Hiroshi Nakajima

Psychological stress affects the immune system and exacerbates autoimmune diseases such as rheumatoid arthritis (RA), but the mechanisms underlying tissue inflammation during remission remain unclear. Here, we show that tube restraint stress exacerbates joint inflammation in a murine arthritis model during remission. This exacerbation required interleukin-6 (IL-6) produced by brown adipose tissue (BAT) following sympathetic activation. Fibroblast-like synoviocytes expressing the IL-6 receptor subunit gp130 were critical mediators, as IL-6 stimulated these cells to produce the neutrophil chemoattractant CXCL1. Pharmacological blockade of the β3-adrenergic receptor significantly attenuated stress-induced arthritis flares. In patients with RA, carriers of the hypofunctional Trp64Arg variant of ADRB3 showed no positive correlation between psychological stress and disease activity, whereas noncarriers did. These findings identify a BAT–IL-6–fibroblast axis that reactivates inflammatory memory in arthritis and suggest that targeting stress-responsive pathways may provide a complementary therapeutic strategy alongside current RA treatments without broadly suppressing systemic immunity.

Acquired amegakaryocytic thrombocytopenia is a rare cause of severe thrombocytopenia characterized by a marked reduction in bone marrow megakaryocytes and may be difficult to distinguish clinically from immune thrombocytopenia. Acquired amegakaryocytic thrombocytopenia has been reported in various autoimmune and non-autoimmune conditions but has not previously been described in a patient with mixed connective tissue disease. We describe the case of a 63-year-old woman with longstanding mixed connective tissue disease who developed severe thrombocytopenia with mucosal bleeding and purpura. Although she was initially treated for presumed immune thrombocytopenia with platelet transfusion, prednisolone, and intravenous immunoglobulin, followed by intravenous methylprednisolone pulse therapy, her platelet count failed to improve. A subsequent bone marrow biopsy revealed relatively preserved erythroid and granulocytic haematopoiesis with a marked reduction in megakaryocytes, and acquired amegakaryocytic thrombocytopenia was diagnosed after myelodysplastic syndrome and leukaemia had been excluded. Treatment with rituximab and eltrombopag resulted in rapid platelet recovery, and remission has been sustained for 14 months, including after two maintenance rituximab doses administered during follow-up. Testing performed during follow-up revealed positivity for an antibody against the thrombopoietin receptor, suggesting a possible immune-mediated mechanism of impaired megakaryopoiesis. The markedly elevated immature platelet fraction and platelet-associated immunoglobulin G also raised the possibility of concomitant immune thrombocytopenia-like peripheral platelet destruction. This case highlights the importance of considering acquired amegakaryocytic thrombocytopenia in patients with systemic autoimmune disease and severe thrombocytopenia refractory to corticosteroids or intravenous immunoglobulin, while recognizing that impaired platelet production and peripheral platelet destruction may overlap.

Primary erythromelalgia (PEM) is a rare autosomal dominant disorder characterised by episodic erythema and burning pain of the extremities, typically triggered by exercise or fatigue. PEM usually begins in childhood and is caused by gain-of-function variants in SCN9A, which encodes the voltage-gated sodium channel Nav1.7. The disease concept of PEM, however, is largely unrecognised among rheumatologists. Here, we report a 20-year-old woman who had experienced recurrent burning pain and redness of the extremities since around age 10. She also exhibited livedo-like rash, leukopenia, and hypocomplementemia and tested positive for antinuclear antibodies. Nerve conduction studies showed abnormalities interpreted as compatible with multifocal mononeuropathy. Based on these findings, she was diagnosed with systemic lupus erythematosus and treated with 20 mg of prednisolone; however, the painful erythema of the extremities did not improve. Given a family history of similar episodic symptoms in her father, PEM was suspected. Genetic testing identified a heterozygous SCN9A p.G856D variant, supporting the diagnosis of autosomal dominant PEM. Direct immunofluorescence/lupus band testing of the biopsied lower-leg lesion was interpreted as negative. This case highlights that SCN9A-associated PEM may present with lupus-like cutaneous erythema in young patients, potentially leading to misdiagnosis and ineffective immunosuppression. PEM should be considered in patients with childhood-onset, trigger-induced painful erythema of the extremities, particularly when there is family history or poor response to steroids.

Dysregulated nucleic acid sensing underlies lethal viral infections and autoimmunity. Endosomal Toll-like receptor 7 (TLR7) recognizes guanosine and oligoribonucleotides (ORNs) from single-stranded RNA via two ligand-binding sites in its leucine-rich repeat (LRR) ectodomain. Recent genetic studies have demonstrated that TLR7 gain-of-function (GOF) variants cause childhood lupus or immune thrombocytopenic purpura by enhancing TLR7 responses to canonical TLR7 ligands. However, no study has demonstrated that altered ligand specificity of TLR7 contributes to autoimmunity. Here, we provide direct evidence that relaxation of ligand specificity by TLR7 genetic variants causes lupus in both humans and mice. We describe a pediatric systemic lupus erythematosus (SLE) patient carrying a private GOF TLR7 missense variant, V825M (VarM), located within the C-terminal region of the LRR (LRR-CT). Knock-in mice harboring VarM allele spontaneously develop lupus-like systemic inflammation, including duodenitis, recapitulating the patient’s clinical features. Mechanistically, the VarM variant markedly amplifies NF-κB activation by synthetic small-molecule agonists and guanosine analogs. Notably, the VarM variant broadens the spectrum of ORN sequences that can engage the receptor. Moreover, certain pathogenic TLR7 variants located at the dimerization interface display functional properties closely resembling those of VarM. Collectively, our findings establish a new paradigm in which alterations in ligand recognition specificity by TLR7 genetic variations can trigger human autoimmune disease.

Group 2 innate lymphoid cells (ILC2s) are a subset of innate lymphocytes that produce type 2 cytokines, including IL-4, IL-5, and IL-13. GATA3 is a critical transcription factor for ILC2 development at multiple stages. However, when and how GATA3 is induced to the levels required for ILC2 development remains unclear. Herein, we identify ILC2-specific GATA3-related tandem super-enhancers (G3SE) that induce high GATA3 in ILC2-committed precursors. G3SE-deficient mice exhibit ILC2 deficiency in the bone marrow, lung, liver, and small intestine with minimal impact on other ILC lineages or Th2 cells. Single-cell RNA-sequencing and subsequent flow cytometry analysis show that GATA3 induction mechanism, which is required for entering the ILC2 stage, is lost in IL-17RB⁺PD-1⁻ late ILC2-committed precursor stage in G3SE-deficient mice. Cnot6l, part of the CCR4-NOT deadenylase complex, is a possible GATA3 target during ILC2 development. Our findings implicate a stage-specific regulatory mechanism for GATA3 expression during ILC2 development.

Asthma is a widespread airway disorder where GATA3-dependent Type-2 helper T (Th2) cells and group 2 innate lymphoid cells (ILC2s) play vital roles. Asthma-associated single nucleotide polymorphisms (SNPs) are enriched in a region located 926-970 kb downstream from GATA3 in the 10p14 (hG900). However, it is unknown how hG900 affects the pathogenesis of allergic airway inflammation. To investigate the roles of the asthma-associated GATA3 enhancer region in experimental allergic airway inflammation, we first examined the correlation between GATA3 expression and the activation of the hG900 region was analyzed by flow cytometry and ChIP-qPCR. We found that The activation of enhancers in the hG900 region was strongly correlated to the levels of GATA3 in human peripheral T cell subsets. We next generated mice lacking the mG900 region (mG900KO mice) were generated by the CRISPR-Cas9 system, and the development and function of helper T cells and ILCs in mG900KO mice were analyzed in steady-state conditions and allergic airway inflammation induced by papain or house dust mite (HDM). The deletion of the mG900 did not affect the development of lymphocytes in steady-state conditions or allergic airway inflammation induced by papain. However, mG900KO mice exhibited reduced allergic inflammation and Th2 differentiation in the HDM-induced allergic airway inflammation. The analysis of the chromatin conformation around Gata3 by circular chromosome conformation capture coupled to high-throughput sequencing (4C-seq) revealed that the mG900 region interacted with the transcription start site of Gata3 with an influencing chromatin conformation in Th2 cells. These findings indicate that the mG900 region plays a pivotal role in Th2 differentiation and thus enhances allergic airway inflammation.

Objectives: This study aimed to determine the immunogenicity and the influence on disease activity of an adjuvanted recombinant varicella-zoster virus (VZV) subunit vaccine (RZV) in patients with rheumatoid arthritis (RA) treated with disease-modifying antirheumatic drugs (DMARDs). Methods: This prospective longitudinal study enrolled 53 patients with RA (aged ≥50 years) treated with DMARDs (conventional synthetic (cs)DMARDs 20, biological (b)DMARDs 23 and targeted synthetic (ts)DMARDs 10) and 10 control individuals. The participants received two intramuscular RZV 2 months apart. VZV-specific CD4⁺ T cell responses (cell-mediated immunity; CMI) and IgG antibody responses (humoral immunity; HI) were assessed at 0 and 3 months after the first RZV administration using flow cytometry and enzyme immunoassay, respectively. Disease activity (Disease Activity Score 28-C reactive protein and Clinical Disease Activity Index), flares and adverse events were monitored for 6 months after the first vaccination. Results: VZV-specific CMI and HI significantly increased in the three DMARDs-treated patients with RA after RZV administration compared with the corresponding prevaccination values (p<0.001–0.014), and the magnitudes and fold-increases of those responses were not significantly different among the three DMARDs-treated patients with RA. Furthermore, the vaccine response rates of CMI and HI were not significantly different between csDMARDs-treated patients and b-DMARDs or ts-DMARDs-treated patients. Meanwhile, no significant increases in disease activity indices or adverse events were observed in these patients during the 6-month follow-up period after the first vaccination. RZV-induced RA flares occurred in two patients (3.8%) but were mild and controllable. Conclusion: RZV is robustly immunogenic and has a clinically acceptable safety profile in elderly patients with RA receiving DMARDs.

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T cells (Tregs) are involved in the induction of oral tolerance. However, the detailed mechanisms of Treg induction in oral tolerance remain largely unknown. Eosinophils have been recognized as effector cells in allergic diseases, but in recent years, the diverse functions of tissue-resident eosinophils have been reported. Eosinophils in the intestine have been reported to induce Tregs by releasing TGF-β, but the role of eosinophils in oral tolerance is still controversial. In this study, we analyzed the roles of eosinophils in oral tolerance using eosinophil-deficient ΔdblGATA mice (mice lacking a high-affinity GATA-binding site in the GATA1 promoter). ΔdblGATA mice showed impaired antigen-induced oral tolerance compared to wild-type mice. The induction of RORγt⁺ Tregs in mesenteric lymph nodes (MLNs) by oral tolerance induction was impaired in ΔdblGATA mice compared to wild-type mice. An increase in RORγt⁺ antigen-presenting cells (APCs), which are involved in RORγt⁺ Treg differentiation, in the intestine and MLNs was not seen in ΔdblGATA mice. Notably, the expansion of group 3 innate lymphoid cells (ILC3s), a subset of RORγt⁺ APCs, by oral tolerance induction was seen in wild-type mice but not ΔdblGATA mice. These results suggest that eosinophils are crucial in the induction of oral tolerance, possibly via the induction of RORγt⁺ APCs and RORγt⁺ Tregs.

The lungs serve as the primary organ for respiration, facilitating the vital exchange of gases with the bloodstream. Given their perpetual exposure to external particulates and pathogens, they possess intricate protective barriers. Cellular adhesion in the lungs is robustly maintained through tight junctions, adherens junctions, and desmosomes. Furthermore, the pulmonary system features a mucociliary clearance mechanism that synthesizes mucus and transports it to the outside. This mucus is enriched with chemical barriers like antimicrobial proteins and immunoglobulin A (IgA). Additionally, a complex immunological network comprising epithelial cells, neural cells, and immune cells plays a pivotal role in pulmonary defense. A comprehensive understanding of these protective systems offers valuable insights into potential pathologies and their therapeutic interventions.