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With the expansion of our knowledge on inborn errors of immunity (IEI), it gradually becomes clear that immune dysregulation plays an important part. In some cases, autoimmunity, hyperinflammation and lymphoproliferation are far more serious than infections. Thus, immune dysregulation has become significant in disease monitoring and treatment. In recent years, the wide application of whole-exome sequencing/whole-genome sequencing has tremendously promoted the discovery and further studies of new IEI. The number of discovered IEI is growing rapidly, followed by numerous studies of their pathogenesis and therapy. In this review, we focus on novel discovered primary immune dysregulation diseases, including deficiency of SLC7A7, CD122, DEF6, FERMT1, TGFB1, RIPK1, CD137, TET2 and SOCS1. We discuss their genetic mutation, symptoms and current therapeutic methods, and point out the gaps in this field.

Background: Sarcoidosis is a systemic inflammatory disease characterized by an altered inflammatory response. Objective: The aim of this study was to evaluate whether immune system alterations detected by lymphocyte typing in peripheral blood correlate with the severity of sarcoidosis, calculated according to two separate severity scores proposed by Wasfi in 2006 and Hamzeh in 2010. Materials and Methods: Eighty-one patients were recruited, and clinical data and laboratory tests at the time of diagnosis were obtained in order to assess the severity index score and investigate any statistically significant correlation with the cytofluorimetry data. Results: Our data demonstrated that none of the two scores show an association with the level of total lymphocytes or lymphocyte subclasses. Limitations: First of all, the sample taken into consideration is small. The assessment was performed only at disease onset and not during the disease. Furthermore, the severity scores do not take into account disease activity (measured by PET/CT or gallium scintigraphy). Conclusions: Lymphocyte subpopulation values at the time of diagnosis do not appear to correlate with disease severity at onset.

Ulcerative colitis represents an inflammatory bowel disease with multiple contributing factors, marked by persistent inflammation of the colonic mucosa, which can lead to a reduced life expectancy and an elevated likelihood of requiring colectomy as well as developing colorectal cancer. Despite impacting roughly 5 million individuals worldwide, the intricate mechanisms underlying ulcerative colitis are still inadequately defined, hindering the development of effective treatments. Extra-intestinal complications, including enteropathic arthritis, are also addressed in the context of disease burden and management. This review explores the multifaceted pathogenesis of ulcerative colitis, emphasizing critical factors such as abnormalities in the epithelial barrier, irregular immune responses, the release of inflammatory mediators, and alterations in gut microbiota composition. We also underscore recent advancements in diagnostic biomarkers that improve the accuracy of disease detection and monitoring. Conventional medicinal strategies are reviewed alongside the emergence of biological therapies, notably those that target tumor necrosis factor (TNF), interleukins, and integrins, which have significantly altered management approaches. Established therapies (eg, 5-aminosalicylic acid, corticosteroids) and emerging agents (eg, JAK inhibitors, S1P modulators) are clearly delineated. Combination strategies-such as dual biologic regimens or JAK inhibitors combined with anti-integrin agents-are also discussed in dedicated subsections. We discuss novel therapies that utilize small molecule targeting, particularly those that inhibit Janus kinase (JAK) and modulate sphingosine-1-phosphate (S1P) receptors, presenting promising avenues for treatment. Additionally, fecal microbiota transplantation (FMT) is evaluated as a therapeutic option, as it shows promise in restoring microbial balance. Collectively, these advances underscore the pivotal roles of immune dysregulation, biologic therapies, and microbiota modulation in reshaping precision management of ulcerative colitis. This synthesis of current knowledge underscores the necessity for continued research to refine therapeutic strategies and improve patient outcomes in ulcerative colitis.

Purpose of ReviewThe most serious DNA damage, DNA double strand breaks (DNA-dsb), leads to mutagenesis, carcinogenesis or apoptosis if left unrepaired. Non-homologous end joining (NHEJ) is the principle repair pathway employed by mammalian cells to repair DNA-dsb. Several proteins are involved in this pathway, defects in which can lead to human disease. This review updates on the most recent information available for the specific diseases associated with the pathway.Recent FindingsA new member of the NHEJ pathway, PAXX, has been identified, although no human disease has been associated with it. The clinical phenotypes of Artemis, DNA ligase 4, Cernunnos-XLF and DNA-PKcs deficiency have been extended. The role of haematopoietic stem cell transplantation, following reduced intensity conditioning chemotherapy, for many of these diseases is being advanced.SummaryIn the era of newborn screening, urgent genetic diagnosis is necessary to correctly target appropriate treatment for patients with DNA-dsb repair disorders.

Beginning in 1970, a committee was constituted under the auspices of the World Health Organization (WHO) to catalog primary immunodeficiencies. Twenty years later, the International Union of Immunological Societies (IUIS) took the remit of this committee. The current report details the categorization and listing of 354 (as of February 2017) inborn errors of immunity. The growth and increasing complexity of the field have been impressive, encompassing an increasing variety of conditions, and the classification described here will serve as a critical reference for immunologists and researchers worldwide.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

Evans syndrome (ES) is a rare disorder characterized by autoimmune cytopenias affecting multiple blood cell lineages. In children, management remains particularly challenging due to the absence of clear guidelines for acute treatment and escalation to second-line therapies. We conducted a retrospective, longitudinal study (2010-2024) including pediatric patients (<18 years) with ES to identify predictors of severe presentation, need for second-line therapy, and fatal outcome. Predictors were identified using Cox Regression. Fifty patients were included (sequential = 27, concomitant = 23), with a median age at diagnosis of 4.1 years (IQR:1.5–8.5). Secondary ES was observed in 41(82%) cases, among which 38 (76%) had IEI. Severe clinical presentation at diagnosis occurred in 50% of patients and was independently associated with age < 24months and hemoglobin level < 80g/L. Corticosteroid dependence was observed in 34 cases (68%), with second-line therapy required in 31 patients (62%, cumulative risk=88%). This was associated with the presence of hepatomegaly and abnormal IgM levels. At last follow-up, 38(76%) patients were in remission and 19(38%) had relapsed. Fatal outcome (8 patients) was associated with age < 24 months at diagnosis (p=0.04), family history of IEI (p=10 -3 ), splenomegaly (p=0.02), and hepatomegaly (p=0.05). Pediatric ES is therefore a severe condition particularly in infants. Outcomes are strongly influenced by underlying immune dysregulation, highlighting the need for early etiological evaluation to guide timely and appropriate therapeutic strategies including the early use of targeted or curative approaches.

Imbalances in gut and reproductive tract microbiota composition, known as dysbiosis, disrupt normal immune function, leading to the elevation of proinflammatory cytokines, compromised immunosurveillance and altered immune cell profiles, all of which may contribute to the pathogenesis of endometriosis. Over time, this immune dysregulation can progress into a chronic state of inflammation, creating an environment conducive to increased adhesion and angiogenesis, which may drive the vicious cycle of endometriosis onset and progression. Recent studies have demonstrated both the ability of endometriosis to induce microbiota changes, and the ability of antibiotics to treat endometriosis. Endometriotic microbiotas have been consistently associated with diminished Lactobacillus dominance, as well as the elevated abundance of bacterial vaginosis-related bacteria and other opportunistic pathogens. Possible explanations for the implications of dysbiosis in endometriosis include the Bacterial Contamination Theory and immune activation, cytokine-impaired gut function, altered estrogen metabolism and signaling, and aberrant progenitor and stem-cell homeostasis. Although preliminary, antibiotic and probiotic treatments have demonstrated efficacy in treating endometriosis, and female reproductive tract (FRT) microbiota sampling has successfully predicted disease risk and stage. Future research should aim to characterize the “core” upper FRT microbiota and elucidate mechanisms behind the relationship between the microbiota and endometriosis.

Mycoplasma pneumoniae (MP) is a leading cause of pediatric community-acquired pneumonia, with clinical manifestations ranging from self-limiting disease to severe refractory pneumonia and long-term pulmonary sequelae. Three interrelated, partially overlapping yet still contested processes can explain the core pathogenic mechanisms of MP pneumonia (MPP). In the acute phase, immune dysregulation is characterized by excessive cytokine release and abnormal activation of innate and adaptive immune cells; however, the origin and regulation of this excessive inflammation remain controversial. During the immune evasion phase, MP employs multiple escape strategies, including adhesion proteins, CARDS toxins, and genomic plasticity, to circumvent host defenses, establish persistent infections, and further leave hidden dangers for acute phase inflammatory dysregulation and chronic phase structural remodeling. However, the exact molecular mediators remain unclear. Macrolide antibiotics remain the primary clinical treatment; however, therapeutic limitations persist owing to increasing drug resistance and the lack of immunopathological interventions. In the migration phase, sustained immune activation and abnormal repair processes persist even after pathogen clearance, resulting in chronic lung injury and fibrosis, with underlying immunological mechanisms still poorly understood. This review synthesizes current insights into immune dysregulation across the acute-to-chronic spectrum of MPP, identifies unresolved immunopathological bottlenecks, and highlights translational opportunities for immune-targeted interventions beyond antibiotics.