Linrong Lu

Objectives: This study aimed to explore the relationship between dermatomyositis (DM) and thyroid cancer and the role of transcriptional intermediary factor 1γ (TIF-1γ) in the pathogenesis of cancer-associated DM. Methods: Five cases of DM with thyroid cancer, including one with metastasis, were summarized and analyzed. Published cases of DM with thyroid cancer were reviewed. Subsequently, a bidirectional two-sample Mendelian randomization (MR) analysis was performed to investigate the relationship between thyroid cancer and myositis using inverse-variance weighting (IVW), MR-Egger, and weighted-median (WM) analyses. Finally, immunohistochemistry (IHC) and immunofluorescence (IF) analysis were performed to detect TIF-1γ in tumor tissues of a DM patient and a thyroid cancer patient without DM. Results: This article reports the first case of a patient with DM and metastatic papillary thyroid carcinoma (PTC), in whom recurrence of the rash prompted the detection of metastasis, with the rash resolving after surgical resection of the metastatic foci. MR analysis showed a potential causal relationship between thyroid cancer and myositis (OR = 1.398; 95% CI = 1.045–1.869; p = 0.029). A higher expression level of TIF-1γ was observed in tumor tissues of DM patients compared with those of thyroid cancer patients without DM by immunofluorescence (IF) analysis ( p < 0.0001). Conclusions: DM symptoms might represent a paraneoplastic phenomenon in patients with thyroid cancer, with the underlying pathological mechanisms requiring further exploration and TIF-1γ overexpression potentially serving as a trigger.

Background: To report a refractory Takayasu arteritis (TAK) patient who developed a severe inflammatory flare after tocilizumab (TCZ) therapy and explore the underlying mechanism. Case presentation: A 21-year-old female with active TAK received TCZ after insufficient response to prednisone. TCZ was temporarily withheld then re-added at 400 mg due to disease relapse. After TCZ reintroduction, the patient developed worsening vascular pain, new abdominal pain, dizziness, fever, and markedly elevated inflammatory markers. Imaging showed worsened arteritis and new superior mesenteric arteritis. Methylprednisolone pulse and infliximab failed to control the flare, but tofacitinib achieved complete symptom resolution and normalized inflammatory markers within one month. In vitro findings: Peripheral blood samples of the patient were collected and peripheral blood mononuclear cells (PBMCs) Fcγ receptor (FcγR) expression and downstream signaling were assessed upon TCZ stimulation. In vitro studies showed that increasing TCZ concentrations were associated with enhanced FcγRIIA, FcγRIIB, and FcγRI expression, along with increased spleen tyrosine kinase (SYK) phosphorylation in the patient’s PBMCs. Conclusion: TCZ can paradoxically trigger an inflammatory flare in refractory TAK, with exploratory evidence suggesting possible involvement of excessive FcγR activation. Non-antibody-based Janus kinase (JAK) inhibitors like tofacitinib may be effective rescue therapy in such cases.

Dysregulation of thymic T cell development compromises immune homeostasis and can lead to leukemic transformation, but the molecular mechanisms linking developmental signals, proliferative cues, and leukemogenesis remain incompletely understood. Here, we integrate deubiquitinase library screening and publicly available single-cell RNA sequencing to analyze mouse and human thymocytes. We find the deubiquitinase USP10 to be expressed in thymocytes, and also elevated in peripheral blood from patients with T-cell acute lymphoblastic leukemia (T-ALL) compared to healthy controls; by contrast, T cell-specific USP10 deficiency blocks mouse thymocyte proliferation and differentiation. Mechanistically, USP10 interacts with SOX4, de-ubiquitinating and protecting SOX4 from degradation to promote thymocyte proliferation, with SOX4 overexpression restoring thymocyte differentiation in USP10-deficient mice. Lastly, MYC induces Usp10 expression, and pharmacologic inhibition of USP10 delays MYC-driven leukemogenesis in a mouse leukemia model. Our results thus identify USP10 as coordinator of developmental signals and oncogenic processes in thymocytes, and implicate USP10 as a potential target for T-ALL therapy.

Importins could inhibit the condensation of RNA-binding proteins, while it remains unknown whether exportins elicit a similar function. Here, we identified that exportin CRM1 binds to the nuclear protein NPAT, which initiates and maintains the formation of the histone locus body (HLB), a membraneless nuclear body regulating histone transcription. CRM1 drives the nuclear export of NPAT by targeting a nuclear export signal (NES) within the LisH domain. The LisH domain contributes to NPAT condensation by mediating its self-association. Mechanistically, CRM1 competitively occupies the self-association sites in the NES motif, thereby suppressing NPAT condensation. In contrast, the two recurrent CRM1 E571K and E571G mutants could not regulate NPAT condensation and HLB remodeling due to their impaired binding to the NES of NPAT. Based on the “competitive occupation” model, we designed a LisH domain–derived short peptide that competes with homotypic intermolecular interactions of NPAT to perturb HLB formation. Our findings reveal that exportin regulates nuclear protein condensation via a competitive occupation strategy.

Recent advances in single-cell technology enable the simultaneous capture of T cell receptor (TCR) sequences and gene expression (GEX), providing an integrated view of T cell function. However, linking TCRαβ information and T cell phenotypes at the population level to elucidate their disease association remains an unaddressed gap. Here, by constructing a large-scale reference of paired single-cell RNA/TCR sequencing (scRNA/TCR-seq) comprising more than 2 million T cells from 70 studies, 1017 biological samples, 583 individuals, and 46 disease conditions, along with their single-cell transcriptome, full-length paired TCR, and human leukocyte antigen (HLA) genotypes, we revealed the intrinsic features of germline-encoded TCR-major histocompatibility complex (MHC) restriction in CD4⁺/CD8⁺ lineages. We also observed widely existing public TCRαβs across the population, associated with higher clonal expansion levels and shared HLA alleles. The most publicly shared TCRs are likely to target epitopes from common viruses, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and influenza A virus (IAV). Furthermore, we introduced TCR-DeepInsight, a computational framework to identify HLA-shared and disease-associated TCRαβ clusters that exhibit similar TCR sequence and GEX profiles, extensible for researchers to incorporate their data with our reference and characterize potentially functional TCRs. In summary, our work presents a panoramic scTCRαβ reference and computational methods for TCR study.

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) plays a crucial role in maintaining peripheral immune tolerance, but its mechanisms of action are highly complicated. Here, through the generation of a gene knock-in (KI) mouse carrying a CTLA-4 Y139C human patient-derived pathogenic mutation, we phenocopied the lethal autoimmune diseases in Ctla4 KO mice due to the impairment of Treg functions. Interestingly, although both KO and KI Treg cells lost the ability to endocytose B7 molecules, the KO and KI mice differed in terms of T-cell proliferation since the KI mutation retained its ability to transmit inhibitory signals. Therefore, this study not only dissected the two distinct immunoregulatory mechanisms of CTLA-4 but also provided genetic evidence highlighting the importance of ligand trans-endocytosis in the function of CTLA-4. Our findings enhance our understanding of CTLA-4 function and CTLA-4 insufficiency disease, providing valuable insights for advancing improved immunotherapy strategies targeting CTLA-4.