Search Results (21)

Introduction: X-linked agammaglobulinemia (XLA) is a prototypical inborn error of immunity (IEI) caused by mutations in the BTK gene, leading to a profound deficiency of mature B cells and severe pan-hypogammaglobulinemia. The Epstein-Barr virus (EBV), which primarily infects B lymphocytes, is believed to be unable to establish persistence in these patients due to the lack of its natural reservoir. Indeed, current evidence supports that EBV infection is typically refractory in individuals with XLA. Methods: We describe the clinical and molecular characterization of a 10-year-old male patient with genetically confirmed XLA who developed EBV viremia, hemophagocytic lymphohistiocytosis (HLH), and EBV-positive cutaneous T cell lymphoma. Diagnosis was supported by flow cytometry, serology, quantitative PCR, EBER in situ hybridization, histopathology, and whole-exome sequencing. Results: Despite the complete absence of peripheral B cells, EBV was detected in leukocytes and multiple tissues, indicating active infection. The patient developed HLH and a T cell lymphoma with EBER-positive infiltrates. Genetic analysis revealed a nonsense mutation in BTK (1558C>T, R520*), confirming XLA. The clinical course included multiple episodes of neutropenia, viral and bacterial infections, and severe systemic inflammation. Conclusions: This is the first documented case of an XLA patient with confirmed BTK mutation presenting with clinical features more consistent with chronic active EBV infection. These findings challenge the prevailing paradigm that XLA confers protection against EBV-related diseases and further support the possibility of EBV noncanonical reservoirs leading to immune dysregulation. EBV should also be considered in the differential diagnosis of XLA patients presenting with systemic inflammation or lymphoproliferative disease. Full article

Folliculin-interacting protein 1 (FNIP1) is a key regulator of cellular metabolism and immune homeostasis, integrating nutrient signaling with proteostasis. FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D. Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function. Evidence from murine models suggests that FNIP1 loss disrupts immune cell development and mitochondrial homeostasis. However, FNIP1 deficiency in humans remains incompletely characterized, and its full phenotypic spectrum is likely underestimated. Notably, FNIP1-deficient patients exhibit immunological and hematological abnormalities, immune dysregulation, and metabolic perturbations, emphasizing its role in cellular adaptation to stress. Understanding the mechanistic basis of FNIP1 dysfunction in human tissues will be critical for delineating its contributions to immune and metabolic disorders and identifying targeted interventions. Full article

Spinal muscular atrophy (SMA) and severe T- and/or B-cell lymphopenias (STBCL) in the form of severe combined immunodeficiencies (SCID) or X-linked agammaglobulinemia (XLA) are rare but potentially fatal pathologies. In January 2021, we initiated the first pilot study in Spain to evaluate the efficacy of a very early detection technique for SMA and SCID. RT–PCR was performed on prospectively collected dried blood spots (DBSs) from newborns in Western Andalusia (Spain). Internal and external controls (SCID, XLA and SMA) were included. The determination of SMA was relative (positive/negative) and that of TRECs and KRECs was quantitative (copies/punch). A total of 14.035 prospective samples were analysed. All controls were correctly identified while no cases of SMA or SCID/XLA were prospectively identified. DBS analysis of infants with suspected SMA or STBCL that presented to our centre showed pathological values in two cases each for SMA and SCID and one for XLA, all of them being subsequently confirmed genetically. In this prospective pilot study, no infants with SMA or STBCL were detected; however, the technique applied here was shown to be reliable and fast, further supporting the benefits and need to include SMA and SCID in national newborn screening (NBS) programs, as it will allow early supportive and curative therapy. Full article

For many genetic disorders, there are no specific metabolic biomarkers nor analytical methods suitable for newborn population screening, even where highly effective preemptive treatments are available. The direct measurement of signature peptides as a surrogate marker for the protein in dried blood spots (DBSs) has been shown to successfully identify patients with Wilson Disease (WD) and three life-threatening inborn errors of immunity, X-linked agammaglobulinemia (XLA), Wiskott–Aldrich syndrome (WAS), and adenosine deaminase deficiency (ADAD). A novel proteomic-based multiplex assay to detect these four conditions from DBS using high-throughput LC-MS/MS was developed and validated. The clinical validation results showed that the assay can accurately identify patients of targeted disorders from controls. Additionally, 30,024 newborn DBS samples from the Washington State Department of Health Newborn Screening Laboratory have been screened from 2022 to 2024. One true presumptive positive case of WD was found along with three false positive cases. Five false positives for WAS were detected, but all of them were premature and/or low-birth-weight babies and four of them had insufficient DNA for confirmation. The pilot study demonstrates the feasibility and effectiveness of utilizing this multiplexed proteomic assay for newborn screening. Full article

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. Full article

This study delves into the intricate landscape of SARS-CoV-2 vaccine response in immunodeficient patients, focusing on the dynamics of both humoral and cell-mediated immunity. The cohort includes patients with common variable immunodeficiency (CVI), agammaglobulinemia (XLA), and combined immunodeficiency (CI). The findings reveal varying degrees of antibody production, with XLA patients exhibiting no measurable response but displaying a robust T-cell-mediated response. The study emphasizes the importance of considering both arms of the immune system in assessing vaccine immunogenicity, particularly in the context of immunodeficiency. The results challenge conventional measures of vaccine efficacy only based on antibody titers, highlighting the need for a more comprehensive understanding of the immune response in this vulnerable population. This research contributes valuable insights to guide clinical decisions regarding vaccination strategies, booster doses, and overall protection in immunodeficient individuals. Full article

The exact etiopathogenesis of Kawasaki disease (KD), the most common childhood vasculitis, remains unknown; however, an aberrant immune response, possibly triggered by an infectious or environmental agent in genetically predisposed children, is believed to be the underlying pathogenetic mechanism. Patients with inborn errors of immunity (IEI) are predisposed to infections that trigger immune dysregulation due to an imbalance in various arms of the immune system. KD may develop as a complication in both primary and secondary immunodeficiencies. KD may occur either at disease presentation or have a later onset in IEIs. These include X-linked agammaglobulinemia (XLA), selective IgA deficiency, transient hypogammaglobulinemia of infancy; Wiskott–Aldrich syndrome (WAS), hyper IgE syndrome (HIES); chronic granulomatous disease (CGD), innate and intrinsic immunity defects, and autoinflammatory diseases, including PFAPA. Hitherto, the association between KD and IEI is confined to specific case reports and case series and, thus, requires extensive research for a comprehensive understanding of the underlying pathophysiological mechanisms. IEIs may serve as excellent disease models that would open new insights into the disease pathogenesis of children affected with KD. The current review highlights this critical association between KD and IEI supported by published literature. Full article

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in serum immunoglobulins and early-onset infections. Coronavirus Disease-2019 (COVID-19) pneumonia in immunocompromised patients presents clinical and radiological peculiarities which have not yet been completely understood. Very few cases of agammaglobulinemic patients with COVID-19 have been reported since the beginning of the pandemic in February 2020. We report two cases of migrant COVID-19 pneumonia in XLA patients. Full article

We present a unique and unusual case of a male patient diagnosed with two coexisting and typically unassociated X-linked conditions: he was initially diagnosed with X-linked agammaglobulinemia (XLA) followed by a diagnosis of X-linked chronic granulomatous disease (XCGD) and an as of yet unpublished hypomorphic gp91phox variant in the CYBB gene. The latter was tested after the finding of granulomatous gingivitis. Hematopoietic stem cell transplant (HSCT) was performed due to severe colitis and nodular regenerative hyperplasia (NRH) of the liver. Following transplant, complete donor engraftment was observed with the restoration of a normal oxidative burst and full restoration of normal levels of circulating, mature CD19+ B cells. This case is singular in that it does not involve a contiguous gene syndrome in which deleted genes are in close proximity to either BTK and CYBB, which has been previously reported. To our knowledge, this is the first reported case of XLA and XCGD co-existing in a single patient and of having both inborn errors of immunity successfully treated by HSCT. Full article

Primary antibody deficiencies (PADs) are the most frequent group of inborn errors of immunity. Impaired B-cell development, reduced production of immunoglobulins (mainly IgG and IgA), and specific antibodies resulting in recurrent infections are their hallmarks. Infections typically affect the respiratory tract; however, gastrointestinal involvement is also common. These include infection with Helicobacter pylori, Salmonella, Campylobacter species, Giardia, and noroviruses. Impaired IgA production also contributes to dysbiosis and thereby an increase in abundance of species with proinflammatory properties, resulting in immune system dysregulation. Dysregulation of the immune system results in a broad spectrum of non-infectious manifestations, including autoimmune, lymphoproliferative, and granulomatous complications. Additionally, it increases the risk of malignancy, which may be present in more than half of patients with PADs. Higher prevalence is often seen in monogenic causes, and gastrointestinal involvement may clinically mimic various conditions including inflammatory bowel diseases and celiac disease but possess different immunological features and response to standard treatment, which make diagnosis and therapy challenging. The spectrum of malignancies includes gastric cancer and lymphoma. Thus, non-infectious manifestations significantly affect mortality and morbidity. In this overview, we provide a comprehensive insight into the epidemiology, genetic background, pathophysiology, and clinical manifestations of infectious and non-infectious complications. Full article

Introduction: Inborn errors of immunity (IEI) represent a heterogeneous group of diseases in which the true prevalence of GI involvement is not well-known. This study evaluates the prevalence of lower GI manifestations in patients with common variable immunodeficiency (CVID), analysing the histologic findings in colonic samples and assessing any correlations with biochemical abnormalities. Materials and Methods: A retrospective study was performed by collecting the data of IEI adult patients followed up at two main Northern Italian centres. Demographic and clinical data, and blood tests were collected. A colonoscopy with multiple biopsies in standard sites, in addition to a biopsy for any macroscopic lesion, was performed. The gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome (GSRS-IBS) and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) were used to assess GI symptoms. Results: 141 patients were included: 121 (86.5%) with CVID, 17 (12.1%) with IgG subclass deficiency, and 2 (1.4%) with X-linked agammaglobulinemia. Of the patients, 72 (51%) complained of GI symptoms. No differences were seen between patients receiving or not IgRT. GI infections were found in 9 patients (6.4%). No significant correlations were found between gut infections and symptoms or leukocyte infiltrates. Colonoscopy alterations were present in 79 patients (56%), and the most common were colon polyps (42%). Microscopical abnormalities were seen in 60 histologic samples (42.5%) and the most frequent was nodular lymphoid hyperplasia (40%). A leukocyte infiltrate was present in 67 samples (47.5%), and the most common was a lymphocyte infiltrate (33%). No correlation was found between GI symptoms and macroscopic alterations, whereas a positive correlation between symptoms and microscopic alterations was detected. Conclusions: GI symptoms and microscopic alterations in colon samples are closely related; hence, it is important to carry out serial colonic biopsies in every CVID patient, even in the absence of macroscopic lesions. Full article

We describe the first case of infection with Helicobacter trogontum in a patient with X-linked agammaglobulinemia. A 22-year-old male with X-linked agammaglobulinemia presented with fever, malaise and a painful skin lesion on the lower left extremity. Spiral shaped Gram-negative rods were isolated from blood cultures and later identified as Helicobacter trogontum. The patient was treated with various intravenous and oral antibiotic regimens over a period of 10 months, each causing seemingly full clinical and paraclinical remission, yet several episodes of relapse occurred after cessation of antibiotic treatment. The review of the literature showed that only a few cases of infections with enterohepatic helicobacters belonging to the Flexispira rappini taxons have previously been reported. The majority of cases included patients with X-linked agammaglobulinemia and the symptomatology and course of disease were similar to the case described here. Infections with enterohepatic helicobacters, including Helicobacter trogontum, should be considered in patients with X-linked agammaglobulinemia presenting with fever, malaise and skin lesions. Careful cultivation and microbiological investigation are essential to determine the diagnosis and a long treatment period of over 6 months must be expected for successful eradication. Full article

X-linked agammaglobulinemia (XLA) is a hereditary immune disorder that predisposes patients to frequent and severe bacterial infections caused by encapsulated bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae). Otitis media, sinusitis, and pneumonia are common complications of XLA that require prompt diagnosis and treatment. Cytomegaloviruses (CMV) cause widespread and severe infections in immunocompromised individuals, affecting the respiratory tract, and consequently, leading to pneumonia, which is associated with a high mortality rate. However, CMV-induced pneumonia is rarely reported in patients with XLA. This case study details a 37-year-old male patient with XLA presenting with fever, productive cough, and dyspnea. The patient was diagnosed with CMV pneumonia and recovered after treatment. To the best of our knowledge, this is the first reported case of CMV pneumonia in a patient with XLA in Taiwan. This case study emphasizes that CMV pneumonia in patients with XLA is a treatable condition if diagnosed promptly, and that a shorter duration of treatment with the antiviral agent, in combination with immunoglobulin replacement therapy, can resolve symptoms. Full article

During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity. Full article

Primary antibody deficiencies (PADs) are the most common primary immunodeficiencies (PIDs). They can be divided into the following groups, depending on their immunological features: agammaglobulinemia; common variable immunodeficiency (CVID) isotype; hyper IgM isotype; light chain or functional deficiencies with normal B cell count; specific antibody deficiency with normal Ig concentrations and normal numbers of B cells and transient hypogammaglobulinemia of infancy. The role of vaccination in PADs is recognized as therapeutic, diagnostic and prognostic and may be used in patients with residual B-cell function to provide humoral immunity to specific infective agents. According to their content and mechanisms, vaccines are grouped as live attenuated, inactivated (conjugated, polysaccharide), mRNA or replication-deficient vector vaccines. Vaccination may be unsafe or less effective when using certain vaccines and in specific types of immunodeficiency. Inactivated vaccines can be administered in PAD patients even if they could not generate a protective response; live attenuated vaccines are not recommended in major antibody deficiencies. From December 2020, European Medicines Agency (EMA) approved vaccines against COVID-19 infection: according to ESID advises, those vaccinations are recommended in patients with PADs. No specific data are available on safety and efficacy in PAD patients. Full article