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22 records · Page 2Linked to original sources
PubMed2026

CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.

Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.

Humans↗
PubMed2026

Early immune dysregulation in Mtb/SIV co-infection resists cART treatment at the single-cell level.

Using single-cell transcriptomics of bronchoalveolar lavage cells from Mtb/SIV co-infected rhesus macaques on cART, we reveal profound immune dysregulation during early SIV co-infection of latent tuberculosis. SIV induces a sharp decline in CD4+ T cells, NK, and NKT cells, with incomplete recovery of Mtb-specific TH1 effector responses despite viral suppression. Instead, a persistent TH17-skewed environment emerges, alongside sustained myeloid inflammation driven by Type I interferon signaling and pro-inflammatory regulators such as KLF6 and NFKB1. Ligand-receptor network analyses demonstrate expanded CD4+ T cell-macrophage crosstalk and loss of immune homeostasis that cART fails to fully restore. These findings expose how SIV remodels the pulmonary immune landscape to impair protective immunity against Mtb, providing a transcriptomic framework to explain TB reactivation in HIV infection. Our work highlights the urgent need for adjunctive immunotherapies to complement cART, aiming to rebalance immune responses and improve TB control in co-infected individuals.

HIV↗
PubMed2025

Cytogenetic and molecular characterization of an atypical ETP-ALL case with BCL2 dependency: therapeutic implications for Venetoclax use.

BACKGROUND: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare, high-risk subtype of T-ALL characterized by distinctive immunophenotypic and genomic features. It is often associated with induction failure and frequent relapses. Despite recent advances in its molecular characterization, the prognosis remains dismal, and effective targeted therapies are limited. METHODS AND RESULTS: We report a pediatric, multi-refractory ETP-ALL case with novel cytogenetic alterations, including a 4q deletion and a t(16;18)(q24;q21) translocation. Molecular profiling revealed progressive activation of the BCL2 pathway and disruption of Th17-related immune markers. Ex vivo sensitivity assays performed at different disease stages demonstrated increasing BCL2 dependency. Based on these findings, venetoclax was administered on a compassionate-use basis, resulting in rapid hematologic recovery and a marked reduction in blast percentage. CONCLUSIONS: This case highlights the role of clonal evolution and immune deregulation in accompanying BCL2 addiction in relapsed ETP-ALL. Altogether, our findings underscore the therapeutic potential of venetoclax in refractory pediatric ETP-ALL cases with progressive BCL2 dependency.

Humans↗
PubMed2025

RELA Haploinsufficiency Manifesting as an Atypical Phenotype of Crohn's Disease.

BACKGROUND: Mutations in RELA, a key component of NF-κB signaling, are associated with dysregulated immune responses and inflammatory disorders. While immunodeficiency phenotypes associated with RELA haploinsufficiency have been reported, gastrointestinal manifestations remain poorly described. This study aimed to characterize the clinical, genomic, and immunological features of a patient presenting with an atypical Crohn's-like phenotype driven by RELA haploinsufficiency. METHODS: Whole-exome sequencing was performed, and results were confirmed by Sanger sequencing. Protein modeling, Western blotting, immunofluorescence, and nuclear extract-based NF-κB activation assays were conducted to assess the functional impact of the identified variant. Immune profiling was performed using mass cytometry time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) and compared to controls. RESULTS: We studied a 17-year-old male diagnosed with pan-enteric Crohn's disease (CD), perianal fistulas, chronic mucocutaneous candidiasis, and chronic lymphopenia. Sequencing identified a heterozygous missense variant in RELA (c.587T>C, p.V196A) that potentially impairs RelA (p65) protein stability, confirmed by reduced activity and diminished protein expression. CyTOF analysis revealed decreased circulating T regulatory cells (Tregs), absence of mucosal Tregs, high apoptotic rates, and elevated IFN-γ induced levels, while scRNA-seq demonstrated a robust type I/II interferon signature in multiple immune subsets. Dysregulated mucosal-associated invariant T (MAIT) and cytotoxic CD4+ T cells exhibited upregulation of IL23R and ADAM12, further linking RELA dysfunction to enhanced pro-inflammatory T cell response and tissue inflammation. CONCLUSION: This study links RELA haploinsufficiency with CD-like features, Th1/Th17 polarization, and interferon-driven inflammation, emphasizing the importance of genetic evaluation in patients with atypical or refractory IBD.

Humans↗