Manish Butte

Front Immunol. 2025 Feb 5;16:1492751. doi: 10.3389/fimmu.2025.1492751. eCollection 2025.

ABSTRACT

INTRODUCTION: Primary immunodeficiencies (PIDs) are a group of rare genetic disorders characterized by dysfunction of the immune system components. Early diagnosis and treatment are essential to prevent severe or life-threatening complications. PIDs are manifested by diverse clinical symptoms, posing challenges for accurate diagnosis. A key aspect of PID diagnosis is identifying specific amino acid substitutions in the proteins related with heritable diseases. In this study, we have developed classification sequence-structure-property relationships (SSPR) models for predicting the pathogenicity of amino acid substitutions (AAS) in 25 proteins associated with the most important and genetically studied PIDs and encoded genes: IL2RG, JAK3, RAG1, RAG2, ADA, DCLRE1C, CD40LG, WAS, ATM, STAT3, KMT2D, BTK, FOXP3, AIRE, FAS, ELANE, ITGB2, CYBB, G6PD, GATA2, STAT1, IFIH1, NLRP3, MEFV, and SERPING1.

METHODS: The data on 4825 pathogenic and benign AASs in the selected proteins were extracted from ClinVar and gnomAD. SSPR models were created for each protein using the MultiPASS software based on the Bayesian algorithm and different levels of MNA (Multilevel Neighborhoods of Atoms) descriptors for the representation of structural formulas of protein fragments including AAS.

RESULTS: The accuracy of prediction was assessed through a 5-fold cross-validation and compared to other bioinformatics tools, such as SIFT4G, Polyphen2 HDIV, FATHMM, MetaSVM, PROVEAN, ClinPred, and Alpha Missense. The best SSPR models demonstrated high accuracy, with an average ROC AUC of 0.831 ± 0.037, a Balanced accuracy of (0.763 ± 0.034), MCC (0.457 ± 0.06), and F-measure (0.623 ± 0.07) across all genes, outperforming the most popular bioinformatics tools.

CONCLUSIONS: The best created SSPR models for the prediction of pathogenicity of amino acid substitutions related with PIDs have been implemented in a freely available web application SAV-Pred (Single Amino acid Variants Predictor, http://www.way2drug.com/SAV-Pred/), which may be a useful tool for medical geneticists and clinicians. The use of SAV-Pred for some clinical cases of PIDs are provided.

PMID:39975544 | PMC:PMC11835853 | DOI:10.3389/fimmu.2025.1492751

Front Immunol. 2025 Feb 4;16:1495666. doi: 10.3389/fimmu.2025.1495666. eCollection 2025.

ABSTRACT

Wiskott-Aldrich syndrome (WAS) is a condition characterized by a low platelet count, eczema, and a weakened immune system. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option. Haploidentical HSCT with posttransplant cyclophosphamide (PTCy) is an emerging approach for children with noncancerous conditions. This case describes a WAS patient who was early diagnosed and successfully treated with haploidentical HSCT. A 3-month-old boy presented with widespread eczema, a low platelet count, and severe infections in infancy. The diagnosis of WAS was quickly confirmed by genetic test. He received immunoglobulin replacement therapy and antimicrobial prophylaxis and underwent HSCT at 4 years 3 months of age. After failed unrelated cord blood HSCT, second rescue haploidentical HSCT had been performed using the patient’s mother as the donor, with stem cells collected from peripheral blood. The conditioning regimen included anti-thymocyte globulin, melphalan, and fludarabine. The stem cell dose was 2.63 × 106 CD34+ cells/kg. GVHD prevention included PTCy, mycophenolat mofetil, and tacrolimus. The patient had no significant complications after the transplant. Neutrophil and platelet engraftment occurred promptly. At 32 months post-HSCT, the patient had complete hematological and immune reconstitution, with full donor chimerism and no GVHD. In conclusion, the PTCy approach to haploidentical HSCT was a safe and effective treatment for this WAS patient.

PMID:39967667 | PMC:PMC11832547 | DOI:10.3389/fimmu.2025.1495666

Front Immunol. 2025 Jan 31;16:1517417. doi: 10.3389/fimmu.2025.1517417. eCollection 2025.

ABSTRACT

Immunodeficiency, centromeric instability, and facial anomalies syndrome (ICF) is a rare genetic disease characterized by hypogammaglobulinemia, T cell immune deficiency with age, pericentromeric hypomethylation, facial abnormalities, and intellectual disability. This study aimed to investigate the phenotype and immune function of a girl with ICF2, identify her genetic defect, and explore the potential pathogenic mechanisms of the disease. We identified a homologous deletion mutation in this girl, which involves exons 1-5 and part of introns 1 and 6 of the ZBTB24 gene (NG_029388.1: g.2831_18,995del). This ZBTB24 variant produces a severely truncated ZBTB24 protein that lacks the BTB, A-T hook and eight zinc fingers. The above changes may lead to abnormal transcriptional function of the ZBTB24 protein. Karyotype analysis showed fragile sites and entire arm deletions were detected on chromosomes 1 and 16 and triradials on chromosome 16. The novel multi-exon deletion of ZBTB24 causes immunodeficiency, severe pneumonia and centromeric instability in the patient. During the follow-up, the patient’s pneumonia continued to progress despite receiving intravenous immunoglobulin (IVIG) replacement and anti-infective therapy. These results indicated that this novel multi-exon deletion variant of ZBTB24 may be the genetic etiology of ICF2. The discovery of this novel mutation expands the mutation spectrum of the ZBTB24 gene and improves our understanding of the molecular mechanisms underlying ICF.

PMID:39958354 | PMC:PMC11825828 | DOI:10.3389/fimmu.2025.1517417

J Allergy Clin Immunol. 2025 Feb 14:S0091-6749(25)00166-6. doi: 10.1016/j.jaci.2025.02.004. Online ahead of print.

ABSTRACT

BACKGROUND: Generative artificial intelligence (GAI) is transforming healthcare in a variety of ways; however, present utility of GAI for supporting clinicians in rare disease such as primary immune disorders (PI) is not well studied. Here we evaluate the ability of 6 state-of-the-art large language models (LLMs) for providing clinical guidance about PI.

OBJECTIVE: We sought to quantitatively and qualitatively measure the utility of current, open-source LLMs for diagnosing and providing helpful clinical decision support about PI.

METHODS: Five expert clinical immunologists provided 5 real-world (n=25), anonymized PI case vignettes via multi-turn prompting to 6 LLMs (OpenAI GPT-4o, Llama-3.1-8B-Instruct, Llama-3.1-70B-Instruct, Mistral-7B-Instruct-v0.3, Mistral-Large-Instruct-2407, and Mixtral-8x7B-Instruct-v0.1). We assessed the diagnostic accuracy of the LLMs and the quality of clinical reasoning using the Revised-IDEA (R-IDEA) score. Qualitative LLM assessment was made by immunologist narratives.

RESULTS: Performance accuracy (>88%) and R-IDEA scores (>=8) were superior for 3 models (GPT-4o, Llama-3.1-70B-Instruct, Mistral-Large-Instruct-2407), with GPT-4o achieving the highest diagnostic accuracy (96.2%). Conversely, the remaining 3 models fell below acceptable accuracy rates near 60% or worse and poor R-IDEA scores (<=0.55), with Mistral-7B-Instruct-v0.3 attaining the worst diagnostic accuracy (42.3%). Compared with the 3 best-performing LLMs, the 3 worst-performing LLMs received a substantially lower median R-IDEA score (p<0.001). Interclass correlation coefficient for R-IDEA score assignments varied substantially by LLM, ranging from good to poor agreement, and did not appear to correlate with either diagnostic accuracy or the median R-IDEA score. Qualitatively, immunologists identified several themes (e.g. correctness, differential diagnosis appropriateness, relative conciseness of explanations) of relevance to PI.

CONCLUSIONS: LLM can support the diagnosis and management of PI; however, further tuning is needed to optimize LLMs for best practice recommendations.

PMID:39956279 | DOI:10.1016/j.jaci.2025.02.004

J Pediatr Endocrinol Metab. 2025 Feb 17. doi: 10.1515/jpem-2024-0510. Online ahead of print.

ABSTRACT

OBJECTIVES: DNA ligase IV (LIG4) deficiency is a rare autosomal recessive disorder associated with impaired DNA damage-response mechanisms. LIG4 deficiency exhibits a broad clinical spectrum, including microcephaly, facial abnormalities, sensitivity to ionizing radiation, ranging from severe combined immunodeficiency to normal immune function, progressive bone marrow failure, and predisposition to malignancy.

CASE PRESENTATION: We report an 18-year-old girl of consanguineous Turkish parents, first evaluated at 13 years old for growth retardation and short stature. She was born preterm at 32 weeks with dysmorphic facial features, lissencephaly, intellectual disability, and without immunodeficiency. Although diagnosed with growth hormone deficiency, she did not receive appropriate hormone therapy due to special circumstances. At the age of 15, she presented with primary amenorrhea. Further evaluation revealed hypergonadotropic hypogonadism due to gonadal failure. Genetic analysis revealed a homozygous c.2440C>T (p.Arg814Ter) mutation in the LIG4 gene. Following genetic counseling, her parents opted for prenatal diagnosis in a subsequent pregnancy, resulting in the birth of another child with the same condition.

CONCLUSIONS: LIG4 syndrome should be considered in the differential diagnosis of cases with growth retardation, microcephaly, and gonadal failure. In the literature, there are limited cases reported with gonadal failure in LIG4 syndrome. Here, we emphasize this aspect to highlight its significance.

PMID:39953892 | DOI:10.1515/jpem-2024-0510

Health Qual Life Outcomes. 2025 Feb 13;23(1):12. doi: 10.1186/s12955-025-02342-6.

ABSTRACT

BACKGROUND: Hereditary angioedema (HAE) adversely affects health-related quality of life (HRQoL). HAE often compromises the HRQoL due to the impact on functional capacity caused by edema, pain, other symptoms, and psychosocial factors. Patient-Reported Outcome Measures (PROMs) focus on HRQoL and are crucial tools for evaluating the burden of the disease and choosing the most appropriate interventions for this population. However, no comprehensive evaluations of the characteristics of the available measurements to assess HRQoL have been conducted for this population.

AIM: To identify, analyze, and summarize the PROMs assessing HRQoL in individuals with HAE-C1-INH, addressing the gap in standardized assessment tools.

METHODS: A systematic review was conducted up to December 2023 in PubMed, Scopus, Web of Science, Embase, and CINAHL databases, following PRISMA guidelines without language or time restrictions. Psychometric properties of the identified PROMs were appraised using COSMIN standards, and evidence was synthesized using a modified GRADE approach.

RESULTS: From seven studies, five HRQoL PROMs were identified: two generic (SF-36 and SF-36v2) and three disease-specific (HAE-QoL, HAEA-QoL, and AE-QoL). These PROMs generally lacked comprehensive content, structural and cross-cultural validation, with none meeting the criteria for measurement invariance. This limitation affects their applicability across different demographics and cultures. However, the HAE-QoL and AE-QoL instruments were recognized for having moderate quality evidence, suggesting their potential reliability and validity.

CONCLUSIONS: This systematic review provides a moderate recommendation for the use of HAE-QoL and AE-QoL in assessing HRQoL in adults with HAE. Despite identified gaps, the moderate evidence quality for these tools supports their use, pending further validation, involving younger age groups and disease-specific contents in the assessments. Developing culturally and demographically adaptable PROMs is, therefore, a priority to improve the accuracy of PROMs in this field.

REVIEW REGISTRATION NUMBER: PROSPERO registration number is CRD42023440137.

PMID:39948647 | DOI:10.1186/s12955-025-02342-6

Rev Med Liege. 2025 Feb;80(2):116-121.

ABSTRACT

Non-tuberculous mycobacterial (NTM) infections present a major challenge in both diagnosis and treatment. The management of NTM varies based on the species involved and the host’s risks factors. With their prevalence continuing to rise, healthcare professionals are likely to encounter these infections more often in the years ahead. It is therefore essential to be aware of the predominant NTM species in our environment, as well as the associated risk factors. In this context, we present a study conducted at the University Hospital of Liège between 2016 and 2020, aimed at identifying the NTM species responsible for infections in the Liège area. We also explore the immune mechanisms involved in fighting these infections, focusing on primary immunodeficiencies that should be considered in adult patients with NTM infections.

PMID:39950527

Vaccine. 2025 Feb 12;51:126853. doi: 10.1016/j.vaccine.2025.126853. Online ahead of print.

ABSTRACT

The COVID-19 pandemic has significantly impacted immunocompromised patients, particularly those with inborn errors of immunity (IEI), transplant recipients, hematologic malignancies, and those undergoing treatment with immunosuppressive biologics and medications. These patients face an elevated risk of experiencing severe or even fatal consequences following SARS-CoV-2 infections. Vaccination is the primary defense against COVID-19; however, immune responses following immunization are often suboptimal in these patients, with variable specific humoral response rates. Despite the expedited regulatory approval and the widespread implementation of COVID-19 vaccines, the efficacy and safety for immunocompromised populations require thorough investigation. In future pandemics, including vulnerable populations (VPs) in vaccine and monoclonal antibody (mAb) trials is crucial to develop safe, effective immunization strategies, address gaps in vaccine efficacy and safety data, and create tailored guidelines for at-risk groups. This review provides a comprehensive examination of the efficacy of COVID-19 vaccines and mAbs in patients with primary and secondary immunodeficiency, with a specific focus on individuals with IEI, considering previous regulatory aspects and the necessity of including VPs in vaccine trials to enhance the quality of patient care and promote equitable health outcomes in future pandemics.

PMID:39946827 | DOI:10.1016/j.vaccine.2025.126853

Proc Natl Acad Sci U S A. 2025 Feb 18;122(7):e2420802122. doi: 10.1073/pnas.2420802122. Epub 2025 Feb 13.

ABSTRACT

Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1-deficient mice exhibit altered splicing of Ripk1. As a result, Raver1-deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1. Consequently, Raver1-deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.

PMID:39946533 | DOI:10.1073/pnas.2420802122

J Clin Immunol. 2025 Feb 13;45(1):75. doi: 10.1007/s10875-025-01858-2.

ABSTRACT

Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially resulting in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as an influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with RS.

PMID:39945898 | DOI:10.1007/s10875-025-01858-2