Journal of Clinical Immunology最新文献

Early diagnosis of inborn errors of immunity (IEIs) has been shown to reduce mortality, morbidity, and healthcare costs. The need for early diagnosis has led to the development of computational tools that trigger earlier clinical suspicion by physicians. Primary care professionals serve as the first line for improving early diagnosis. To this end, a computer-based tool (based on extended Jeffrey Modell Foundation (JMF) Warning Signs) was developed to assist physicians with diagnosis decisions for IEIs in the primary care setting. Two expert-guided scoring systems (one pediatric, one adult) were developed. IEI warning signs were identified and a panel of 36 experts reached a consensus on which signs to include and how they should be weighted. The resulting scoring system was tested against a retrospective registry of patients with confirmed IEI using primary care EHRs. A pilot study to assess the feasibility of implementation in primary care was conducted. The scoring system includes 27 warning signs for pediatric patients and 24 for adults, adding additional clinically relevant criteria established by expert consensus to the JMF Warning Signs. Cytopenias, ≥ 2 systemic infections, recurrent fever and bronchiectasis were the leading warning signs in children, as bronchiectasis, autoimmune diseases, cytopenias, and > 3 pneumonias were in adults. The PIDCAP (Primary Immune Deficiency "Centre d'Atenció Primària" that stands for Primary Care Center in Catalan) tool was implemented in the primary care workstation in a pilot area. The expert-based approach has the potential to lessen under-reporting and minimize diagnostic delays of IEIs. It can be seamlessly integrated into clinical primary care workstations.

X-linked agammaglobulinemia (XLA) due to a mutation in Bruton's tyrosine kinase (BTK), leads to the arrested development of B cells at the pro-B cell stage. This results in absent B cells and severe hypogammaglobulinemia. XLA patients usually present with recurrent sinopulmonary infection. Bacterial infections are the commonest [2], fungal infections like Pneumocystis jirovecii, Aspergillus and Candida species are rarely reported and they are associated with mortality in XLA [3]. We report a 3.5-year-old boy with disseminated aspergillosis, an uncommon presentation of XLA. Despite treatment with antifungals, including voriconazole and amphotericin B, the patient succumbed to the illness. Genetic analysis revealed a pathogenic variant in the BTK gene (R28H), confirming XLA diagnosis. This case highlights the potential for severe fungal infections in XLA patients and suggests broader immune system dysregulation beyond B-cell defects.

Inborn errors of immunity (IEI) are a heterogeneous group of genetic diseases characterized by impaired immune system function. This prospective study aimed to determine the frequency, characteristics, and clinical course of IEI patients admitted to the pediatric intensive care unit (PICU) and identify mortality-related factors. Using a comprehensive immunological evaluation protocol, we screened 753 PICU admissions for potential IEIs during three years. Patients with pre-existing IEI diagnoses, chronic diseases, ongoing chronic medication regimens, other known comorbidities, trauma cases, post-surgical cases, and poisonings were excluded. Thirty-three patients were newly diagnosed with IEIs during or as a result of their PICU stay, representing an incidence of 4.39%. The most common disorders were immunodeficiencies with immune dysregulation (48.5%), followed by combined immunodeficiencies (24.2%). Severe viral infections (61%) and life-threatening infections (51.7%) were the most frequent warning signs. Only 31% of patients exhibited at least two Jeffrey Modell Foundation warning signs. The mortality rate was 58%, highlighting the need for early diagnosis and treatment. Newborn screening and family segregation studies are crucial to improving outcomes for IEI patients in intensive care settings.

Objective: FAS gene defects lead to autoimmune lymphoproliferative syndrome (ALPS), which is often inherited in an autosomal dominant and rarely in an autosomal recessive manner. We report a case of a newborn girl with novel compound heterozygous variants in FAS and reveal the underlying mechanism.

Methods: Whole-exome sequencing (WES) was used to identify pathogenic variants. Multiparametric flow cytometry analysis, phosflow analysis, and FAS-induced apoptosis assays were used to explore the effects of the variants on FAS expression, apoptosis, and immunophenotype. The HEK293T cells were used to assess the impact of the variants on protein expression and FAS-induced apoptosis.

Results: The patient was born with hepatosplenomegaly, anemia, and thrombocytopenia. She also experienced COVID-19, rotavirus infection, herpes simplex virus infection, and severe pneumonia. The proportion of double-negative T cells (DNTs) was significantly elevated. Novel FAS compound heterozygous variants c.310T > A (p.C104S) and c.702_704del (p.T235del) were identified. The apoptotic ability of T cells was defective, and FAS expression on the surface of T cells was deficient. The T235del variant decreased FAS expression, and the C104S protein remained in the endoplasmic reticulum (ER) and could not translocate to the cell surface. Both mutations resulted in loss-of-function in terms of FAS-induced apoptosis in HEK293T cells. The DNTs were mainly terminally differentiated T (TEMRA) and CD45RA⁺HLA-DR⁺, with high expression of CD85j, PD-1, and CD57. The percentage of Th1, Tfh, and autoreactive B cells were significantly increased in the patient. The abnormal immunophenotyping was partially attenuated by sirolimus treatment.

Conclusions: We identified two variants that significantly affect FAS expression or localization, leading to early disease onset of in the fetus. Abnormalities in the mTOR pathway are associated with a favorable response to sirolimus.

Granulomatous disease affects up to 20% of patients with Common Variable Immunodeficiency (CVID). Granulomas are comprised of highly activated immune cells, and emerge in response to antigenic triggers. In CVID granulomas however, the underlying pathophysiology is unclear and the specific trigger remains unknown. Granuloma formation in CVID is often compared to sarcoidosis, although clinical context and prognosis differ, suggesting a different pathogenesis. The aim of this study was to investigate if the cellular organization and proteomics of granulomas in CVID is different from other granulomatous diseases. Therefore, tissue slides from formaldehyde fixed paraffin embedded biopsies obtained from patients with CVID, sarcoidosis, tuberculosis and foreign-material induced pseudo-sarcoidosis were stained with hematoxylin and eosin and assessed for histopathological characteristics. Targeted spatial protein analysis was performed, and immune fluorescent multiplex assays were used to analyze the cellular organization. Histological analysis revealed that CVID granulomas were smaller, less circumscribed, with fewer multinucleated giant cells and minimal fibrosis compared to the other granulomatous diseases. Spatial protein analysis showed that granulomas in all diseases expressed CD68, CD11c, CD44, CD127, and PD-L1. However in CVID, reduced expression of the fibrosis-related protein fibronectin, but enrichment of CD163, CD3 and FAPα inside CVID granulomas was observed. Immunofluorescence analysis conformed a different cellular organization in CVID granulomas with increased influx of neutrophils, macrophages, T and B lymphocytes. In conclusion, granulomas in CVID display a different histological and cellular organization with increased influx of myeloid and lymphoid cells, compared to sarcoidosis, tuberculosis and pseudo-sarcoidosis, indicating a distinct pathogenesis underlying granuloma formation.

Background: ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy.

Objective: To characterize the laboratory and molecular features of two patients from different families affected by the same ISG15 variant.

Methods: We began with clinical characterization and investigation, assessed IL-12/IFN-γ production, performed genetic characterization through WES and Sanger sequencing, conducted an in silico molecular analysis of the genetic ISG15 variant's protein impact, and utilized RNAseq for transcriptome analysis to understand pathway impacts on ISG15-deficient subjects from unrelated families.

Results: A mutation in the ISG15 gene was identified, affecting two patients treated in different hospitals and cities in Brazil (Fortaleza and Sao Paulo), who are also members of unrelated families. Both patients showed low IFN-γ production when stimulated with BCG or BCG + IL-12. ISG15 deficiency presented with two distinct clinical phenotypes: infectious and neurological. It was identified that both patients are homozygous for the variant (c.83 T > A). Furthermore, it was observed that the mutant protein p.L28Q results in an unstable protein with increased flexibility (ΔΔG: -2.400 kcal/mol). Transcriptome analysis revealed 1321 differentially expressed genes, with significant upregulation in interferon pathways, showing higher expression in patients compared to controls.

Conclusion: This study describes the first reported cases in Brazil of two unrelated patients with the same ISG15 mutation c.83 T > A, exhibiting infectious features such as mycobacterial infections and systemic candidiasis, neurological findings, and skin lesions, without adverse reactions to the BCG vaccine.

Clinical implications: Reporting ISG15 gene mutations in Brazilian patients enhances understanding of genetic susceptibilities, guiding effective diagnostics and treatment. Identifying high-risk individuals aids clinical practices, genetic counseling, and influences public health policies. We have identified the first case in Brazil of the same ISG15 variant c.83 T > A that was identified in two unrelated patients with distinct clinical phenotypes, infectious and neurological.

Introduction: This study investigates the frequency of hospital attendances, emergency care attendances and geographical influences on service interaction in cohorts of patients with primary and secondary antibody deficiency, to inform future service planning and delivery.

Methods: The COVID-19 in Antibody Deficiency (COV-AD) study was a United Kingdom study that enrolled 525 participants between April 2021 and September 2022. Data on health care utilisation was extracted from a screening cohort of participants at one participating site (Birmingham, UK). Hospital attendance (i.e. all outpatient and inpatient care episodes, including hospital-based IVIG treatment) and emergency care attendance patterns were analysed. Geographical differences in travel times to hospitals and associated costs were considered for all participants at all recruiting sites.

Results: Individuals with antibody deficiency had a median of 7 hospital attendances per year. A diagnosis of secondary antibody deficiency, and antibody deficiency severe enough to require treatment with immunoglobulin replacement were associated with an increased frequency of hospital attendance. 12.7% of the cohort attended the Emergency Department at least once in the preceding twelve months. Individuals with secondary antibody deficiency were at greater risk of requiring emergency care over the preceding one-year and five-year periods. Individuals receiving subcutaneous immunoglobulin lived further from their local immunology centre and were more likely to engage with the COV-AD research study remotely, via dried blood spots sampling.

Conclusion: This study highlights the utilisation of emergency and secondary care usage amongst patient with immunodeficiency and may inform service adaptation and development to better accommodate patient needs and circumstances.

Background: Talaromyces marneffei (T. marneffei) is an opportunistic pathogen that causes endemic mycoses, which could lead to multiple organ damage. Talaromycosis is frequently disregarded as an early cautionary sign of immune system disorders in non-HIV-infected children.

Objective: We conduct a comprehensive review of the genotypes and clinical features of talaromycosis in patients with IEI to enhance clinical awareness regarding T. marneffei as a potential opportunistic pathogen in individuals with immune deficiencies.

Methods: A systematic literature review was performed by searching PubMed, Cochrane Central Register of Controlled Trials, Web of Science, EMBASE, and Scopus. Data on IEI patients with talaromycosis, including genotypes and their immunological and clinical features, were collected.

Results: Fifty patients with talaromycosis and IEI were included: XHIM (30.0%), STAT3-LOF deficiency (20.0%), STAT1-GOF (20.0%), IL2RG (6.00%), IFNGR1 (6.0%), IL12RB1 (4.0%), CARD9 (4.0%), COPA (4.0%), ADA (2.0%), RELB deficiency (2.0%), and NFKB2 (2.0%). Common symptoms of respiratory (43/50, 86.0%), skin (17/50, 34.0%), lymph node (31/50, 62.0%), digestive (34/50, 68.0%), and hematologic (22/50, 44.0%) systems were involved. The CT findings of the lungs may include lymph node calcification (9/30), interstitial lesions (8/30), pulmonary cavities (8/30), or specific pathogens (4/30), which could be easily misdiagnosed as tuberculosis infection. Amphotericin B (26/43), Voriconazole (24/43) and Itraconazole (22/43) were used for induction therapy. Ten patients were treated with Itraconazole sequentially and prophylaxis. 68.0% (34/50) of patients were still alive, and 4.0% (2/50) of were lost to follow-up. The disseminated T. marneffei infection resulted in the deaths of 14 individuals.

Conclusions: The XHIM, STAT1-GOF, and STAT3-LOF demonstrated the highest susceptibility to talaromycosis, indicating the potential involvement of cellular immunity, IL-17 signaling, and the IL-12/IFN-γ axis in T. marneffei defense. T. marneffei infection may serve as an early warning indicator of IEI. For IEI patients suspected of T. marneffei, metagenomic next-generation sequencing (mNGS) could rapidly and effectively identify the causative pathogen. Prompt initiation of antifungal therapy is crucial for optimizing patient outcomes.