Persistent immune exhaustion despite suppressive ART is increasingly recognised in PLWH, but NK-cell involvement remains unclear. In a single-centre longitudinal cohort, 100 PLWH were evaluated at baseline and 12 months (median age 41.5 years; 56% male; 58% newly diagnosed). At the 12-month endpoint, NK-cell frequency and PD-L1 expression were analysed cross-sectionally in 89 participants in relation to CD4⁺ T- and CD19⁺ B-cell PD-1/PD-L1 expression, the CD4⁺/CD8⁺ ratio and SCORE2, using Spearman correlations with Benjamini–Hochberg correction. NK PD-L1 strongly correlated with PD-L1 on CD4⁺ (ρ = 0.778, q < 0.001) and CD19+ (ρ = 0.684, q < 0.001) cells, and moderately with B-cell PD-1 (ρ = 0.365, q = 0.0013). NK frequency inversely correlated with PD-L1 on CD4⁺ (ρ = −0.459, q < 0.001) and CD19+ (ρ = −0.320, q = 0.00545) cells and with B-cell PD-1 (ρ = −0.236, q = 0.0409). No statistically significant associations with the CD4⁺/CD8⁺ ratio or SCORE2, or differences by treatment history or the INSTI-based regimens examined, were detected. These findings describe associations between NK-cell phenotype and adaptive checkpoint expression without establishing functional exhaustion.
Background Gaucher disease (GD), an inborn error of metabolism, and Common variable immunodeficiency (CVID), an inborn error of immunity, have distinct etiologies but may exhibit convergent downstream transcriptional responses. We investigated transcriptional robustness and pathway-level convergence using a robustness-oriented transcriptomic framework. Methods Public datasets were analyzed independently for GD and CVID. Patient-level GD fibroblast profiles (GSE124283) underwent differential-expression analysis, leave-one-patient-out (LOPO) testing, expression-scale sensitivity analysis, and Reactome gene-set enrichment analysis (GSEA), with validation in GSE21899 and GSE303993. CVID whole-blood profiles (GSE51404) were analyzed using group-only and age/sex-adjusted models. Cross-disease convergence was assessed among robust Reactome pathways. Results 18 Reactome pathways remained robust across GD patient-exclusion and expression-scale analyses. The validation demonstrated context-dependent replication, including concordant enrichment of 11/18 pathways in the neuronopathic GD organoid model. In CVID, only 2 genes were differentially expressed between inflammatory and non-inflammatory CVID at FDR < 0.05, whereas 143 pathways remained robust to demographic adjustment. 11 robust GD pathways overlapped with this CVID comparison, all with concordant enrichment direction, prominently involving interferon and antigen-processing programs; mitochondrial pathways showed context-dependent patterns. Conclusion GD and CVID exhibit selective pathway-level transcriptional convergence rather than a shared causal mechanism, supporting robustness-aware pathway analysis across heterogeneous disorders.
Background Regulatory B cells (Bregs) suppress allergic inflammation primarily through interleukin-10 (IL-10), yet the intrinsic mechanisms constraining their regulatory capacity remain incompletely understood. Although the anti-apoptotic protein Mcl-1 is essential for B cell survival, its potential non-canonical roles in Breg-mediated immune regulation are unknown. Methods B cell-specific Mcl1ΔCD19mice and OVA-induced airway allergy models were used to assess Breg function. Translational studies employed lentiviral MCL1overexpression in primary human B cells, PBMC-reconstituted NSG mice, and clinical B cell profiling from asthma patients. Rigorous experimental controls were implemented to exclude confounding effects from B cell developmental defects and compensatory anti-apoptotic signaling. Results Compared with littermate controls, Mcl1ΔCD19mice exhibited significantly attenuated airway hyperresponsiveness, pulmonary eosinophilia, and antigen-specific IgE levels (all p < 0.01), accompanied by a 4.2-fold increase in the absolute number of IL-10+Bregs (p < 0.001). B cells isolated from Mcl1ΔCD19mice potently suppressed Th2 cytokine production and promoted type 1 regulatory T (Tr1) cell differentiation in an IL-10R-dependent manner. Mechanistically, Mcl-1 associates with the Il10promoter; this chromatin binding coincides with enrichment of the repressive histone mark H3K27me3 and reduced recruitment of RNA polymerase II. In humanized mice, enforced MCL1 overexpression in human B cells reduced IL-10 secretion by 65% and exacerbated airway inflammation. Furthermore, B cells from asthma patients displayed elevated endogenous MCL1 expression and correspondingly diminished IL-10 production. It should be noted that our human-subject analysis is limited by modest sample size, and further validation in larger patient cohorts is required. Conclusions Mcl-1 functions as an epigenetic suppressor of Il10transcription in B cells, independently of its canonical pro-survival role, thereby restraining Breg-mediated immune tolerance and promoting allergic airway inflammation. The B-cell Mcl-1/IL-10 axisrepresents a promising preclinical pathway for further investigation as a potential therapeutic target for allergic asthma, though pharmacological validation is still needed.
Background Persistent circulating SARS-CoV-2 spike protein has been proposed as a potential contributor to long-COVID pathophysiology. Whether administration of spike-targeting monoclonal antibodies is followed by changes in spike protein concentrations, autonomic receptor autoantibodies, or clinical outcomes remains uncertain. Methods In this prospective, non-randomized observational study, 21 participants were enrolled. Ten immunodeficient patients with long-COVID-associated ME/CFS and detectable circulating spike protein received Tixagevimab/Cilgavimab for SARS-CoV-2 pre-exposure prophylaxis. One patient subsequently withdrew consent, leaving nine patients for paired baseline and 30-day follow-up analyses. Eleven healthy individuals with previous SARS-CoV-2 infection but without long COVID provided descriptive reference data and were not considered an efficacy control group. Results β1-adrenergic receptor autoantibody concentrations decreased from 26.8 ± 18.2 to 21.2 ± 14.7 U/ml (unadjusted p = 0.003). No statistically significant changes were observed for β2-adrenergic or M3/M4-muscarinic receptor autoantibodies. Median spike protein concentrations changed from 63 pg/ml (IQR 9–127) to 26 pg/ml (IQR 10–120; p = 0.63), with individual decreases observed in five of nine patients. None of the assessed clinical outcomes changed significantly at group level. Changes in spike protein concentrations were not significantly correlated with changes in the assessed autonomic receptor autoantibodies. Conclusion Tixagevimab/Cilgavimab administration was followed by a nominally significant within-patient reduction in β1-adrenergic receptor autoantibody concentrations, but not by conclusive changes in circulating spike protein or clinical outcomes. These findings are preliminary and hypothesis-generating. The small sample size, non-randomized design, brief 30-day follow-up, inclusion of only immunodeficient patients, and absence of an untreated disease-matched control group preclude conclusions regarding therapeutic efficacy.
