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#自身免疫

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Oct 15Thu
  1. nature.com83

    Engineered TYK2 dependence enables myeloid-selective IL-10 receptor agonism

    IL-10's therapeutic use is limited because its myeloid-suppressive and T-cell-activating effects cannot be separated. Using the JAK1 inhibitor VVD-118313 in bone-marrow-derived macrophages, the authors show that JAK1-JAK1 transphosphorylation only partially reduces IL-10-induced STAT3 phosphorylation, with TYK2-mediated transphosphorylation compensating; in TYK2-deficient BMDMs, VVD-118313 fully abrogated STAT3 phosphorylation and IL-10 function. In human monocytes, the TYK2 inhibitor zasocitinib similarly partially reduced IL-10-driven STAT3 phosphorylation, revealing differential TYK2 dependence that may enable myeloid-selective IL-10 receptor agonism.

    Why it matters: It maps a signalling route that could separate IL-10's anti-inflammatory benefit from its toxic T-cell activation.

Oct 10Sat
  1. doi.org49

    JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function

    JAK inhibitors produced rapid but incomplete immune reconstitution in two STAT1 gain-of-function patients carrying p.R321S and p.T385M mutations. Changes were seen as early as 1 week after treatment: T cells rebalanced toward a homeostatic status, TCR repertoire diversity increased quickly, and transcriptional dysregulation in monocytes improved, though defects such as natural killer deficiency persisted in one patient. The work defines both the therapeutic reach and the limits of JAK inhibition in STAT1 GOF.

Oct 9Fri
  1. Sci Adv57

    Kupffer cells are key mediators of antigen-specific immune tolerance by peptide-coupled red blood cells.

    Red blood cells coupled with multiple sclerosis immunodominant peptides prevented experimental autoimmune encephalomyelitis when given prophylactically and reduced symptoms when given therapeutically, with tolerance dependent on antigen, cell dose and peptide dose. Kupffer cells were the main phagocytes of the peptide-coupled RBCs, took them up without complement component 3, SIRPα, or Stabilin 1 and 2, and were indispensable for tolerance, showing PD-L1 up-regulation and a tolerogenic transcriptional shift. The work positions Kupffer cells as the central mediators of this tolerogenic strategy for autoimmune disease.

Oct 7Wed
  1. Mol Cell57

    DNASE1L3 maintains homeostatic levels of mitochondrial DNA on the mammalian cell surface.

    Mitochondrial DNA is tethered to the surface of select mammalian cells through cell surface proteins and heparan sulfate proteoglycans, accumulating in large clusters that partially overlap with RNA binding protein domains. The secreted nuclease DNASE1L3 clears this surface DNA from human and murine B cells. Patients carrying a DNASE1L3 missense variant linked to autoimmune disease risk show increased surface DNA on B and T cells, connecting cell-surface molecules to DNA targeting in autoimmunity.

Oct 3Sat
Oct 2Fri
  1. Nature79

    Population-scale immune multiome atlas reveals regulatory disease mechanisms.

    Simultaneous single-nucleus profiling of chromatin accessibility and gene expression in 10 million peripheral blood mononuclear cells from 1,108 Finnish individuals yields 51,083 cis-expression QTLs, 338,100 cis-chromatin accessibility QTLs and 593,765 peak-gene links. Variants completing chromatin-to-expression cascades show twice the disease colocalization of chromatin-only effects, and massively parallel reporter assays validate 10,428 fine-mapped QTLs. The atlas supplies testable hypotheses for over half of immune disease associations and explains why disease variants preferentially target evolutionarily constrained genes through regulatory buffering at the chromatin-to-expression interface.

    Why it matters: It converts non-coding immune disease variants into mechanistic chromatin-to-expression cascades for most immune disease associations.

  2. Nature73

    A two-hit mechanism triggers autoimmune hair loss.

    Autoimmune alopecia can be triggered by a two-hit mechanism: transient regulatory T cell depletion during the anagen phase of the hair cycle causes CD8+ T-cell-mediated destruction of hair follicle stem cells and hair loss, while telogen skin is resistant. Anagen susceptibility depends on sympathetic nerve activity, which drives noradrenaline-ADRB2 signalling, reactivation of endogenous retroviruses, and AIM2-dependent innate immune activation. Genetic ablation of Aim2 or pharmacological inhibition of ERV reverse transcription protects against disease; stress or optogenetic sympathetic activation renders telogen skin susceptible.

    Why it matters: It defines a mechanistic trigger for tissue-specific autoimmunity, linking neural activity, endogenous retroviruses and Treg cells, with druggable entry points.

  3. biorxiv.org45

    Genetic risk and inflammatory signaling converge on cell type-specific regulatory programs in type 1 diabetes

    A subset of type 1 diabetes-associated variants may drive beta-cell dysfunction by disrupting transcription factor binding at cell type-specific candidate cis-regulatory elements. The authors integrated epigenomic and single-cell multiomic data from human pancreatic islets with T1D GWAS variants, and used the deep learning model ChromBPNet plus TF footprinting to nominate several disease-associated SNPs predicted to alter chromatin accessibility at candidate TF binding sites. The work links noncoding variants to cell type-specific enhancer activity and provides candidates for future mechanistic studies.

Oct 1Thu
  1. nature.com68

    A two-hit mechanism triggers autoimmune hair loss

    The paper reports a two-hit mechanism that triggers autoimmune hair loss, drawing on single-cell RNA-seq and bulk RNA-seq datasets generated in the study. The sequencing data have been deposited in the NCBI Gene Expression Omnibus under accession codes GSE343853 and GSE343613.

    Why it matters: It proposes a defined two-hit mechanism for autoimmune hair loss with underlying transcriptomic data now public.

Sep 28Mon
  1. doi.org41

    Brief report: Effectiveness and safety of recombinant zoster vaccine in inflammatory bowel disease patients aged 18 years and older: A matched cohort and self-controlled case series study

    Two doses of recombinant zoster vaccine prevented herpes zoster in inflammatory bowel disease patients, with adjusted vaccine effectiveness of 65.4% (95% CI 40.6%-79.9%) overall, 62.7% in ulcerative colitis and 70.2% in Crohn's disease. In a self-controlled case series, the IBD flare rate ratio after vaccination was 0.80 (95% CI 0.58-1.12), indicating no increased flare risk. The results support RZV use in this higher-risk population.

Sep 25Fri
  1. nature.com56

    Single-cell analysis of chromatin accessibility in the human intestine identifies regulatory programs and clarifies genetic associations in Crohn’s disease

    Single-cell ATAC-seq was used to map chromatin accessibility in intestinal mucosa from patients with Crohn's disease and healthy controls. The work characterizes regulatory programs associated with inflammation and genetic effects, clarifying genetic associations in Crohn's disease.

    Why it matters: Links Crohn's disease genetic associations to specific cell-type regulatory programs, aiding interpretation of risk variants.

Sep 10Thu
  1. Sci Transl Med57

    Monoclonal antibodies inhibiting MMP-9 activity alleviate peripheral neuropathy in diabetic mice.

    Systemically administered monoclonal antibodies that selectively inhibit MMP-9 relieved mechanical and cold pain and restored hind paw wound healing in diabetic mice. The antibodies reduced epidermal nerve fiber degeneration by improving nerve mitochondrial function and promoting skin angiogenesis. Human relevance is supported by increased MMP-9 expression in dorsal root ganglia of patients with diabetes and by associations of MMP9 variants with neuropathic pain phenotypes.

    Why it matters: It identifies a specific druggable target with antibody therapy for a diabetic complication lacking disease-modifying treatments.

  2. nature.com51

    A bispecific CD3×CD19 antibody for systemic lupus erythematosus: a phase 1 trial

    A next-generation CD3×CD19 bispecific T cell engager given intravenously was well tolerated in patients with active systemic lupus erythematosus in a phase 1 trial, and most patients showed improvements in disease activity scores. The findings support further testing of B cell-directed T cell engagers in systemic lupus erythematosus.

    Why it matters: First-in-class tolerability and disease activity signal for a CD3×CD19 bispecific antibody in active SLE.

  3. Nat Med53

    Antifungal therapy improves microbiome dynamics in inflammatory bowel disease.

    Fluconazole, but not nystatin, reduced intestinal Candida burden and reshaped gut fungal-community composition in 53 patients with mild-to-moderate ulcerative colitis or Crohn's disease. The gastrointestinal and oral fluconazole fungal targeting arm (n = 35) showed increased bacterial diversity, expansion of short-chain fatty-acid-producing taxa, restored anti-inflammatory metabolites, and improved disease activity indices with decreased risk of progression over 8 weeks. The work establishes a framework for antifungal cotherapy in fungal-associated IBD.

    Why it matters: It provides first evidence that targeted antifungal therapy can reshape the gut microbiome and improve disease activity in IBD.

Sep 8Tue
  1. Mol Cell64

    Selective decay of interferon mRNAs controls antiviral immunity and innate memory.

    The RNA-binding protein tristetraprolin (TTP) and the mRNA decay machinery selectively limit type I and type III interferon (IFN) mRNA levels at steady state and after stimulation. Loss of this pathway increases IFN mRNA poly(A) tail length, stability and translation, raising IFN expression enough to block SARS-CoV-2 infection in vitro and in vivo. A human TTP variant linked to autoimmunity shows reduced TTP levels and increased IFN signaling, and transient loss of mRNA decay primes innate memory for long-term antiviral protection.

    Why it matters: It identifies TTP-mediated IFN mRNA decay as a tunable switch controlling antiviral immunity and autoimmune risk.

  2. Nature64

    Intracellular complement factor H protects neurons during CNS inflammation.

    Intracellular complement factor H (CFH) protects neurons from inflammatory injury through a non-canonical role independent of complement C3. In single-nucleus RNA-sequencing of retinal ganglion cells from donors with multiple sclerosis and controls, CFH expression correlated strongly with resilience to degeneration. CFH was induced by inflammatory and oxidative stress, localized to the endoplasmic reticulum, limited reactive oxygen species accumulation and lipid peroxidation, and its protection depended on the C-terminal SCR20 domain in mice and humans.

    Why it matters: Identifies a complement-independent, intracellular neuroprotective mechanism relevant to MS therapy.

Sep 1Tue
Aug 29Sat
  1. Cell70

    Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.

    A genome-scale perturb-seq platform perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors, measuring transcriptome effects at rest and after stimulation. The resulting maps identify regulators of immune pathways, including previously uncharacterized regulators of cytokine production, and show that active regulators and the programs they control change dramatically across stimulation conditions. The signatures nominate regulators of T cell polarization, age-related phenotypes, and context-specific pathways in autoimmune disease risk.

    Why it matters: It maps context-specific gene regulators in primary human CD4+ T cells and links them to immune traits and autoimmune disease risk.

Aug 19Wed
  1. Nature81

    Antigen presentation by CD40+MHC-II+ astrocytes promotes CNS autoimmunity.

    Astrocytes expressing CD40 and MHC-II present antigen to CD4+ T cells and drive CNS autoimmunity. Direct astrocyte-CD4+ T cell interactions enhanced pathogenic Th17 responses in experimental autoimmune encephalomyelitis, and CD40 activation by T cell CD40L induced PLIN4-positive lipid droplets that supply acetyl-CoA for p65 acetylation-dependent NF-κB activation and antigen presentation. CD40+MHC-II+LD+ astrocytes were detected in multiple sclerosis samples by single-nucleus RNA sequencing and immunohistochemistry, defining a previously unrecognized mechanism of astrocyte-driven autoimmunity.

    Why it matters: It identifies astrocytes as antigen-presenting cells driving CNS autoimmunity, with evidence in mouse models and multiple sclerosis tissue.

Aug 14Fri
  1. Sci Immunol69

    An autoinflammatory CDC42 variant M45L demonstrates the mechanism of pyrin inflammasome activation.

    The CDC42 M45L variant causes a previously unrecognized autoinflammatory condition by activating the pyrin inflammasome. CDC42 binds the PYD and B30.2 domains of pyrin, and M45L greatly enhances the B30.2 interaction, with methionine-45 sitting in a hydrophobic cleft of the B30.2 domain; all affected individuals showed highly elevated circulating IL-18. Blocking IL-1 was therapeutically effective in this CDC42 M45L endotype, supporting a model in which CDC42 nucleates pyrin to liberate the PYD for inflammasome activation.

    Why it matters: It defines a new autoinflammatory endotype with a mechanistic explanation and an effective IL-1-blocking treatment.

  2. Sci Immunol64

    An N-terminal CDC42 T43I variant reveals the mechanism of pyrin inflammasome activation.

    An amino-terminal p.T43I variant in the RHO GTPase CDC42, found in patients with autoinflammation, directly activates the pyrin inflammasome. The T43 region of CDC42 binds the B30.2 domain of pyrin, and the T43I substitution strengthens this interaction, causing increased ASC speck formation, enhanced pyroptosis, and excessive IL-1β and IL-18 production. CDC42 thus joins RHOA as a second RHO GTPase regulating pyrin.

    Why it matters: It identifies CDC42 as a pyrin ligand and explains how a patient variant drives pyrin inflammasome activation.

CBACBA Frontier Insights (CFI)Chinese Biopharmaceutical Association (CBA)www.cba-usa.org