Search Results (225)

Compelling research has consistently demonstrated a strong relationship between immunometabolism and infectious disease, including the ways in which viral infections alter the metabolic state of immune cells to promote survival. Human immunodeficiency virus (HIV) has been particularly noted for its ability to reprogram the metabolism of cells that contribute to viral persistence. The purpose of this review is to summarize current knowledge of the metabolic state of CD4 T cells and myeloid cells (monocytes/macrophages), two of the primary cell types targeted by HIV. The studies discussed reveal distinct metabolic profiles in both cell types during initial infection, active replication, and latency. In addition, we examine how these metabolic alterations may contribute to the increased frequency and severity of comorbidities observed in people with HIV (PWH). Understanding the impact of HIV infection and latency on immunometabolism may provide deeper insight into long-term viral persistence and support the identification of novel therapeutic targets to reduce chronic inflammation and inform future cure strategies for PWH. Full article

Objective: Varicella zoster virus (VZV), a member of the Herpesviridae family, is known as the causative agent of chickenpox (varicella). Following primary infection, VZV can remain latent for life and may reactivate over time to cause herpes zoster (shingles). Advanced age, immunodeficiency, and certain chronic illnesses are major risk factors for the development of herpes zoster. To prevent herpes zoster, a live zoster vaccine was licensed in 2006, followed by a recombinant zoster vaccine with higher efficacy in 2018. In Türkiye, the recombinant zoster vaccine was licensed in 2024. Raising awareness among healthcare workers is important both for their own health and the safety of vulnerable patients. This study aimed to evaluate healthcare workers’ knowledge and awareness of herpes zoster infection and zoster vaccines across the country, as well as to determine the prevalence of prior herpes zoster infection among them. Methods: After obtaining ethical approval, a nationwide multicenter survey was conducted. A questionnaire was distributed to healthcare workers via an online link. Participation was entirely voluntary. The survey collected demographic information (age, sex, profession, years of experience) and included questions on knowledge of herpes zoster, history of zoster infection, symptoms and severity (if applicable), awareness of the zoster vaccine, and vaccination attitudes. Results: A total of 5180 healthcare workers participated, of whom 3505 were female. The participants ranged in age from 18 to 79 years (mean age: 34.24 ± 11.52). Regarding professions: 47.9% were physicians, 21.3% were nurses or midwives, 0.8% were dentists or dental technicians, and 30% were from other healthcare professions. Among participants, 54.4% had ≤10 years of professional experience, 20% had comorbidities, and 10.5% were using immunosuppressive medications. It was found that 9.6% had previously had herpes zoster, 8.8% had no knowledge of the disease, 39.6% were aware of the vaccine, and 20.1% were unwilling to pay for vaccination. Multivariate binary logistic regression analysis revealed that being a physician significantly increased the likelihood of having correct knowledge by 1.961 times compared to other professions (p < 0.001, CI: 1.608–2.392). Similarly, those who had heard of herpes zoster were 3.191 times more likely to answer correctly than those who had not (p = 0.011, CI: 1.650–6.172). Male gender was significantly associated with a lower likelihood of having accurate knowledge compared to females (p = 0.001, OR = 0.720, CI: 0.594–0.874). Conclusions: This study revealed that healthcare workers’ knowledge and awareness regarding herpes zoster and its vaccines are generally insufficient. The recent licensing of the vaccine in Türkiye may explain this, but it is critical for healthcare professionals to be more informed about risk groups and vaccination indications in order to enhance the effectiveness of preventive healthcare services. Given the potential for serious complications of herpes zoster in elderly and immunocompromised individuals, the importance of vaccination should be emphasized more strongly to healthcare workers. Furthermore, the finding that 20.1% of those aware of the vaccine were deterred by its cost highlights the need to improve vaccine accessibility. Economic barriers preventing healthcare workers from being vaccinated emphasize the importance of making the vaccine widely available through public support to protect both healthcare workers and patient safety. Full article

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder caused by biallelic loss-of-function mutations in the ADA2 gene (formerly CECR1). First described in 2014, DADA2 has emerged as a paradigm for monogenic vasculitis, bridging the gap between primary immunodeficiencies and systemic vasculitides. The disease is characterized by a remarkably broad clinical spectrum encompassing early-onset lacunar stroke, systemic vasculitis resembling polyarteritis nodosa (PAN), hematologic abnormalities ranging from pure red cell aplasia to pancytopenia, humoral immunodeficiency, and variable lymphoproliferation. ADA2, predominantly secreted by myeloid cells, serves dual functions as a growth factor for endothelial cells and a modulator of extracellular adenosine metabolism. Its deficiency leads to a proinflammatory state driven by macrophage dysregulation, excessive tumor necrosis factor (TNF) production, neutrophil extracellular trap (NET) formation, and endothelial dysfunction. The genotype–phenotype correlation is complex, with certain mutations predisposing to vasculitic versus hematologic-predominant phenotypes. Emerging evidence further links ADA2 deficiency to cellular senescence and inflammaging pathways, suggesting a connection between monogenic vasculitis and aging-related biological mechanisms. Anti-TNF therapy has revolutionized disease management, achieving sustained remission in the majority of vasculitic manifestations. Hematopoietic stem cell transplantation (HSCT) offers a definitive cure for severe hematologic disease, while gene therapy approaches are under active investigation. This review synthesizes current knowledge on the immunopathogenesis, clinical heterogeneity, genotype–phenotype correlations, multi-omics insights, and evolving precision therapeutic strategies for DADA2, positioning it as an instructive model for understanding monogenic immune vasculopathy. Despite this progress, fundamental questions remain—including the relative contribution of ADA2 enzymatic versus growth factor functions to disease pathogenesis, the mechanisms underlying tissue-specific vulnerability, the basis of differential treatment responsiveness, and the identity of genetic and environmental modifiers that determine phenotypic heterogeneity—that define the frontier of current DADA2 research. This review critically evaluates both established knowledge and persistent uncertainties, positioning DADA2 as an instructive model for the study of monogenic immune vasculopathy. Full article

Ataxia–telangiectasia is a rare, autosomal recessive primary immunodeficiency caused by mutations in the ATM gene on chromosome 11, which encodes a serine–threonine kinase essential for the recognition and repair of DNA double-strand breaks. The disease is characterized by progressive neurological impairment, immunological dysfunction, and an increased susceptibility to recurrent infections and malignancies. Pulmonary involvement represents a major source of morbidity and frequently arises from chronic infections, aspiration, and impaired airway clearance, ultimately leading to the development of bronchiectasis. The case of a 15-year-old adolescent with a history of recurrent aspiration pneumonias, neuropsychomotor developmental delay, and severe malnutrition is reported, who was admitted for evaluation of chronic productive cough, fever, and dysphagia. Comprehensive clinical assessment and ancillary investigations revealed recurrent respiratory infections, gastroesophageal reflux, and typical features of ataxia–telangiectasia, including cerebellar ataxia, oculomotor apraxia, and conjunctival telangiectasias. Additionally, bronchiectasis was identified as a secondary consequence of the underlying neurological and immunological impairment. This case highlights the diagnostic challenges posed by ataxia–telangiectasia in pediatric patients presenting with chronic respiratory symptoms and emphasizes the importance of early recognition of the underlying systemic disorder. A multidisciplinary approach is essential for accurate diagnosis and optimized management, aiming to address both the primary disease and its pulmonary complications. Full article

Inborn errors of immunity, including primary immunodeficiency disorders (PIDs), comprise a heterogeneous group of genetic conditions characterized by immune system dysfunction. One such rare PID is CD137 deficiency, which results from TNFRSF9 mutations. CD137, also known as 4-1BB, plays a pivotal role in immune system regulation and co-stimulation. This literature review explores CD137 deficiency and its implications, emphasizing its association with EBV-associated lymphoproliferative disease and potential therapeutic targets. We present the case of a 21-year-old female patient with CD137 deficiency who experienced recurrent infections, autoimmunity, and lymphoma. Genetic analysis revealed that the patient had a homozygous TNFRSF9 variant. The patient subsequently developed severe Epstein–Barr virus (EBV)-associated lymphoproliferative disease, which is one of the clinical manifestations associated with CD137 deficiency. Additionally, this review discusses similar cases in the literature and details the clinical manifestations and immune abnormalities associated with CD137 deficiency. Understanding the genetic complexity of CD137 deficiency and the immune system dysregulation it causes provides insights into potential therapeutic interventions for affected individuals. This review highlights the role of CD137 as a crucial regulator of immune homeostasis and a potential target for immunotherapy in autoimmune diseases and malignancies. Full article

Background: Food protein-induced allergic proctocolitis (FPIAP) is generally considered a benign and self-limited condition; however, both its natural course and the impact of management strategies on prognosis remain controversial. Data on modifiable factors influencing tolerance acquisition are limited. Methods: We conducted a retrospective cohort study including 180 infants with cow’s milk-induced FPIAP. Clinical characteristics, management strategies, and outcomes were analysed. Logistic regression was used to identify factors associated with delayed tolerance, and Kaplan–Meier and Cox regression analyses were performed to evaluate time to tolerance. Results: Tolerance was achieved in 91.2% of infants, with a median time from diagnosis to tolerance of 31.1 weeks. In multivariable logistic regression, multi-food elimination at presentation (OR, 2.58; 95% CI, 1.02–6.54; p = 0.046) and a longer interval from diagnosis to reintroduction (OR per week, 1.08; 95% CI, 1.02–1.14; p = 0.022) were independently associated with delayed tolerance. Exclusive breastfeeding was associated with lower odds of delayed tolerance in univariable analysis but not after adjustment. In unadjusted time-to-event analyses, observation-first management was associated with earlier tolerance acquisition (HR, 0.37; 95% CI, 0.22–0.62; p < 0.001), whereas multiple food allergy was associated with a lower probability of tolerance acquisition over time (HR, 0.60; 95% CI, 0.41–0.88; p = 0.009). Feeding modality also showed an unadjusted temporal association with tolerance acquisition, with exclusively breastfed infants demonstrating a more favorable pattern than formula-fed infants. Conclusions: The course of FPIAP appears to be influenced not only by clinical characteristics but also by management strategies. Delayed reintroduction and multi-food elimination were associated with later tolerance, while observation-first management was associated with earlier tolerance acquisition. These findings suggest that commonly used strategies such as prolonged elimination or delayed reintroduction may warrant reconsideration in selected infants and support a more individualized and less restrictive approach to management. Full article

Background: CD8A-related CD8α deficiency (Immunodeficiency 116) is a rare autosomal recessive primary immunodeficiency disease characterized by absent CD8⁺ T cells and variable sinopulmonary disease. Case Presentation: A seven-year-old boy from a consanguineous family was referred for chronic wet cough and “uncontrolled asthma” despite being prescribed high-dose inhaled corticosteroids and montelukast. He was hospitalized seven times over a two-year period for presumed asthma exacerbations complicated by pneumonia. An examination revealed bilateral crackles without wheezing. Throat culture tested positive for Haemophilus influenzae. CT imaging showed signs of chronic rhinosinusitis (maxillary mucosal thickening) and chronic airway disease with bronchiectatic changes. The patient’s immunoglobulin levels were within normal ranges for his age group. Flow cytometry revealed profound CD8⁺ T-cell lymphopenia (CD8⁺ 0.21%; 11 cells/µL; near-absent after excluding dual-positive cells) with expansion of CD3⁺CD4⁻CD8⁻ T cells (29.5%). CD8A gene sequencing identified a novel homozygous nonsense variant NM_001768.7:c.319C>T (p.Arg107Ter; GRCh38: chr2:86790412G>A), consistent with loss of CD8α and secondary loss of CD8β surface expression. A literature review identified three previously reported symptomatic patients (and two asymptomatic sisters in the first family), all with recurrent respiratory infections and variable structural lung disease. Conclusions: This case highlights CD8A deficiency as a rare mimic of pediatric asthma and expands the genotype spectrum with a truncating CD8A variant. Early lymphocyte immunophenotyping in children with recurrent sinopulmonary infections may prevent delayed diagnosis and progressive airway damage. Full article

Background: X-linked immunodeficiency with magnesium defect, Epstein–Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect. Full article

Background/Objectives: Cutaneous manifestations of inborn errors of immunity (IEI) are among the most common and often early signs of these disorders, estimated to affect about 40% of patients with IEI, and in some cases, they provide the first diagnostic clue. Skin findings in IEI are heterogeneous and include recurrent skin infections, severe atopic dermatitis, autoimmune manifestations, as well as atypical granulomatous dermatoses, neoplastic lesions, pigmentation disorders, and changes involving hair and nails. Early recognition of these manifestations and linking them to the appropriate immunologic defect is crucial for establishing the diagnosis and initiating targeted therapy. Methods: This paper reviews the dermatologic phenotypes associated with IEI, with particular emphasis on a tabular classification of skin lesions corresponding to specific immunologic defects. Relevant literature was analyzed to summarize characteristic cutaneous presentations and current diagnostic approaches, highlighting the importance of interdisciplinary evaluation. Results: Cutaneous findings in IEI encompass a wide spectrum of infectious, inflammatory, autoimmune, and neoplastic manifestations. Systematic classification of these lesions facilitates earlier recognition of underlying immune defects and supports differential diagnosis. Dermatologic signs frequently precede systemic manifestations, making them valuable early clinical indicators of IEI. Conclusions: Recognition of dermatologic manifestations is critical for early diagnosis of IEI. Interdisciplinary collaboration between dermatologists, immunologists, and other specialists improves diagnostic accuracy and patient management. Current therapeutic strategies range from symptomatic treatment to targeted therapies, and personalized approaches improve prognosis and quality of life in patients with IEI. Full article

Background and Objectives: Respiratory syncytial virus (RSV) is a leading cause of hospitalization among infants and young children. The clinical course of RSV infection varies considerably depending on age and selected clinical factors. The objective of this study was to identify demographic and clinical variables associated with the course of hospitalization in children admitted due to laboratory-confirmed RSV infection. Materials and Methods: A retrospective observational study was conducted based on the medical records of 100 immunocompetent pediatric patients hospitalized due to RSV infection in the Department of Pediatrics of Hospital in Wadowice, Poland, between December 2021 and April 2023. Inclusion criteria were age ≤ 5 years and laboratory-confirmed RSV infection. Patients with congenital heart disease, chronic lung disease (including cystic fibrosis), immunodeficiency, or other severe chronic conditions were excluded. Collected data included age, gestational age at birth, mode of delivery, vaccination status, clinical presentation, length of hospital stay, C-reactive protein (CRP) levels, seasonality of infection, and use of antibiotic therapy. Results: The median length of hospitalization was 6 days (range: 0–18). Younger age was significantly associated with longer hospital stay (p < 0.05) and higher CRP levels (p < 0.05). No significant associations were observed between hospitalization duration and mode of delivery or vaccination status. Gestational age at birth did not influence the number of clinical symptoms. The need for antibiotic therapy differed significantly according to the season of infection (p < 0.05). Conclusions: In children hospitalized with RSV infection, age and seasonality were the primary factors influencing the course of hospitalization, whereas perinatal factors such as mode of delivery and vaccination status had no significant impact. These findings underscore the importance of age-oriented clinical assessment and support efforts to optimize antimicrobial stewardship during RSV seasons. Full article

Canine prostatic adenocarcinoma is a rare but highly aggressive cancer that is typically diagnosed at an advanced stage, due to the lack of effective screening methods and poor recognition of early lesions. Cancer stem cells are known to drive tumour progression and treatment resistance in human prostate cancer, but their role in naturally occurring canine disease remains poorly defined. A deeper understanding of the biology of canine prostatic adenocarcinoma is therefore essential to improve prognosis and to develop relevant comparative models. We established and comprehensively characterised two novel canine prostatic adenocarcinoma cell lines, Kodiak and Bobby, with detailed comparison to their tumours of origin and, for Kodiak, xenografts generated in immunodeficient mice. Both lines displayed variable epithelial morphology influenced by culture conditions, and Kodiak xenografts recapitulated key histopathological patterns of the primary tumour. Expression of the luminal epithelial marker CK8/18 and the basal marker CK14 was largely retained across tumour, cell line, and xenograft, whereas the basal markers CK5 and p63, and the urothelial marker UPIII, were diminished or lost during in vitro culture. Evaluation of cancer stem cell-associated markers showed consistent expression of CD44, Nanog, Oct3/4, and Sox2 in the original tumours and cell lines, while CD133, Nestin, and Trop2 were present in the tumours but absent in vitro, indicating selective loss of specific stem-like populations. Media-dependent plasticity was evident in the Bobby line. These models retain key epithelial and stemness features and provide robust platforms for translational prostate cancer research in dogs and humans. Full article

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency or inborn error of immunity (IEI) encountered in clinical practice. Characterized by a remarkably broad clinical spectrum, CVID presents with phenotypes spanning from “infection only” to significant non-infectious complications. The frequent overlap between these classifications underscores that their distinction is more accurately viewed as a continuous spectrum, rather than a binary categorization. CVID-associated liver disease is a significant source of morbidity, yet often poses diagnostic challenges due to its insidious and clinically silent nature, typically becoming apparent only upon the development of complications. Manifestations range from abnormal liver tests to irreversible organ damage, with reports including granulomas, autoimmune hepatitis, fibrosis, and porto-sinusoidal vascular disorder (PSVD). Regenerative nodular hyperplasia (RNH), commonly associated with PSVD, is a frequent histopathological finding. Management requires a multidisciplinary approach, including cause-directed immunosuppression and supportive treatment for non-cirrhotic portal hypertension. Despite significant advances in comprehending CVID-associated liver involvement, substantial gaps persist concerning its pathogenesis, its optimal management, and the correlation between histological findings and clinical outcomes. A heightened awareness of CVID-associated liver disease is paramount for multidisciplinary teams across IEI centers. Furthermore, given its prevalence, its insidious clinical phenotype until advanced complications, and the significant diagnostic delay and underdiagnosis, such awareness is critical across a broader range of medical specialties. In this paper, we aim to consolidate current knowledge regarding CVID-related liver disease, examining its clinical presentation, recent genetic and pathogenetic advancements along with current diagnostic methodologies, and therapeutic strategies. Full article

Vitamin D is a fat-soluble hormone essential for bone mineralization. In addition to this role, vitamin D is known for its immunomodulatory effects through its binding to intracellular vitamin D receptors (VDRs), which translocate to the nucleus of immune cells, including antigen-presenting cells (APC), B lymphocytes, T lymphocytes and monocytes, thereby modulating the transcription of genes responsible for the immune response. Vitamin D deficiency is associated with an increased risk of developing infections and autoimmune diseases. The purpose of this review is to evaluate vitamin D deficiency in patients with primary immunodeficiency (CVID, XLA, DGS, APECED, SCID, WAS, HIES), to assess its clinical and therapeutic impact. Vitamin D deficiency, often asymptomatic, is associated with more severe clinical conditions in subjects with PID. It can be associated with osteoporosis, fractures, myelofibrosis and endocrine disorders such as hypocalcemia. These patients responded beneficially to calcitriol therapy, underscoring the need for long-term monitoring. Full article

Although neurological disease is common in people with human immunodeficiency virus (HIV) (PWH), the contributing factors and underlying inflammatory mechanisms remain challenging to identify. Extracellular vesicles (EVs) constitute a relatively uncharacterized modality of intercellular communication and bioactive cargo transport in the setting of viral infection and pathogenesis. EVs carry inflammatory mediators to areas of the periphery during antiretroviral therapy (ART) suppression but are understudied in the brain. Using a biologically relevant simian–human immunodeficiency chimeric virus with a clade D HIV envelope (SHIV.D)-infected rhesus macaque (RM) model of HIV persistence in the central nervous system (CNS), we investigate circulating EV populations and the protein cargo of myeloid-derived EVs during SHIV infection. Using EV flow cytometry to quantify specific EV subpopulations, we found a significant increase in TMEM119+ microglial EVs and CD171+ neuronal EVs in RM plasma during viremia and ART suppression. Using primary RM monocyte-derived macrophages (MDMs), we determined that MDMs increased EV production after SHIV infection. Whole proteomic analysis of these EVs demonstrated that myeloid EVs isolated from SHIV.D-infected MDMs carried significantly increased levels of neuropathogenic and inflammatory proteins. Altogether, these studies improve our understanding of the contribution of myeloid EVs to neurological disease during SHIV/HIV infection. Full article

Primary humoral immunodeficiencies are a heterogeneous group of disorders defined by quantitative and/or functional defects in one or more immunoglobulin classes, often with associated cellular immune abnormalities. Their link with bronchiectasis, whose prevalence varies across specific defects, is largely driven by recurrent respiratory infections. Selective Immunoglobulin-(Ig)A deficiency and IgG2 subclass deficiency are the most frequent forms, but common variable immunodeficiency (CVID) is the condition most often associated with bronchiectasis and is usually diagnosed earlier because of its characteristic phenotype. In contrast, the contribution of isolated IgA deficiency or selective IgG subclass deficiencies to bronchiectasis remains controversial. Other reported associations include X-linked agammaglobulinemia, selective IgM or IgG deficiency, and rarer entities such as selective IgE deficiency, unclassified hypogammaglobulinemia, specific antibody deficiency, specific polysaccharide antibody deficiency, and heavy- or light-chain deficiencies. Current bronchiectasis guidelines recommend measurement of serum immunoglobulins and IgG subclasses in patients with compatible features, recurrent infections, or no clear etiology before labeling disease as idiopathic. Identifying immunoglobulin defects is clinically important because they represent treatable traits. The potential role of emerging therapies such as the DPP1 inhibitor brensocatib in immunodeficiency-related bronchiectasis remains uncertain, and ongoing registries will be key to clarifying these relationships. Full article