bims-hummad 2025-06-22 papers

Cell Rep. 2025 Jun 13. pii: S2211-1247(25)00622-9. [Epub ahead of print]44(6): 115851

ENPP1 governs the metabolic regulation of effector T cells in autoimmunity by detecting cytosolic mitochondrial DNA.

Huiyan Ji, Wanwan Jiang, Juan Zhang, Mengdi Liu, Danhua Su, Jiaxin Lei, Lingyi Li, Ming Zheng, Ting Liu, Zhichun Liu, Qinghua Cao, Lin Xu, Sidong Xiong, Zhenke Wen.

T cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE), yet the underlying molecular mechanisms governing their fate remain elusive. Here, we identify cytosolic mitochondrial DNA (mtDNA) as an intrinsic trigger for driving effector T cell differentiation in patients with SLE. Specifically, accumulated cytosolic mtDNA is sensed by ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which enhances the transcription of GLUT1 and glycolysis in SLE T cells. This metabolic shift reduces lipogenesis and depletes free fatty acids (FFAs), impairing the N-myristylation and lysosomal localization of AMP-activated protein kinase (AMPK). Inactive AMPK fails to restrain mammalian target of rapamycin complex 1 (mTORC1), leading to its hyperactivation and driving the mal-differentiation of effector T cells. Consequently, interventions targeting ENPP1, glycolysis, AMPK, and mTORC1 effectively inhibit the generation of immunoglobulin (Ig)G anti-double-stranded DNA (dsDNA) and the progression of lupus nephritis in humanized SLE chimeras. Overall, our findings uncover an mtDNA-ENPP1-metabolic axis that governs effector T cell fate in autoimmunity.

Keywords: AMPK; CP: Immunology; CP: Molecular biology; ENPP1; SLE; T cell; mitochondrial DNA

DOI: https://doi.org/10.1016/j.celrep.2025.115851

Nat Commun. 2025 Jun 17. 16(1): 5292

Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis.

Anti-NMDA receptor (NMDAR) encephalitis is a devastating disease with severe psychiatric and neurological symptoms believed to be caused by pathogenic autoantibodies that bind to the N-terminal domain (NTD) of the NMDAR GluN1 subunit (GluN1-NTD) crosslinking adjacent NMDARs and driving their internalization. Here we describe ART5803, a humanized monovalent antibody, as a potential therapy for anti-NMDAR encephalitis. ART5803 binds with a high affinity (KD = 0.69 nM) to GluN1-NTD without affecting NMDAR activity or inducing internalization. ART5803 blocks NMDAR internalization induced by patients' pathogenic autoantibodies, and restores NMDAR function. A marmoset animal model was developed using sustained intracerebroventricular (ICV) administration of a human pathogenic autoantibody to evoke behavioral and motor abnormalities. ART5803 ICV infusion or peripheral injections rapidly reversed these abnormalities. These data, together with the pharmacokinetic profile in cynomolgus monkeys, indicate a therapeutic potential for intravenous (IV)-administered ART5803 as a fast-acting and efficacious option for anti-NMDAR encephalitis.

DOI: https://doi.org/10.1038/s41467-025-60628-1

Science. 2025 Jun 19. 388(6753): 1311-1317

In vivo CAR T cell generation to treat cancer and autoimmune disease.

Chimeric antigen receptor (CAR) T cell therapies have transformed treatment of B cell malignancies. However, their broader application is limited by complex manufacturing processes and the necessity for lymphodepleting chemotherapy, restricting patient accessibility. We present an in vivo engineering strategy using targeted lipid nanoparticles (tLNPs) for messenger RNA delivery to specific T cell subsets. These tLNPs reprogrammed CD8+ T cells in both healthy donor and autoimmune patient samples, and in vivo dosing resulted in tumor control in humanized mice and B cell depletion in cynomolgus monkeys. In cynomolgus monkeys, the reconstituted B cells after depletion were predominantly naïve, suggesting an immune system reset. By eliminating the requirements for complex ex vivo manufacturing, this tLNP platform holds the potential to make CAR T cell therapies more accessible and applicable across additional clinical indications.

DOI: https://doi.org/10.1126/science.ads8473