Manish Butte

J Clin Immunol. 2025 Feb 11;45(1):74. doi: 10.1007/s10875-025-01863-5.

ABSTRACT

Reticular dysgenesis (RD) is a rare inborn error of immune cell formation defined by severe combined immunodeficiency, agranulocytosis and sensorineural deafness. We report a case of successful haploidentical maternal hematopoietic stem cell transplantation (HSCT) in a boy with RD detected by TREC newborn screening. The patient was admitted to our hospital at 2 weeks of age and was kept in laminar-air flow / hepa-filtered isolation until HSCT was performed at 8 weeks of age with a busulfan, fludarabine conditioning regime. Except few episodes of acute skin graft-versus-host disease (aGVHD) the peritransplant period was uneventful. The patient was discharged 7 weeks post-HSCT. At 18 months of age cochlear implants were placed. The patient was thriving well, showed full donor chimerism and a T cell count > 1000 TCRab + CD3 + cells/µl after one year. Our case highlights that severely immune-compromised patients with RD benefit from early diagnosis by newborn screening, immediate isolation to prevent infections, and early haploidentical HSCT to overcome neonatal neutropenia and establish protective immunity.

PMID:39932644 | DOI:10.1007/s10875-025-01863-5

Ocul Immunol Inflamm. 2025 Feb 11:1-4. doi: 10.1080/09273948.2025.2461240. Online ahead of print.

ABSTRACT

PURPOSE: To present a unique case of recurrent panuveitis in a young patient associated with a novel pathogenic variant in the PIK3CD gene, expanding the clinical spectrum of Activated PIK3 delta syndrome (APDS), a primary immunodeficiency that predisposes individuals to infections, autoimmunity, and malignancies.

METHODS: We evaluated a 15-year-old boy with refractory panuveitis, recurrent infections, and lymphadenopathy with Hodgkin lymphoma. Ophthalmic assessment and ultra-wide field fundus fluorescein angiography were conducted. Whole exome sequencing identified a novel heterozygous pathogenic variant in the PIK3CD gene. Immunological and histopathological evaluations further supported the diagnosis of APDS.

RESULTS: The patient experienced progressive vision loss despite immunosuppressive therapy with prednisolone, methotrexate, and mycophenolate mofetil. Genetic testing revealed a novel PIK3CD pathogenic variant (c.1002C>G;p.Asn334Lys), confirmed via Sanger sequencing and predicted by in-silico tools to be pathogenic. Initial improvement was observed with steroids, but frequent relapses upon tapering underscored the chronicity of his inflammatory condition.

CONCLUSION: This case underscores the importance of genetic testing in diagnosing complex, treatment-resistant uveitis in children. The novel PIK3CD pathogenic variant expands the genetic landscape of APDS, indicating the need to consider underlying genetic causes in cases with recurrent systemic inflammation and infections. Managing APDS requires a careful balance of immunosuppressive treatment and monitoring for potential malignancies, emphasizing a multidisciplinary approach to optimize patient outcomes.

PMID:39932361 | DOI:10.1080/09273948.2025.2461240

J Clin Immunol. 2025 Feb 10;45(1):73. doi: 10.1007/s10875-025-01867-1.

ABSTRACT

Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF). STAT3 N-terminal domain (NTD) mutations are rare, and their biological effects remain incompletely understood. We explored the significance of STAT3 NTD p.Trp37* variant in a patient with chronic pulmonary aspergillosis and a low Hyper-IgE syndrome (HIES) score. In cell culture models, the expression of full-length p.Trp37* allele showed shorter STAT3 protein expression suggesting a re-initiation (Met99 or Met143). STAT3 activity using luciferase reporter assay showed a twofold-increased activity of the STAT3 p.Trp37* STAT3 protein compared with WT STAT3 at basal level and upon IL-6 stimulation. In contrast, the activity of the short pTrp37* peptide (amino acids 1 to 37) was amorphic but without dominant negative (DN) effect on transcriptional activity or STAT3 Tyr705 phosphorylation. The proteins initiated at Met99 and Met143 were surprisingly hypermorphic. In carriers’ peripheral blood mononuclear cells (PBMCs), both WT and mutated STAT3 mRNA were equally present and the global amount of STAT3 protein was not significantly reduced. In stimulated heterozygous carriers’ PBMCs, however, STAT3 Tyr705 phosphorylation and Th17 were reduced but not completely abolished. This suggests a DN effect of an unknown product of the p.Trp37* allele. Transcriptomics analysis of PBMCs from the index revealed selectively distinct gene expression. We conclude that heterozygosity for the NTD p.Trp37* STAT3 mutation defines a novel allelic form of STAT3 deficiency, associated with a chronic pulmonary aspergillosis and minor signs of HIES.

PMID:39928202 | DOI:10.1007/s10875-025-01867-1

Gastroenterology. 2025 Feb 10:S0016-5085(24)05694-4. doi: 10.1053/j.gastro.2024.08.046. Online ahead of print.

ABSTRACT

The risk of microbial infections is increased in cirrhosis and other forms of advanced liver disease such as alcohol-associated hepatitis. Such infections may precipitate new or further decompensation and death, especially in patients with clinical features of acute-on-chronic liver failure. The severe immune dysfunction or “immune paralysis” caused by advanced liver disease is associated with high short-term mortality. However, the pathogenic mechanisms underlying immune dysfunction and immunodeficiency are incompletely understood. Evidence to date suggests a complex, dynamic process that perturbs the physiological roles of the liver as a master regulator of systemic immunity and protector against noxious effects of exogenous molecules in the portal vein flowing from the gut. Thus, in cirrhosis and severe alcohol-associated hepatitis, the ability of hepatocytes and intrahepatic immune cells to balance normal context-dependent dichotomous responses of tolerance vs immune activation is lost. Contributing factors include loss of the gut barrier with translocation of microbial products through the portal vein, culminating in development of functional defects in innate and adaptive immune cells, and generation of immune-regulatory myeloid cells that permit microbial colonization and infection. This review addresses key evidence supporting the paradigm of immune dysfunction as a risk for microbial infections and identifies potential therapeutic targets for intervention. The primary focus is on cirrhosis-associated immune dysfunction and alcohol-associated liver disease, because the bulk of available data are from these 2 conditions.

PMID:39927926 | DOI:10.1053/j.gastro.2024.08.046

Pak J Med Sci. 2025 Feb;41(2):569-574. doi: 10.12669/pjms.41.2.9511.

ABSTRACT

OBJECTIVE: To determine the frequency and spectrum of different categories of Primary immunodeficiency disorders (PIDD).

METHODOLOGY: This was a prospective, observational analytical study, conducted in the Pediatric Medicine Department, University of Child Health Sciences (UCHS) from January 2021 to January 2023.We recruited 81 patients, initially suspected based on Jeffrey Modell Foundation(JMF) warning signs, followed by detailed evaluation. Descriptive statistics were applied.

RESULTS: Male patients exceeded female (47: 31). Median age of presentation was 17 months. Median diagnostic delay was 10.5 months. Need of I/V antibiotics was the most frequent JMF warning sign (88.5%). Consanguinity, previous hospital admissions, family history and sibling death were present in 80%, 78%, 54%, 37% of cases respectively. The most conspicuous clinical feature was persistent or recurrent thrush (51%). Patients were categorized into six main groups: B-Cell defect (29.5%), SCID (24.4%), CID (14.1%), T-Cell defect (12.8 %), Phagocytic defect (11.5%) and NK deficiency (7.7%). Main bulk of patients 37 (47.4 %) were in age-group up to one year. Most common site of infection was recurrent pneumonia (76%) and the least was septic arthritis (5.1%).

CONCLUSION: PIDD should no longer be considered a rarity. B-Cell defect is the most common while earliest to diagnose are SCID and LAD. International health authorities should advocate EQUITABLE utilization of genetic testing across the globe.

PMID:39926682 | PMC:PMC11803810 | DOI:10.12669/pjms.41.2.9511

J Allergy Clin Immunol Pract. 2025 Feb 5:S2213-2198(25)00150-3. doi: 10.1016/j.jaip.2025.01.031. Online ahead of print.

NO ABSTRACT

PMID:39921087 | DOI:10.1016/j.jaip.2025.01.031

PLoS One. 2025 Feb 7;20(2):e0316926. doi: 10.1371/journal.pone.0316926. eCollection 2025.

ABSTRACT

BACKGROUND: Intravenous immunoglobulin is a replacement therapy for patients living with primary immunodeficiencies. Each batch of intravenous immunoglobulin is required by the Food and Drug Administration to contain threshold levels of measles neutralising antibodies. Widespread use of the measles vaccine has decreased measles antibody potency in the United States plasma supply. There is limited data on measles antibody trough levels in treated primary immunodeficiency patients. The aim of this sub-analysis was to evaluate the measles antibody trough levels in treated primary immunodeficiency patients.

METHODS: GMX07 was an open-label, two-period, crossover bioequivalence study which randomized 33 adult patients with primary immunodeficiency disease in 16 centres across the United States, the United Kingdom and Hungary. Eligible adult patients received five infusions of Gammaplex® 5% followed by five infusions of Gammaplex® 10%, or vice versa, on either a 21- or 28-day dosing regimen. The trial included 15 paediatric patients who were not randomized, receiving only five infusions of 10% product. This sub-analysis measured trough levels of measles neutralising antibodies using a Vero cell-based measles virus neutralisation assay.

RESULTS: Median measles antibody trough levels were ~ 1300 mIU/mL with no significant difference between Gammaplex 5% and Gammaplex 10% treatment (p > 0.9) or the 21-day or 28-day dosing regimen (p > 0.3). There was also no difference between mean measles neutralising antibody levels following Gammaplex 10% in adult or paediatric patients.

CONCLUSIONS: Levels of measles neutralising antibodies in the 5% and 10% formulations of this intravenous immunoglobulin product provided protective antibodies well above accepted thresholds and were similar in adult and paediatric patients across both 21-day and 28-day dosing regimens. Switching between Gammaplex products did not affect antibody levels.

TRIAL REGISTRATION: ClinicalTrials.gov NCT01963143.

PMID:39919133 | DOI:10.1371/journal.pone.0316926

J Clin Immunol. 2025 Feb 7;45(1):72. doi: 10.1007/s10875-025-01865-3.

NO ABSTRACT

PMID:39918595 | DOI:10.1007/s10875-025-01865-3

Front Immunol. 2025 Jan 23;16:1517347. doi: 10.3389/fimmu.2025.1517347. eCollection 2025.

ABSTRACT

Wiskott-Aldrich syndrome (WAS) (MIM #301000) is a rare X-linked primary immunodeficiency due to mutations in the WAS gene, characterized by thrombocytopenia with small platelets, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies. A wide spectrum of mutations has been identified in the WAS gene responsible for a broad variety of clinical phenotypes. By using targeted next-generation sequencing (t-NGS), we identified in a 2-month-old boy with thrombocytopenia and immunological alterations a 4-nucleotide deletion from position +3 to +6 of intron 8 (c.777 + 3_777 + 6delGAGT) of WAS, currently classified on ClinVar as a variant of uncertain significance. The in-vitro characterization of the variant revealed the complete retention of intron 8 in the mature transcript, suggesting a splicing defect due to the loss of a splice donor site at the 5′-end of intron 8. By sequencing the polymerase chain reaction product, we identified a premature stop at codon 269; thus, consequently, no Wiskott-Aldrich syndrome protein (WASp) was detectable in peripheral blood mononuclear cells from the patient. Due to the total absence of a full-length WASp, it is expected that the patient will develop the severe form of the disease, although further monitoring is needed to better define his phenotype.

PMID:39917307 | PMC:PMC11798879 | DOI:10.3389/fimmu.2025.1517347

J Allergy Clin Immunol. 2025 Feb 4:S0091-6749(25)00119-8. doi: 10.1016/j.jaci.2025.01.030. Online ahead of print.

ABSTRACT

BACKGROUND: Natural killer (NK) cell deficiency (NKD) is an immunodeficiency phenotype in which abnormality of NK cells is the major clinically relevant immune defect.

OBJECTIVE: We sought to define the clinical, immunologic and genetic characteristics of patients with NKD to aid in the understanding of these individuals and this cell type, and guide future research and clinical practice.

METHODS: During 2006-2022, 168 individuals suspected of having NKD were enrolled, with comprehensive clinical, immunological and genetic data collected and analyzed. Research exome sequencing was performed to identify both known and novel genetic associations.

RESULTS: NK cell abnormalities consistent with NKD were confirmed in 148 individuals. Most presented during childhood (median age 13y, range 0-76y), though 34% were adults. All tested individuals exhibited reduced NK cell cytotoxic function; 44% also had decreased NK cell numbers and/or mature NK cells. Herpesvirus and/or papillomavirus infections were observed in 71%, malignancies in 7%, and a 5% case-fatality rate was noted. Among the 99 individuals who underwent research exome sequencing, 29% were considered solved for a likely contributing variant allele, 52% of these cases involving known genes and 48% involving novel genes.

CONCLUSIONS: NKD is a phenotypic immunodeficiency associated with increased susceptibility to certain viral infections and cancer, with multiple genetic etiologies, revealing key biological pathways for NK cell development and function. This research underscores the role of NK cells in human immune defenses, and helps advance the identification of at-risk populations, precise genetic diagnoses, and informed clinical management for those with NKD.

PMID:39914554 | DOI:10.1016/j.jaci.2025.01.030