Search Results (429)

Background and Objectives: Inborn errors of immunity are increasingly diagnosed in developing countries. Immunoglobulin replacement therapy (IGRT) remains the cornerstone of treatment in these patients, and its monitoring has gained importance for optimizing outcomes. We conducted a retrospective study to evaluate the relationship between IgG trough levels and infections in adults with inborn errors of immunity receiving IGRT. Materials and Methods: Adults diagnosed with primary immunodeficiency and receiving IGRT for at least six months were included. Serum IgG trough levels were measured, and infections during follow-up were systematically recorded. Results: A total of 31 adult patients (CVID: 29, XLA: 2) were analyzed. The mean follow-up was 13 months, with a mean serum IgG trough level of 815.8 ± 205.9 mg/dL, achieved with an average IGRT dose of 498.8 ± 93.0 mg/kg/month. Dose adjustments were made in 35.5% of patients, mostly due to weight changes and clinical indications. Overall, 74.2% of patients had at least one infection requiring antibiotics. Patients with mean IgG trough levels below 850 mg/dL had significantly higher rates of antibiotic-requiring infections (p = 0.032, Mann–Whitney U; mean difference = 0.109, 95% CI: 0.037–0.182; p = 0.005 via t-test). Multivariate regression confirmed that lower IgG trough levels were independently associated with higher antibiotic-requiring infection rates (B = −0.024, 95% CI: −0.045 to −0.002, p = 0.033), while IGRT dose and comorbidities were not significant. Conclusions: IGRT plays a key role in reducing antibiotic-requiring infections in patients with primary immunodeficiency. Regular monitoring and individualized dose adjustments may help optimize outcomes. Further prospective studies are needed to confirm these findings. Full article

Background: Inborn errors of immunity (IEI) are mainly genetically driven disorders that affect immune function and present with highly heterogeneous clinical manifestations, ranging from severe combined immunodeficiency (SCID) to adult-onset immune dysregulatory diseases. This clinical heterogeneity, coupled with limited awareness and the absence of a universal diagnostic test, makes early and accurate diagnosis challenging. Although genetic testing methods such as whole-exome and genome sequencing have improved detection, they are often expensive, complex, and require functional validation. Recently, artificial intelligence (AI) tools have emerged as promising for enhancing diagnostic accuracy and clinical decision-making for IEI. Methods: We conducted a systematic review of four major databases (PubMed, Scopus, Web of Science, and Embase) to identify peer-reviewed English-published studies focusing on the application of AI techniques in the diagnosis and treatment of IEI across pediatric and adult populations. Twenty-three retrospective/prospective studies and clinical trials were included. Results: AI methodologies demonstrated high diagnostic accuracy, improved detection of pathogenic mutations, and enhanced prediction of clinical outcomes. AI tools effectively integrated and analyzed electronic health records (EHRs), clinical, immunological, and genetic data, thereby accelerating the diagnostic process and supporting personalized treatment strategies. Conclusions: AI technologies show significant promise in the early detection and management of IEI by reducing diagnostic delays and healthcare costs. While offering substantial benefits, limitations such as data bias and methodological inconsistencies among studies must be addressed to ensure broader clinical applicability. Full article

Background/Objectives: Subcutaneous immunoglobulin (SCIg) is a well-established alternative to intravenous immunoglobulin (IVIg) in patients with primary (PID) and secondary immunodeficiency (SID), with demonstrated benefits in safety and quality of life. However, its implementation remains limited in parts of Southern Europe, partly due to frequent local adverse reactions (LARs), which, despite being mild, can affect adherence and clinician confidence. This study aimed to identify clinical, anatomical, psychosocial, and geographical factors associated with LARs and to develop an exploratory model for individualized risk estimation. Methods: We conducted a retrospective, multicenter observational study in eight Spanish hospitals using data from the GEIE Registry. Patients aged ≥14 years with PID or SID receiving SCIg for ≥1 month were included. Demographic, clinical, anatomical, and psychosocial variables were collected. A multivariable logistic regression model was built to identify independent predictors of LARs and internally validated using bootstrap resampling (500 iterations). A nomogram was constructed for personalized risk prediction. Results: Among 223 included patients, 73.1% reported LARs, primarily swelling, pruritus, and rash. Independent predictors included smaller abdominal perimeter (OR 0.955, p < 0.001), history of skin disease (OR 2.75, p = 0.044), greater distance to hospital (OR 1.01, p = 0.050), and absence of anxiety (OR 0.089, p = 0.001). Model discrimination was good (AUC 0.801), with minimal optimism after internal validation (validated AUC 0.788). Conclusions: LARs are common among patients receiving SCIg and could be influenced by anatomical, dermatological, psychological, and geographical factors. This exploratory multicenter study underscores the clinical relevance of these factors and may guide more personalized and safer use of SCIg. Full article

STAT3 mutations are commonly observed in human pathology yet have no uniform patient presentation. Their effects range from cancer and autoimmunity to primary immunodeficiencies and bone deformity. Designing animal models of those mutations can help researchers identify their direct effects to better inform the clinical setting. In this manuscript, we report a mouse model harboring the same mutation as an autosomal-dominant hyper-IgE syndrome (AD-HIES) patient reported in the literature. Surprisingly, while the deletion of five amino acids in the SH2 domain of STAT3 did result in frequency changes in several immune populations as measured by complete blood count and flow cytometry analysis, it did not yield the expected phenotype of AD-HIES, with no increase in serum IgE or eosinophil count. We additionally provide structural analysis of the STAT3^G656_M660del deletion, visualizing changes in protein architecture and potential effects on the neighboring Y705 phosphorylation site. Our model showcases the sexually dimorphic immune dysregulation caused by a STAT3 mutation and highlights that predicted gain- and loss-of-function mutations can yield unexpected phenotypes. Full article

Immunoglobulin light chains are essential components of intact immunoglobulins, traditionally believed to be produced exclusively by B cells. Physiologically, excess light chains not assembled into intact antibodies exist as free light chains (FLCs). Increasingly recognized as important biomarkers for diseases such as multiple myeloma, systemic amyloidosis, and light chain-related renal injuries, FLCs have also been shown in recent decades to originate from non-B cell sources, including epithelial and carcinoma cells. This review primarily focuses on novel non-B cell-derived FLCs, which challenge the conventional paradigms. It systematically compares B cell-derived and non-B cell-derived FLCs, analyzing differences in genetic features, physicochemical properties, and functional roles in both health and disease. By elucidating the distinctions and similarities in their nature as immune regulators and disease mediators, we highlight the significant clinical potential of FLCs, particularly non-B cell-derived FLCs, for novel diagnostic and therapeutic strategies. Full article

Background/Objectives: Inborn errors of immunity (IEIs) represent a wide spectrum of diseases characterized by a predisposition to recurrent infections, as well as increased susceptibility to autoimmune, atopic, and autoinflammatory diseases and malignancies. The aim of this study was to report the registry-based frequency and describe the clinical characteristics of IEIs among patients in the Republic of Kazakhstan. Methods: We analyzed data from 269 patients belonging to 204 families who were either self-referred or referred by healthcare providers to the University Medical Center of Nazarbayev University with suspected IEIs. All patients resided in various regions across Kazakhstan. Results: A total of 269 diagnosed cases were identified in the national registry. The estimated prevalence was 1.3 per 100,000 population. The gender ratio was nearly equal, with 139 males and 130 females. The median age at diagnosis was 5 years (range: 1 month to 70 years), while the mean age was 11.3 years. The most common diagnosis was humoral immunodeficiency, observed in 120 individuals (44.6%), followed by complement deficiencies in 83 individuals (30.8%). Combined immunodeficiencies with syndromic features were found in 35 patients (13%), and phagocytic cell defects were identified in 12 patients (4.5%). The predominant clinical manifestations included severe recurrent infections and autoimmune cytopenias, while atopic and autoinflammatory symptoms were reported less frequently. Conclusions: These findings contribute to a better understanding of the registry-based distribution and clinical spectrum of IEIs in Kazakhstan and underscore the importance of early diagnosis and targeted care for affected individuals. Full article

Primary and secondary immunodeficiencies comprise a wide array of illnesses marked by immune system abnormalities, resulting in heightened vulnerability to infections, autoimmunity, and cancers. Notwithstanding progress in diagnostic instruments and an enhanced comprehension of the underlying pathophysiology, delayed diagnosis and underreporting persist as considerable obstacles. The implementation of artificial intelligence into clinical practice has surfaced as a viable method to enhance early detection, risk assessment, and management of immunodeficiencies. Recent advancements illustrate how artificial intelligence-driven models, such as predictive algorithms, electronic phenotyping, and automated flow cytometry analysis, might enable early diagnosis, minimize diagnostic delays, and enhance personalized treatment methods. Furthermore, artificial intelligence-driven immunopeptidomics and phenotypic categorization are enhancing vaccine development and biomarker identification. Successful implementation necessitates overcoming problems associated with data standardization, model validation, and ethical issues. Future advancements will necessitate a multidisciplinary partnership among physicians, data scientists, and governments to effectively use the revolutionary capabilities of artificial intelligence, therefore ushering in an age of precision medicine in immunodeficiencies. Full article

Background: Regulatory T cells (Tregs) are the main suppressor cells that maintain immune tolerance and prevent autoimmunity. Changes in Treg number or function are implicated in a wide range of autoimmune and inflammatory (AI/I) diseases, with or without underlying inborn errors of immunity (IEI). Understanding the phenotypic profiles of Treg subsets and their associations with immune dysregulation is crucial to identifying potential robust and holistic biomarkers for disease activity. Methods: We examined peripheral blood mononuclear cells from 40 patients diagnosed with various autoimmune/inflammatory diseases, including those with genetically confirmed inborn errors of immunity (IEIs), and compared these samples to those from 38 healthy controls of the same age. Utilizing multiparametric flow cytometry, we measured multiple Treg sub-populations and investigated their correlations with lymphocyte subset profiles and the diversity of autoantibodies. We applied advanced statistical and machine learning techniques, such as t-SNE, k-means clustering, and ROC analysis, to analyze immunophenotypic patterns in the patients. Results: Among all Treg sub-populations, only CD4⁺CD127^lowCD25^highFOXP3⁺ Tregs showed a significant decrease in patients compared to healthy controls (p < 0.05), while other Treg phenotypes did not differ. FOXP3 expression showed reduced intensity in patients and demonstrated diagnostic potential (AUC = 0.754). Notably, this Treg subset negatively correlated with CD19⁺ B cell percentages and positively correlated with the diversity of circulating autoantibodies. Unsupervised clustering revealed three distinct immunophenotypic profiles, highlighting heterogeneity among patients and underlining FOXP3-centered immune dysregulation. Conclusions: Our results presented that patients have an impairment in the CD4⁺CD127^lowCD25^highFOXP3⁺ regulatory T cell subset, which is identified by significantly decreased frequency and decreased expression of FOXP3. Immunological heterogeneity among patients was further uncovered by unsupervised clustering, highlighting the critical role that FOXP3-centered regulatory failure plays in the pathophysiology of illness. The combined evaluation of these three immunological factors, centered around FOXP3, holds promise as an integrative tool for monitoring disease progression across various autoimmune and immunodeficient contexts. Full article

Background/Objective: People living with human immunodeficiency virus (PHIV) are at increased risk for malignancies, yet their access to immunotherapy remains limited due to concerns about safety and efficacy. This systematic scoping review evaluates the use of immune checkpoint inhibitors (ICIs) in HIV-associated cancers, analyzing patient outcomes, safety profiles, and the impact on HIV status. Methods: A comprehensive literature search was conducted in databases including PubMed, Scopus, Web of Science (WoS), and Medline, up to January 2025. Studies included assessing the efficacy of ICIs in cancer patients with HIV. The primary outcomes were (a) the efficacy of immune ICIs on prognosis, progression-free survival (PFS), and overall survival (OS). Secondary outcomes were the immune-related adverse events (irAEs) and the survival rate of cancer patients receiving ICIs. Results: A total of 107 cases from 19 studies published between 2011 and 2024 were reviewed. Responses to programmed death 1 (PD-1) inhibitors varied, with 27.1% achieving partial response, 23.36% experiencing stable disease, and 6.54% achieving complete response, while 34.57% had disease progression. Adverse events, including hematologic and endocrine toxicities, were common but mostly manageable. HIV viral loads remained stable in most cases. Conclusions: PD-1 inhibitors demonstrated potential efficacy in HIV-associated malignancies with a safety profile comparable to the general population. However, disease progression remained a concern, highlighting the need for optimized patient selection. Further well-controlled trials are essential to establish treatment guidelines and ensure equitable access to immunotherapy for PHIV. Full article

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option. Full article

Predominantly antibody deficiencies (PADs) are the most prevalent types of inherited errors of immunity (IEI) and are characterized by a broad range of clinical manifestations, such as recurrent infections, autoimmunity, lymphoproliferation, atopy and malignancy. The aim of this study was to identify genetic defects associated with PADs in order to improve diagnosis and personalized care. Twenty patients (male/female: 12/8, median age of disease onset: 16.5 years, range: 1–50) were analyzed by next-generation sequencing (NGS) using a custom panel of 30 genes associated with PADs and their possible disease phenotype. The detected variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and inheritance, and the penetrance patterns were evaluated by PCR–Sanger sequencing. Novel and rare mutations associated with the phenotype of common variable immunodeficiency (CVID) in genes encoding the transcription factors NFKB1, NFKB2 and IKZF1/IKAROS were identified. Alphafold3 protein structure prediction was utilized to perform a comprehensive visualization strategy and further delineate the mutation-bearing domains and elucidate their potential impact on protein function. This study highlights the value of genetic testing in PADs and will guide further research and improvement in diagnosis and treatment. Full article

Non-celiac villous atrophy (NCVA) is a multifaceted and under-recognized clinical entity with an etiology beyond celiac disease. This review critically examines the diverse pathophysiological mechanisms underlying NCVA, including autoimmune enteropathies, immune deficiency-related disorders, infectious processes, drug-induced trauma, and metabolic or environmental influences. A comprehensive synthesis of peer-reviewed literature, clinical studies, and case reports was conducted, adopting a multidisciplinary perspective that integrates immunologic, infectious, metabolic, and pharmacologic insights. The literature search was performed in three phases: identification of relevant studies, critical assessment of selected publications, and synthesis of key findings. Searches were carried out in PubMed, Scopus, Web of Science, and Google Scholar databases. The final search, completed in June 2025, included international, English-language articles, electronic books, and online reports. Studies were included if they addressed NCVA in the context of pathophysiology, clinical manifestations, or management strategies, with priority given to publications from the last ten years (2015–2025). The search strategy used the primary term “non-celiac villous atrophy” combined with supplementary keywords such as autoimmune enteropathy, common variable immunodeficiency, tropical sprue, drug-related enteropathy, pathophysiology, immunological mechanisms, chronic inflammation, genetic factors, environmental influences, and clinical management. Histopathological evaluations reveal that NCVA often manifests with varying degrees of villous blunting, crypt hypertrophy, and intraepithelial lymphocytosis, albeit without the gliadin-specific immune response seen in celiac disease. Various immune pathways are involved, such as autoimmune deregulation and chronic inflammatory responses, while drug-induced and environmental factors further complicate its clinical picture. These findings highlight significant diagnostic challenges and underscore the need to adapt diagnostic algorithms that combine clinical history, serologic evaluations, and histopathologic analysis. In conclusion, an in-depth understanding of the heterogeneous etiology of NCVA is critical to improving diagnostic accuracy and optimizing therapeutic strategies. Future research should prioritize the identification of specific biomarkers and the development of targeted interventions to address the unique mechanisms underlying NCVA, thereby improving patient management and outcomes. Full article

Background and Clinical Significance: Common variable immunodeficiency (CVID) is a primary B-cell immunodeficiency disorder, characterized by severe hypogammaglobulinemia and disturbed antibody production. In addition to increased susceptibility to recurrent respiratory and gastrointestinal infections, CVID can lead to a wide array of complications associated with immune dysregulation, which can also affect the liver. Liver involvement occurs in about 10% of patients with CVID, and can result from a range of causes, including infections, autoimmune disorders, lymphoproliferative conditions, granulomatous inflammation, and infiltrative processes. The most common liver manifestations include nodular regenerative hyperplasia, granulomatous or autoimmune hepatitis, and lymphocytic infiltration. The prevalence, pathophysiology, extent, and prognosis of liver involvement in CVID have not been systematically studied. Case Presentation: The object of this article is to present two patients with CVID-related liver disease and to illuminate the most relevant causes of liver involvement in CVID, describe the clinical features of their liver disease, and summarize the diagnostic and therapeutic approaches for its management. Conclusions: Liver involvement is an expected complication in patients with CVID syndrome. The delayed recognition of this pathology significantly worsens the disease prognosis, making the early detection of this potential complication crucial. Full article

Wastewater-based epidemiology (WBE) offers a promising tool for sexually transmitted infection (STI) surveillance, especially in settings where underdiagnosis or social stigma complicates conventional reporting. To assess its utility, we conducted a year-long study examining six STIs, Chlamydia trachomatis, Treponema pallidum, Neisseria gonorrhoeae, human immunodeficiency virus (HIV), hepatitis C virus (HCV), and herpes simplex virus (HSV), in weekly composite samples from the primary influent of a small-sized Midwestern wastewater treatment plant. Pathogen detection and quantification were performed via digital PCR. Among the tested targets, Gonorrhea, HIV, HCV, and HSV were detected at the highest frequencies, often in 40–50% of the samples, while Chlamydia and Syphilis appeared less frequently. Despite the variability in detection patterns, this study demonstrates that even infrequent signals can reveal community-level shedding of poorly reported or asymptomatic infections. Although month-to-month wastewater data were not strongly correlated with corresponding clinical records, which could potentially reflect delayed healthcare seeking and pathogen-specific shedding dynamics, the overall findings underscore WBE’s ability to complement existing surveillance by capturing infections outside traditional healthcare channels. These results not only advance our understanding of STI prevalence and population shedding but also highlight the practical benefits of WBE as an early warning and targeted intervention tool. Full article

Allergic diseases represent a major and growing global health concern, with increasing prevalence among both children and adults. This manuscript presents an extensive review of allergy mechanisms, epidemiology, diagnostics, and clinical challenges, highlighting the complex interplay between immune system dysregulation and environmental exposures. The authors provide a structured analysis of hypersensitivity types, with particular focus on IgE-mediated responses, and emphasize the role of immune barrier defects, epigenetics, and the microbiota in allergic pathogenesis. This manuscript explores diagnostic limitations, including test sensitivity, specificity, and the presence of hidden allergens, as well as challenges in identifying food-related or atypical allergic reactions. A novel and valuable aspect is the discussion of allergy as a potential clinical manifestation of primary immunodeficiencies, such as selective IgA deficiency, Wiskott–Aldrich syndrome, hyper-IgE syndrome, and Netherton syndrome. This review also outlines challenges in treatment, especially among polysensitized patients, and examines the psychosocial burden and complications of allergic diseases, including mental health, nutritional deficiencies, and impaired sleep. This comprehensive synthesis underscores the need for early diagnosis, multidisciplinary management, and personalized therapeutic strategies to improve quality of life of allergic patients. Full article