this study was descriptive analysis, paired T-test (NPSLE vs. non-NPSLE as the dependent variable), Fischer exact test, and Pearson Chi-square test using SPSS ver. 21. A total of 90 patients with juvenile SLE were enrolled, but only 71 patients were eligible as participants with complete medical records obtained. Mex-SLEDAI score was significantly higher on NPSLE compared to non-NPSLE (p=0.001). There are no significant differences of body height, body weight, and body mass index between each group (p>0.05). The incidence of NPSLE was 29.57%, with clinical main symptoms were delirium (33.33%), seizures (33.33%), and psychosis (14.29%). 33.33% MRI/CT-scan findings noted brain abnormalities with the most prevalent were ischemic (14.29%), hypodense lesion, brain atrophy, multiple lymphadenopathy, and transverse myelitis (4.76%). The higher disease activity in NP SLE indicates the needs to close observation, the higher patient adherence to medication, and more comprehensive management to achieve therapeutic success. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity may present with autoimmunity and autoinflammation as hallmark clinical manifestations. We aimed to identify the potential monogenic causes of autoimmune disorders in 26 patients from a pediatric reference hospital in Mexico through whole-exome sequencing. We specifically selected patients with a family history of autoimmune diseases, early-onset symptoms, and difficult-to-control autoimmune disorders or autoimmunity associated with infection predisposition. We identified the genetic variants that were compatible with the patients' phenotype in 54% of the patients. Autoimmune diseases are often caused by a combination of genetic factors, but cases that appear at a young age are resistant to treatment or occur in clusters, as well as the presence of autoimmune symptoms alongside infectious diseases should raise suspicion for an underlying inborn error of immunity. [ABSTRACT FROM AUTHOR]

Inborn errors of immunity (IEI) are multifaced diseases which can present with a variety of phenotypes, ranging from infections to autoimmunity, lymphoproliferation, and neoplasms. In recent decades, research has investigated the relationship between autoimmunity and IEI. Autoimmunity is more prevalent in primary humoral immunodeficiencies than in most other IEI and it can even be their first manifestation. Among these, the two most common primary immunodeficiencies are selective IgA deficiency and common variable immunodeficiency. More than half of the patients with these conditions develop non-infectious complications due to immune dysregulation: autoimmune, autoinflammatory, allergic disorders, and malignancies. Around 30% of these patients present with autoimmune phenomena, such as cytopenia, gastrointestinal and respiratory complications, and endocrine and dermatologic features. Complex alterations of the central and peripheral mechanisms of tolerance are involved, affecting mainly B lymphocytes but also T cells and cytokines. Not only the immunophenotype but also advances in genetics allow us to diagnose monogenic variants of these diseases and to investigate the pathogenetic basis of the immune dysregulation. The diagnosis and therapy of the primary humoral immunodeficiencies has been mostly focused on the infectious complications, while patients with predominant features of immune dysregulation and autoimmunity still present a challenge for the clinician and an opportunity for pathogenetic and therapeutic research. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a malignancy that manifests in serial stages and has been observed to have an escalating incidence in modern societies, causing a significant global health problem. The development of CRC is influenced by various exogenous factors, including lifestyle, diet, nutrition, environment, and microbiota, that can affect host cells, including immune cells. Various immune dysfunctions have been recognized in patients with CRC at different stages of this disease. The signature of microbiota in the development of CRC—inflammation related to obesity, diet, and reactive host cells, such as dendritic cells (DCs)—has been highlighted by many studies. This study focuses on DCs, the primary cellular mediators linking innate and adaptive immune responses against cancer. In addition, this review focuses on the role of microbiota in dysbiosis and how it affects DCs and, in turn, the immune response and progression of CRC by stimulating different sets of T cells. Additionally, DCs' role in protecting this delicate balance is examined. This is to determine how gene yields of commensal microbiota may be critical in restoring this balance when disrupted. The stages of the disease and major checkpoints are discussed, as well as the role of the C-type lectin receptor of immature DCs pattern recognition receptor in CRC. Finally, based on a thorough examination of worldwide clinical studies and recent advancements in cancer immunotherapy, it is recommended that innovative approaches that integrate DC vaccination strategies with checkpoint inhibitors be considered. This approach holds great promise for improving CRC management. [ABSTRACT FROM AUTHOR]

Despite the advanced knowledge concerning autoinflammatory diseases (AID), more data regarding the optimal treatment options and outcomes of the children who met the criteria of more than one AID are required. This study aimed to describe the demographic and clinical characteristics of children from familial Mediterranean fever (FMF)-endemic countries who meet both the FMF and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome criteria. Moreover, we aimed to measure the response rates to colchicine and tonsillectomy and evaluate the factors affecting the colchicine response in these patients. The study was conducted at pediatric rheumatology tertiary centre. A total of 131 patients (58 females; 73 males) who met both the modified Marshall and pediatric FMF criteria were included. The median age at onset was 18 months (1–77 months), and the mean age at diagnosis was 47 ± 21.88 months. The median interval between episodes was 21 (7–90) days. The median disease duration was 46 (6–128) months. Consanguineous marriage was detected in 17 (13%) of the patients. The most common clinical finding was fever (100%), followed by exudative pharyngitis (88.5%), abdominal pain (86.3%), arthralgia (61.8%), stomatitis (51.1%), adenitis (42%), myalgia (28.7%), chest pain (16%), maculopapular rash (12.2%), arthritis (8.4%), and erysipelas-like rash (4.6%). MEFV gene variants were identified in 106 (80.9%) patients. The most common variants were M694V heterozygous (29%). We found that patients with tonsillopharyngitis, aphthous stomatitis, and PFAPA family history were more likely to be colchicine-resistant and tonsillectomy responsive, while those with exon 10 MEFV gene mutations were more prone to have a favorable response to colchicine. Conclusion: PFAPA syndrome patients with exon 10 MEFV gene mutation, showing typical FMF symptoms, should be treated with colchicine, even after tonsillectomy. In multivariate analysis, PFAPA family history and lack of exon 10 MEFV gene mutations were independent risk factors for colchicine resistance. Thus, tonsillectomy may be recommended as a possible treatment option for these patients. It has yet to be clarified when colchicine treatment will be discontinued in patients whose attacks ceased after tonsillectomy that was performed due to colchicine unresponsiveness. What is Known: • A certain number of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome concomitantly fulfill the familial Mediterranean fever (FMF) criteria. • While colchicine is proposed as a first treatment choice in familial Mediterranean fever (FMF), corticosteroids are recommended as a first-line treatment in PFAPA syndrome patients. What is New: • In patients with concomitant PFAPA syndrome and FMF, PFAPA family history and lack of exon 10 MEFV gene mutation are predictive factors of colchicine resistance. • The presence of exon 10 MEFV gene mutations in patients with concomitant FMF and PFAPA syndrome has a favourable effect on response to colchicine treatment. [ABSTRACT FROM AUTHOR]

Hematological diseases, due to their complex nature and diverse manifestations, pose significant diagnostic challenges in healthcare. The pressing need for early and accurate diagnosis has driven the exploration of novel diagnostic techniques. Infrared (IR) spectroscopy, renowned for its noninvasive, rapid, and cost-effective characteristics, has emerged as a promising adjunct in hematological diagnostics. This review delves into the transformative role of IR spectroscopy and highlights its applications in detecting and diagnosing various blood-related ailments. We discuss groundbreaking research findings and real-world applications while providing a balanced view of the potential and limitations of the technique. By integrating advanced technology with clinical needs, we offer insights into how IR spectroscopy may herald a new era of hematological disease diagnosis. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of common variable immunodeficiency disorder (CVID) is complex, especially when combined with autoimmunity. Genetic factors may be potential explanations for this complex situation, and whole genome sequencing (WGS) provide the basis for this potential. Methods: Genetic information of patients with CVID with autoimmunity, together with their first-degree relatives, was collected through WGS. The association between genetic factors and clinical phenotypes was studied using genetic analysis strategies such as sporadic and pedigree. Results: We collected 42 blood samples for WGS (16 CVID patients and 26 first-degree relatives of healthy controls). Through pedigree, sporadic screening strategies and low-frequency deleterious screening of rare diseases, we obtained 9,148 mutation sites, including 8,171 single-nucleotide variants (SNVs) and 977 Insertion-deletions (InDels). Finally, we obtained a total of 28 candidate genes (32 loci), of which the most common mutant was LRBA. The most common autoimmunity in the 16 patients was systematic lupus erythematosis. Through KEGG pathway enrichment, we identified the top ten signaling pathways, including "primary immunodeficiency", "JAK-STAT signaling pathway", and "T-cell receptor signaling pathway". We used PyMOL to predict and analyse the three-dimensional protein structures of the NFKB1, RAG1, TIRAP, NCF2, and MYB genes. In addition, we constructed a PPI network by combining candidate mutants with genes associated with CVID in the OMIM database via the STRING database. Conclusion: The genetic background of CVID includes not only monogenic origins but also oligogenic effects. Our study showed that immunodeficiency and autoimmunity may overlap in genetic backgrounds. [ABSTRACT FROM AUTHOR]

Evidence is accumulating that the Coronavirus disease (COVID-19) can bring forth deficits in executive functioning via alterations in the dopaminergic system. Importantly, dopaminergic pathways have been shown to modulate how actions and perceptions are integrated within the brain. Such alterations in event file binding could thus underlie the cognitive deficits developing after a COVID-19 infection. We examined action-perception integration in a group of young people (11–19 years of age) that had been infected with COVID-19 before study participation (n = 34) and compared them to a group of uninfected healthy controls (n = 29) on the behavioral (i.e., task accuracy, reaction time) and neurophysiological (EEG) level using an established event file binding paradigm. Groups did not differ from each other regarding demographic variables or in reporting psychiatric symptoms. Overall, multiple lines of evidence (behavioral and neurophysiological) suggest that action-perception integration is preserved in adolescents who suffered from COVID-19 prior to study participation. Event file binding processes were intact in both groups on all levels. While cognitive impairments can occur following a COVID-19 infection, the study demonstrates that action-perception integration as one of the basic building blocks of cognition seems to be largely unaffected in adolescents with a rather mild course of the disease. [ABSTRACT FROM AUTHOR]

This narrative review aims to report the main clinical manifestations, therapeutic strategies, outcomes, and complications of acute SARS-CoV-2 infection in childhood and to summarize the data relating the SARS-CoV-2 vaccination efficacy and safety in pediatric age. SARS-CoV-2 infection mostly occurs asymptomatically in the pediatric population, while multisystem inflammatory syndrome in children (MIS-C) represents the most severe coronavirus disease 2019 (COVID-19)-related illness, a life-threatening event with a high morbidity rate. After the development of SARS-CoV-2 vaccines and their subsequent approval in children, the rate of infection as well as the number of its related complications have shown a drastic decrease. Fully vaccinated children are protected from the risk of developing a severe disease and a similar protective role has been observed in the reduction of complications, in particular MIS-C. However, long-lasting immunity has not been demonstrated, booster doses have been required, and reinfection has been observed. With regards to vaccine safety, adverse events were generally mild to moderate in all age groups: local adverse events were the most commonly reported. Nevertheless, a potential association between SARS-CoV-2 vaccine and the subsequent development of inflammatory manifestations has been suggested. Myocarditis has rarely been observed following vaccination; it appeared to be more frequent among adolescent males with a mild clinical course leading to a complete recovery. SARS-CoV-2 vaccine-related MIS-C cases have been described, although a univocal definition and an exact time interval with respect to vaccination has not been reported, thus not establishing a direct causal link. Current evidence about COVID-19 vaccination in children and adolescents suggest that benefits outweigh potential risks. Long-term data collection of the post-authorization safety surveillance programs will better define the real incidence of SARS-CoV-2 vaccine-related complications in the pediatric population. [ABSTRACT FROM AUTHOR]

Simple Summary: Our research explores the realm of immune cells to better understand patients with chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID). By examining immune checkpoints such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in different blood lymphocyte subpopulations, we aim to extract valuable insights that may improve not only our understanding of these diseases but also contribute to improving treatment conditions and the occurrence of subsequent complications and the development of hematological cancers. We hope that the knowledge about the role of these signaling pathways in the development and progression of these two diseases will allow us to develop modern and personalized diagnostic and therapeutic strategies, which in the future may allow monitoring the immune system of patients with CVID and CLL. This study aims to gain a deeper understanding of chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID) by studying immune cells and specific immune checkpoint signaling pathways. The analysis of the percentage of selected immune points and their ligands (PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200) on peripheral blood lymphocyte subpopulations was performed using flow cytometry, and additional analyses determining the serum concentration of the above-mentioned molecules were performed using enzyme immunoassay tests. The obtained results indicate several significant changes in the percentage of almost all tested molecules on selected subpopulations of T and B lymphocytes in both CVID and CLL patients in relation to healthy volunteers and between the disease subunits themselves. The results obtained were also supported by the analysis of the serum concentration of soluble molecules tested. By uncovering valuable insights, we hope to enhance our comprehension and management of these conditions, considering both immunodeficiencies and hematological malignancies. Understanding the role of these signaling pathways in disease development and progression may lead to the development of modern, personalized diagnostic and therapeutic strategies. Ultimately, this knowledge may enable the monitoring of the immune system in patients with CVID and CLL, paving the way for improved patient care in the future. [ABSTRACT FROM AUTHOR]

Aging is associated with a decline in immune function, thereby causing an increased susceptibility to various diseases. Herein, we review immune diseases associated with aging, focusing on tumors, atherosclerosis, and immunodeficiency disorders. The molecular mechanisms underlying these conditions are discussed, highlighting telomere shortening, tissue inflammation, and altered signaling pathways, e.g., the mammalian target of the rapamycin (mTOR) pathway, as key contributors to immune dysfunction. The role of the senescence-associated secretory phenotype in driving chronic tissue inflammation and disruption has been examined. Our review underscores the significance of targeting tissue inflammation and immunomodulation for treating immune disorders. In addition, anti-inflammatory medications, including corticosteroids and nonsteroidal anti-inflammatory drugs, and novel approaches, e.g., probiotics and polyphenols, are discussed. Immunotherapy, particularly immune checkpoint inhibitor therapy and adoptive T-cell therapy, has been explored for its potential to enhance immune responses in older populations. A comprehensive analysis of immune disorders associated with aging and underlying molecular mechanisms provides insights into potential treatment strategies to alleviate the burden of these conditions in the aging population. The interplay among immune dysfunction, chronic tissue inflammation, and innovative therapeutic approaches highlights the importance of elucidating these complex processes to develop effective interventions to improve the quality of life in older adults. [ABSTRACT FROM AUTHOR]

Purpose: Infection is a common complication following left ventricular assist device (LVAD) implantation. Patients with obesity are particularly at risk due to their high percentage of adipose tissue and the resulting chronic inflammatory state and resulting immunological changes. This study investigated changes of immunological parameters in relation to body mass index (BMI) during the first year after LVAD implantation. Methods: Blood samples were obtained prior to LVAD implantation and at 3 (1st FU), 6 (2nd FU) and 12 mo (3rd FU) after LVAD implantation. Patients were divided into three groups (normal weight: BMI of 18.5-24.9 kg/m2; n=12; pre-obesity: 25.0-29.9 kg/m2; n=15; obesity: ≥ 30.0 kg/m2; n=17) based on their BMI at the time of LVAD implantation. Flow cytometric analyses for CD4+ and CD8+ T cells, regulatory T cells (Tregs), B cells as well as dendritic cells (DCs) were performed. Results: After LVAD implantation, obese patients (0.51 ± 0.20%) showed a higher proportion of overall DCs than normal-weight (0.28 ± 0.10%) and pre-obese patients (0.32 ± 0.11%, p<0.01) at 3rd FU. The proportion of BDCA3+ myeloid DCs was lower in obese patients (64.3 ± 26.5%) compared to normal-weight patients (82.7 ± 10.0%, pnormal-weight vs. obesity=0.05) at 2nd FU after LVAD implantation. The analysis of BDCA4+ plasmacytoid DCs revealed a reduced proportion in preobese (21.1 ± 9.8%, pnormal-weight vs. pre-obesity=0.01) and obese patients (23.7 ± 10.6%, pnormal-weight vs. obesity=0.05) compared to normal-weight patients (33.1 ± 8.2%) in the 1st FU. T cell analysis showed that CD4+ T cells of obese patients (62.4 ± 9.0%) significantly increased in comparison to pre-obese patients (52.7 ± 10.0%, ppre-obesity vs. obesity=0.05) and CD8+ T cells were lower in obese patients (31.8 ± 8.5%) than in normal-weight patients (42.4 ± 14.2%; pnormal-weight vs. obesity=0.04) at the 3rd FU. Furthermore, we observed significantly reduced proportions of Tregs in pre-obese patients compared to normal-weight and obese patients at 2nd FU (p=0.02) and 3rd FU (p=0.01) after LVAD implantation. Conclusion: This study reported changes of the innate and adaptive immune system of pre-obese and obese compared to normal-weight patients one year after LVAD implantation. DCs and their subsets, CD8+ T cells and Tregs were affected immune cell populations that indicate immunological changes which might increase the incidence of postoperative infection. [ABSTRACT FROM AUTHOR]

B Methods: b 21 patients were recruited in rheumatology centres in Flanders: 4 patients with oligo-articular JIA, 4 HLA-B27 SP + sp enthesitis-related JIA patients (JIA-ERA), 2 juvenile PsA patients, 4 adult PsA patients, 1 adult HLA-B27 SP + sp SpA patient, 3 RA patients, and 3 Lyme arthritis patients. In addition, incidental findings included one patient with a glandule pineal lesion, five patients with cysts, two patients with gliosis, one patient with optic neuritis, one patient with venous angioma, one patient with optic nerve atrophy and one patient with plexus papilloma. B Objectives: b to evaluate the levels of sTNF-RI and sTNF-RII in the blood sera of patients with sJA and monogenic autoinflammatory diseses(mAIDs) and their correlation with serum levels of commonly accepted markers of inflammation (C-reactive protein, Serum Amyloid A, Ferritin) B Methods: b 114 patients were included in the study, 43 of them with sJA(38%): male/female 20/23; age of inclusion in the study 3-19 years, FMF 33 (29%) patients; male/female 15/18; age 3-37 years, CAPS 23(20%)patients; male/female 15/8; age 1-51 years,, TRAPS 15(13%)patients; male/female 8/7, age 4-51 years. B Results: b The 28 patients enrolled were stratified into three subgroups based on the position of the variants on the NOD2 gene: N-Terminal (1 patient), Exon 4 (15 patients) and C-Terminal (12 patients). B Methods: b Eighty-three patients with CNO, nine patients with growth pain, nine patients with bone tumor, nine patients with juvenile idiopathic arthritis (JIA), and 30 healthy controls (HCs) who were followed up in Hacettepe University Pediatric Rheumatology Outpatient Clinics were included in the study. [Extracted from the article]

Background: Metabolic syndrome (MetS), a worldwide public health problem, affects human health and quality of life in a dramatic manner. A growing evidence base suggests that MetS is strongly associated with levels of systemic immune inflammation. The present study aimed to investigate the possible relationship between the systemic immune-inflammation index (SII), a novel inflammatory marker, and MetS to provide data support for effective MetS prevention by reducing the systemic inflammatory response. Methods: We included adult participants with complete SII and MetS information from the 2011–2016 National Health and Nutrition Examination Survey (NHANES). MetS was defined as using the criteria developed by the Adult Treatment Program III of the National Cholesterol Education Program. The formula for SII was as follows: SII = platelet counts × neutrophil counts/ lymphocyte counts. Weighted linear regression was used to assess differences in variables across SII quartile groups after the SII score was divided into 4 quartiles. The independent interaction between SII and MetS was investigated using weighted multivariate logistic regression analysis and subgroup analysis, and the relationship between SII levels and 5 particular MetS items was further explored in depth. Results: A total of 12,402 participants, 3,489 of whom were diagnosed with MetS, were included in this study. After correcting for covariates, the results of a logistic regression of multistage weighted complex sampling data revealed that participants with higher SII scores had a higher chance of developing MetS (odds ratio (OR) = 1.33, 95% confidence interval (CI): 1.14–1.55) and that SII levels could be used as an independent risk factor to predict that likelihood of MetS onset. In the Q1–Q4 SII quartile group, the risk of developing MetS was 1.33 times higher in the Q4 group, which had the highest level of systemic immune inflammation than in the Q1 group. After adjusting for all confounding factors, SII scores were found to have a negative correlation with high-density lipoprotein cholesterol (OR = 1.29; 95% CI, 0.99–1.67, P = 0.056) and a significant positive correlation with waist circumference (OR = 2.17; 95% CI, 1.65–2.87, P < 0.001) and blood pressure (BP) (OR = 1.65; 95% CI, 1.20–2.27, P = 0.003). Gender, age, and smoking status were shown to alter the positive association between SII and MetS in subgroup analyses and interaction tests (p for interaction < 0.05). Additionally, we demonstrated a nonlinear correlation between SII and MetS. The findings of the restricted cubic spline indicated that there was an inverted U-shaped association between SII and MetS. Conclusions: Our findings imply that increased SII levels are related to MetS, and SII may be a simple and cost-effective method to identify individuals with MetS. Therefore, protective measures such as early investigation and anti-inflammatory interventions are necessary to reduce the overall incidence of MetS. [ABSTRACT FROM AUTHOR]

Background:The 2016 WHO classification of Tcell acute lymphoblastic leukemia suggest that cases of pre and pro T-cell Acute Lymphoblastic Leukaemia (T-ALL) now fall under Early T-cell precursor ALL (ETP-ALL) or Near ETP-ALL. Accurate subtyping is essential as the subsets are characterized by distinct molecular profiles and identifying molecular aberrations allow patients to receive novel treatment agents. Aim and Objectives: To study the immuno-phenotypic characteristics in T-ALLcases and assess the diagnostic difficulties encountered in its subtyping. Material and Methods: Thirty-seven cases of T-ALL were analysed on flow cytometry using a 6/8 colour panel of monoclonal antibodies, including B cell, T-cell, myeloid and stem cell markers. The cases were categorized as ETP-ALL, near ETP-ALL, cortical T-ALL and medullary T-ALL. Clinical details were retrieved from patient case files. Results: Patient age ranged from 1 to 64 years. Male to female ratio was 2.1: 1 and 35.1% cases were documented to have 3 mediastinal mass. Mean haemoglobin level was 8.6 g/dl, and median total WBC count was 118.3 × 10 /µl. Blast percentage ranged from 39-98%, with mean of 84.8%. On flow cytometry analysis, all cases expressed CD7 and cytoplasmic CD3. CALLA+ (CD10+) were 32.4% cases. The aberrant expression of B-cell marker (CD79a) was observed in 5.4% cases. Majority of the cases were classified as medullary T-ALL, constituting 37.8% cases. ETP-ALL were 21.6% cases, 13.5% cases were near ETP-ALL and 24.3% cases were cortical T-ALL. One case could not be definitely assigned to a specific category. Conclusion: This study reflects the difficulties encountered in subtyping of T-ALLcases due to antigenic overlap and/or due to lack of an extended panel of secondary markers. [ABSTRACT FROM AUTHOR]

Background: The large-scale utilization of immunoglobulins in patients with inborn errors of immunity (IEIs) since 1952 prompted the discovery of their key role at high doses as immunomodulatory and anti-inflammatory therapy, in the treatment of IEI-related immune dysregulation disorders, according to labelled and off-label indications. Recent years have been dominated by a progressive imbalance between the gradual but constant increase in the use of immunoglobulins and their availability, exacerbated by the SARS-CoV-2 pandemic. Objectives: To provide pragmatic indications for a need-based application of high-dose immunoglobulins in the pediatric context. Sources: A literature search was performed using PubMed, from inception until 1st August 2023, including the following keywords: anti-inflammatory; children; high dose gammaglobulin; high dose immunoglobulin; immune dysregulation; immunomodulation; immunomodulatory; inflammation; intravenous gammaglobulin; intravenous immunoglobulin; off-label; pediatric; subcutaneous gammaglobulin; subcutaneous immunoglobulin. All article types were considered. Implications: In the light of the current imbalance between gammaglobulins' demand and availability, this review advocates the urgency of a more conscious utilization of this medical product, giving indications about benefits, risks, cost-effectiveness, and administration routes of high-dose immunoglobulins in children with hematologic, neurologic, and inflammatory immune dysregulation disorders, prompting further research towards a responsible employment of gammaglobulins and improving the therapeutical decisional process. [ABSTRACT FROM AUTHOR]

Introduction: Drug-resistant epilepsy in infancy and childhood is a devastating condition, frequently associated with neuropsychiatry comorbidities. West syndrome is one of the most severe epilepsy syndromes. Adrenocorticotropic hormone (ACTH) treatment is recommended in such cases, but its mechanism of action is still unknown. We prospectively observed levels of selected cytokines in order to identify biomarkers of response to ACTH and the potential mechanism of its antiseizure effect. Material and methods: Fifty-three infants and young children with pharmacoresistant epilepsy receiving ACTH124 were included. There were 2 control groups - children with epilepsy responding to the first medication and children with no history of epilepsy. Blood concentrations of IL-1β, IL-1Rα, IL-6, IL-8, IL-10, TNF-α, IFN-γ, MCP-1 and MIP-1α were analyzed at three time points: T0 (before ACTH), T1 (after intensive ACTH treatment) and at T2 (at the end of ACTH withdrawal). The results were correlated with the response to treatment, dose of ACTH and concomitant medications. Results: We found statistically significantly higher concentrations of IL-1, IL-8 and MIP-1α at baseline (T0) in the study group compared to the control groups. ACTH significantly lowered levels of IL-6, IFN-γ and MCP from time T0 to T1. This effect was short lasting and no significant changes in cytokine levels were found between T2 and T0. We did not find any differences in immunological markers between the responders and non-responders to ACTH. Our research did not allow us to identify any reliable immunological marker of response to ACTH treatment. We did not observe a positive effect of higher ACTH doses on the response rate in the patients. Our study showed significantly lower concentrations of IL-10 and IFN in the group of patients receiving levetiracetam. The concentration of TNF was higher and the concentration of MIP was lower in the group receiving valproic acid. Conclusions: Our study indicates that increased levels of IL-1, IL-8 and MIP-1α are associated with drug-resistant epilepsy in infants and young children and might be considered immunological markers. IL-6, IFN-γ and MCP-1 take part in the effect of ACTH. Immunological mechanisms seem also to be involved in the mechanism of action of classical antiseizure drugs. [ABSTRACT FROM AUTHOR]

Summary: A subset of individuals with 'primary' or 'idiopathic' immune thrombocytopenia (ITP) who fail to respond to conventional first‐ and second‐line agents or who lose responsiveness are considered to have 'refractory' disease (rITP), placing them at increased risk of bleeding and complications of intensive treatment. However, the criteria used to define the refractory state vary among studies, which complicates research and clinical investigation. Moreover, it is unclear whether rITP is simply 'more severe' ITP, or if there are specific pathogenic pathways that are more likely to result in refractory disease, and whether the presence or development of rITP can be established or anticipated based on these differences. This paper reviews potential biological features that may be associated with rITP, including genetic and epigenetic risk factors, dysregulation of T cells and cytokine networks, antibody affinity and specificity, activation of complement, impaired platelet production and alterations in platelet viability and clearance. These findings indicate the need for longitudinal studies using novel clinically available methodologies to identify and monitor pathogenic T cells, platelet antibodies and other clues to the development of refractory disease. [ABSTRACT FROM AUTHOR]

There appear to be huge variations and aberrations in the reported data in COVID-19 2 years now into the pandemic. Conflicting data exist at almost every level and also in the reported epidemiological statistics across different regions. It is becoming clear that COVID-19 is a polymorphic inflammatory spectrum of diseases, and there is a wide range of inflammation-related pathology and symptoms in those infected with the virus. The host's inflammatory response to COVID-19 appears to be determined by genetics, age, immune status, health status and stage of disease. The interplay of these factors may decide the magnitude, duration, types of pathology, symptoms and prognosis in the spectrum of COVID-19 disorders, and whether neuropsychiatric disorders continue to be significant. Early and successful management of inflammation reduces morbidity and mortality in all stages of COVID-19. [ABSTRACT FROM AUTHOR]

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is, as the name implies, characterized by an extremely regular cycle of fevers that is accompanied by one or more other symptoms such as oral ulcers, pharyngitis, adenitis, tonsillitis, sore throat, cervical adenopathy, and headache. Originally known as Marshall syndrome, PFAPA is most commonly identified in children younger than age 5 years; however, adults may also present with the disease, though they may report additional symptoms. PFAPA is now understood to be a diagnosis of exclusion. Laboratory studies are typically unremarkable except for increases in acute phase reactants such as C-reactive protein. Treatment is primarily supportive and most frequently uses systemic steroids to suppress the inflammatory response. Acute flares are self-limited, and the syndrome typically resolves on its own as the child reaches age 7 or 8 years. [ABSTRACT FROM AUTHOR]

Purpose of Review: To outline recent advances in imaging and treatment for recurrent pericarditis (RP)., Recent Findings: Greater understanding of NLRP3 inflammasome activation in the pathogenesis of RP has led to the development of several anti-interleukin (IL-1) agents, and technological advancements have increased the utility of multimodality imaging in RP. Multimodality imaging plays a crucial role in the assessment of RP, with echocardiography serving as the initial imaging modality; cardiac magnetic resonance (CMR) as a pivotal test for diagnosis, grading severity, and surveillance; and cardiac computed tomography (CT) providing complimentary information and assisting operative assessment. Anti-IL-1 agents are now well-established as second line therapy for RP, with recent clinical trials demonstrating their efficacy., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Extracorporeal photopheresis (ECP) has emerged as a prophylactic and therapeutic immunomodulatory option for managing acute rejection in heart transplants (HTx). The underlying mechanisms through which ECP exerts its immunomodulatory effects remain under investigation. Regulatory T cells (Treg) are a heterogeneous subset of immune lymphocytes that ensure the maintenance of tissue homeostasis, avoiding graft rejection. The transcription factor forkhead box protein 3 (FoxP3) is an essential molecular marker of Treg, acting as a "master regulator" of their genesis, stability, and functions. No study has investigated whether ECP impacts FoxP3 expression and its highly suppressive variants containing the exon 2 (FoxP3-E2), particularly in HTx., Methods: In the current study, we recruited 14 HTx participants who had undergone ECP therapy. We explored the effect of in vivo ECP on CD4+FoxP3+ Treg frequency and in vitro suppressive function in 8 HTx participants before (T0) and after 3 (T1), 6 (T2), and 12 (T3) mo of treatment. As a control group, we included 4 HTx individuals who had not undergone ECP therapy., Results: We found that ECP increases the frequency of CD4+FoxP3+ Treg subset with highly suppressive phenotype, including CD4+FoxP3-E2+ Treg. At functional levels, we observed that ECP treatment in HTx individuals effectively improves Treg suppressive ability in controlling the proliferation of autologous conventional CD4+ T lymphocytes., Conclusions: Our findings collectively suggest that ECP exerts its immunomodulatory effects in HTx individuals by positively impacting the frequency and regulatory function of the FoxP3+ Treg compartment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Childhood interstitial lung disease (chILD) associated with connective tissue and immune mediated disorders is the second most common chILD diagnostic category. As knowledge of the molecular and genetic underpinnings of these rare disorders advances, the recognized clinical spectrum of associated pulmonary manifestations continues to expand. Pulmonary complications of these diseases, including ILD, confer increased risk for morbidity and mortality and contribute to increased complexity for providers tasked with managing the multiple organ systems that can be impacted in these systemic disorders. While pulmonologists play an important role in diagnosis and management of these conditions, thankfully they do not have to work alone. In collaboration with a multidisciplinary team of subspecialists, the pulmonary and other systemic manifestations of these conditions can be managed effectively together. The goal of this review is to familiarize the reader with the classic patterns of chILD and other pulmonary complications associated with primary immune-mediated disorders (monogenic inborn errors of immunity) and acquired systemic autoimmune and autoinflammatory diseases. In addition, this review will highlight current, emerging, and innovative therapeutic strategies and will underscore the important role of multidisciplinary management to improving outcomes for these patients., (© 2024 Wiley Periodicals LLC.)

Aim: To investigate the rate of dispensed antibiotic prescriptions to children and adolescents with PFAPA and compare this with the rate for children in the general population. Furthermore, to compare dispensed antibiotic prescription rates before and after a diagnosis of PFAPA was established., Methods: Patients aged 0-17 years and diagnosed with PFAPA between 1 January 2006 to 31 October 2017 were included retrospectively. Data on dispensed drug prescriptions were obtained from the Swedish National Prescribed Drug Register., Results: The PFAPA cohort received more antibiotic prescriptions than the general population in all but one of the age groups and time periods that were analysed. The largest difference was seen in 2014-2017 in the youngest age group (0-4 years) when children with PFAPA received 1218 antibiotic prescriptions per 1000 person years compared to 345 in the general population (IRR 3.5; 95% CI 2.8-4.4). The yearly number of antibiotic prescriptions to PFAPA patients was reduced from 2.1 before diagnosis to 0.8 after diagnosis, a reduction of 62%., Conclusion: This study shows higher rates of dispensed antibiotic prescriptions for children with PFAPA than in the general population. The reduction of prescriptions after an established PFAPA diagnosis indicates that antibiotics were previously incorrectly prescribed for PFAPA episodes., (© 2024 The Authors. Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Pediatric pericarditis presents challenges in its management, necessitating effective therapeutic interventions. Colchicine, known for its efficacy in adults, requires further investigation for its application and safety in pediatric cohorts. A systematic search across renowned databases identified relevant literature on colchicine use in pediatric pericarditis. Twenty-nine articles underwent rigorous screening, with 18 studies meeting inclusion criteria. Data extraction, quality assessment, and synthesis were conducted meticulously. Included studies comprised case reports, case series, and retrospective cohort studies. Colchicine demonstrated efficacy in reducing recurrence rates and symptom burden, with doses ranging from 0.25 mg/day to 2 mg/day. Adverse events were minimal, predominantly gastrointestinal. Notably, nausea was the most common side effect reported. The safety profile of colchicine was favorable, with rare instances of hepatic and hematologic toxicity. Colchicine emerges as a promising therapeutic option for pediatric pericarditis, demonstrating efficacy in reducing recurrence rates and alleviating symptoms. Its favorable safety profile suggests potential as a preferred long-term therapy. However, further research, including randomized controlled trials, is warranted to confirm its efficacy and safety and explore potential combination therapies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype-phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene., Objective: In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs., Methods: The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants., Results: A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations. There were 175 LOF cases in NFKB1 and 122 p52 LOF /IκBδ GOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52 LOF /IκBδ GOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52 LOF /IκBδ GOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52 LOF /IκBδ GOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52 LOF /IκBδ GOF ) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52 LOF /IκBδ GOF cases showed low CD19 + B cells, with p52 LOF /IκBδ GOF having more cases of this type. Low memory B cells were more common in p52 LOF /IκBδ GOF patients., Conclusions: Patients with NFKB2 mutations, particularly p52 LOF /IκBδ GOF , are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Plasmacytoid dendritic cells (pDCs), a subtype of DC, possess unique developmental, morphological, and functional traits that have sparked much debate over the years whether they should be categorized as DCs. The digestive system has the greatest mucosal tissue overall, and the pDC therein is responsible for shaping the adaptive and innate immunity of the gastrointestinal tract, resisting pathogen invasion through generating type I interferons, presenting antigens, and participating in immunological responses. Therefore, its alleged importance in the gut has received a lot of attention in recent years, and a fresh functional overview is still required. Here, we summarize the current understanding of mouse and human pDCs, ranging from their formation and different qualities compared with related cell types to their functional characteristics in intestinal disorders, including colon cancer, infections, autoimmune diseases, and intestinal graft‐versus‐host disease. The purpose of this review is to convey our insights, demonstrate the limits of existing research, and lay a theoretical foundation for the rational development and use of pDCs in future clinical practice. HIGHLIGHTS: pDCs are a subset of dendritic cells, and transcription factors play a crucial role in the process.pDCs contribute to intestinal immune responses by generating interferon (IFN) and presenting antigens.pDCs guard the intestinal mucosa and protect against the invasion of microbiota and pathogens in the gut, playing a pivotal role in gut infection and colon cancer. [ABSTRACT FROM AUTHOR]

With the progressive lengthening of the average age of the population, especially in some countries such as Italy, vaccination of the elderly is a fixed point on which most of the public health efforts are concentrating as epidemic infectious diseases, especially those of the winter, have a major impact on the progression of severe disease, hospitalization, and death. The protection of the elderly against acute infectious diseases should not only limit mortality but also have a positive impact on the fragility of these people in terms of less disability and fewer care needs. However, vaccination of the elderly population differs in efficacy and safety compared to that of other population categories since aging and the consequent loss of efficiency of the immune system lead to a reduction in the immunogenicity of vaccines without achieving a lasting antibody coverage. There are various strategies to avoid the failure of immunization by vaccines such as resorting to supplementary doses with adjuvant vaccines, increasing the dosage of the antigen used, or choosing to inoculate the serum relying on various routes of administration of the vaccine. Vaccination in the elderly is also an important factor in light of growing antibiotic resistance because it can indirectly contribute to combating antibiotic resistance, reducing theoretically the use of those agents. Furthermore, vaccination in old age reduces mortality from infectious diseases preventable with vaccines and reduces the same rate of resistance to antibiotics. Given the importance and complexity of the topic, in this review, we will deal with the main aspects of vaccination in the elderly and how it can influence mortality and healthcare costs, especially in those countries where population aging is more evident. Therefore, we conducted a systematic literature search in PubMed to identify all types of studies published up to 31 May 2023 that examined the association between vaccination and the elderly. Data extraction and quality assessment were conducted by two reviewers (PC and TC) who independently extracted the following data and assessed the quality of each study. [ABSTRACT FROM AUTHOR]

A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and Crohn's disease was attended in the Regional Hospital of Presidente Prudente and HC-FMUSP, São Paulo, Brazil. Anti-IL-12/IL-23 (ustekinumab) monoclonal antibody was prescribed due to the failure of other treatments (phototherapy, oral acitretin) for psoriasis and a Psoriasis Area Severity Index >10. We evaluated the impact of treatment with ustekinumab on severe infectious diseases in a patient with uncontrolled psoriasis and LOCID followed for 8 years. Four quarterly doses of ustekinumab 90 mg and human immunoglobulin replacement (10,000 mg at 28-day intervals) were administered. Immunophenotyping, cultures of lymphocytes, genetic sequencing, and whole exome sequencing were performed to investigate the primary immunodeficiency. Normal lymphocyte proliferation; pathogenic variants in genetic sequencing, and clinically significant variants in the whole exome for primary immunodeficiencies were not detected. The main infections before and after treatment with ustekinumab were chronic sinusitis and gastroenteritis. The patient was infected with COVID-19, dengue (twice) and influenza and was hospitalized three times for intravenous antibiotic therapy. Ustekinumab did not influence the susceptibility of the patient with LOCID to severe infections and significantly improved psoriasis, psoriatic arthritis, and Crohn's disease. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia in the absence of other disorders. Vitamin D (VD) has been shown to modulate the immune system and its deficiency is linked to many immunological disorders. Supplementation with VD in ITP has promising results. This work aims at evaluating VD values in children with persistent and chronic ITP and the effect of its deficiency on disease severity and treatment response. A case–control study including 50 persistent and chronic ITP patients and 50 healthy controls was conducted. 25 OH vitamin D level was determined using ELISA technique. VD median value was significantly higher among the control group than that of the patients' group (28 vs 21.5 and p = 0.002). Severe deficiency was detected significantly more among the patients' group than the control group (12 (24%) vs 3 (6%), p = 0.048) respectively. Forty-four percent of complete responders belong to sufficient VD category ((15/34) ~ 44% (p = 0.005)) representing all patients with sufficient VD status (n = 15). Also, a positive correlation between serum level of vitamin D and mean PLT count was observed (r = 0.316, p value = 0.025). Sufficient vitamin D was associated with better treatment response and less disease severity. Vitamin D supplementation may be a new therapeutic option for chronic ITP. [ABSTRACT FROM AUTHOR]

Background: Silent lupus nephritis (SLN) is systemic lupus erythematosus (SLE) without clinical and laboratory features of kidney involvement but with biopsy-proven nephritis. This study aims to describe and compare the baseline characteristics and outcomes of pediatric SLN with overt LN (OLN) and to identify associated risk factors and biochemical markers. Methods: In this retrospective, observational study, multivariate logistic regression and receiver operating characteristic (ROC) analyses studied age, sex, race, serum complements, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Results: In our cohort of 69 patients, 47 were OLN, and 22 were SLN. OLN (OR = 4.9, p = 0.03) and non-African Americans (AA) (OR = 13.0, p < 0.01) had higher odds, and increasing C3 and C4 were associated with lower odds of proliferative nephritis (OR 0.95 and 0.65 per one unit increase in C3 and C4, respectively, p < 0.01). They demonstrated a good discriminative ability to detect proliferative nephritis as assessed by the area under the ROC curve (C3 = 0.78, C4 = 0.78). C3 and C4 in proliferative SLN and OLN were comparable and significantly lower than their non-proliferative counterparts. No association was observed between age, sex, anti-double-stranded-DNA antibody, anti-Smith antibody, eGFR, and proliferative nephritis. Proliferative SLN and OLN patients received similar treatments. Adverse events were identified in the proliferative OLN only. Conclusions: Lower complement levels are associated with proliferative lesions in pediatric LN—both SLN and OLN. The non-AA population had higher odds of having proliferative nephritis than the AA. Prospective, randomized, long-term follow-up of proliferative SLN patients is needed to ascertain the beneficial effect of early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Transient hypogammaglobulinemia of infancy (THI) is a primary immunodeficiency caused by a temporary decline in serum immunoglobulin G (IgG) levels greater than two standard deviations below the mean age-specific reference values in infants between 5 and 24 months of age. Preterm infants are particularly susceptible to THI, as IgG is only transferred across the placenta from mother to infant during the third trimester of pregnancy. This study aimed to conduct a systematic review of the diagnostic criteria for transient hypogammaglobulinemia of infancy. Systematic review: Three electronic databases (PubMed, MEDLINE, and Google Scholar) were manually searched from September 2021 to April 2022. Abstracts were screened to assess their fit to the inclusion criteria. Data were extracted from the selected studies using an adapted extraction tool (Cochrane). The studies were then assessed for bias using an assessment tool adapted from Cochrane. Of the 215 identified articles, 16 were eligible for examining the diagnostic criteria of THI. These studies were also assessed for bias in the six domains. A total of five studies (31%) had a low risk of bias, while four studies (25%) had a high risk of bias, and bias in the case of seven studies (44%) was unclear. We conclude that THI is only definitively diagnosed after abnormal IgG levels normalise. Hence, THI is not a benign condition, and monitoring for subsequent recurrent infections must be conducted. The diagnostic criteria should also include vaccine and isohaemagglutinin responses to differentiate THI from other immunological disorders in infants. [ABSTRACT FROM AUTHOR]

The thymus gland is a central lymphoid organ in which developing T cell precursors, known as thymocytes, undergo differentiation into distinct type of mature T cells, ultimately migrating to the periphery where they exert specialized effector functions and orchestrate the immune responses against tumor cells, pathogens and selfantigens. The mechanisms supporting intrathymic T cell differentiation are pleiotropically regulated by thymic peptide hormones and cytokines produced by stromal cells in the thymic microenvironment and developing thymocytes. Interestingly, in the same way as T cells, thymic hormones (herein exemplified by thymosin, thymulin and thymopoietin), can circulate to impact immune cells and other cellular components in the periphery. Evidence on how thymic function influences tumor cell biology and response of patients with cancer to therapies remains unsatisfactory, although there has been some improvement in the knowledge provided by recent studies. Herein, we summarize research progression in the field of thymus-mediated immunoendocrine control of cancer, providing insights into how manipulation of the thymic microenvironment can influence treatment outcomes, including clinical responses and adverse effects of therapies. We review data obtained from clinical and preclinical cancer research to evidence the complexity of immunoendocrine interactions underpinning anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a leading cause of death worldwide. Improved preclinical tumor models are needed to make treatment screening clinically relevant and address disease mortality. Advancements in 3D cell culture have enabled a greater recapitulation of the architecture and heterogeneity of the tumor microenvironment (TME). This has enhanced their pathophysiological relevance and enabled more accurate predictions of tumor progression and drug response in patients. An increasing number of 3D CRC spheroid models include cell populations such as cancer-associated fibroblasts (CAFs), endothelial cells (ECs), immune cells, and gut bacteria to better mimic the in vivo regulation of signaling pathways. Furthermore, cell heterogeneity within the 3D spheroid models enables the identification of new therapeutic targets to develop alternative treatments and test TME-target therapies. In this mini review, we present the advances in mimicking tumor heterogeneity in 3D CRC spheroid models by incorporating CAFs, ECs, immune cells, and gut bacteria. We introduce how, in these models, the diverse cells influence chemoresistance and tumor progression of the CRC spheroids. We also highlight important parameters evaluated during drug screening in the CRC heterocellular spheroids. [ABSTRACT FROM AUTHOR]