Complement activation has been increasingly recognized in immune thrombocytopenia (ITP). However, the involvement of alternative pathways in ITP and relevance of complement activation in refractory ITP remain unclear. This multicenter observational study aimed to characterize complement activation in primary ITP (pITP). C3a des-Arg levels were significantly higher in patients with pITP than in patients with systemic lupus erythematosus/antiphospholipid syndrome and healthy donors (HD). The expression of Bb, an alternative pathway-specific marker, did not differ between groups. sC5b-9 levels were significantly elevated in patients with pITP compared to those in HD patients. Patients with a partial response to pITP who met the criteria for refractory ITP with repeated relapses despite standard treatments exhibited elevated levels of C3a des-Arg and sC5b-9. Complement activation was observed in pITP, whereas involvement of the alternative pathway was limited. These findings highlight the importance of complement assessment in patients with pITP and may guide the optimal use of complement-targeted therapies.
Risankizumab is a selective interleukin (IL)-23p19 inhibitor used for psoriasis. Although IL-23 is implicated in giant cell arteritis (GCA), biologic therapy can occasionally be associated with paradoxical immune-mediated events. We report a 67-year-old woman who developed GCA during long-term risankizumab therapy for psoriasis vulgaris. She presented with progressive night sweats and fatigue, with marked systemic inflammation. Contrast-enhanced computed tomography and gadolinium-enhanced magnetic resonance imaging demonstrated large-vessel inflammation involving the aorta and its major branches. Temporal artery biopsy showed intimal hyperplasia, fragmentation of the internal elastic lamina, and mild inflammatory cell infiltration. She fulfilled the 2022 ACR/EULAR classification criteria for GCA and was treated with high-dose prednisolone, followed by methotrexate. Her symptoms and inflammatory markers improved rapidly, and risankizumab was continued because of excellent psoriasis control. Pretreatment serum cytokine analysis showed low IL-17 levels, whereas IFN-γ, IL-6, and TNF-α were comparable to or higher than those in other patients with GCA. This case highlights that GCA can develop during selective IL-23 blockade and may involve Th1-skewed inflammation or a paradoxical immune reaction.
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been implicated in Epstein-Barr virus (EBV) reactivation. In this study, we aimed to investigate the role of iguratimod, an NF-κB activator inhibitor, in EBV lytic cycle activation in EBV-infected cells. EBV-producing cells, AKATA, and B-lymphoblastoid cells (BLBC) with 1 μM iguratimod. EBV DNA copy numbers were measured using real-time polymerase chain reaction. The inhibitory effect of iguratimod on NF-κB nuclear translocation in AKATA cells was examined. Immunohistochemical staining revealed significantly increased EBV early antigen diffuse type (EA-D) production in IgG-stimulated AKATA cells and IgM-stimulated BLBC compared with unstimulated cells, whereas co-culture with iguratimod suppressed the production of EBV EA-D. Additionally, AKATA cells/BLBC stimulated with anti-human IgG/IgM showed a significant increase in EBV DNA copy number compared to unstimulated cells, which was significantly reduced by co-culture with iguratimod. Nuclear expression of NF-κB was observed in AKATA cells stimulated with anti-human IgG, and NF-κB expression was suppressed by treatment with iguratimod. These findings suggest that iguratimod may reduce rheumatoid arthritis disease activity by partially inhibiting EBV reactivation. This may partially suppress the onset of RA.
Lipopolysaccharide (LPS)-induced endotoxemia is widely used to model sepsis. This study aimed to identify the LPS dose that reliably induces hyperlactatemia, Murine Sepsis Score (MSS) ≥3 (clinically defined sepsis), dose-dependent differences in 48-hour survival, and optimal histone H3K18 lactylation in male BALB/c mice. Sixty-six male BALB/c mice (8-10 weeks) received intraperitoneal LPS at doses of 1, 2.5, 5, 10, 15, and 20 mg/kgBW (N = 11 per group). Blood lactate was measured at 6 h, MSS was used to assess disease severity, and survival was monitored for 48 h. Peritoneal macrophages were isolated, and histone H3K18 lactylation normalized to total H3 (H3K18la/H3) was quantified. All groups developed hyperlactatemia (>4 mmol/L) without dose-dependent differences (p = 0.289). Meanwhile, MSS increased proportionally with LPS dose (ρ = 0.785; p= <0.001) and negatively correlated with lactate (ρ=-0.527; p = 0.025). Survival showed a general dose-related downward trend that did not reach significance, with a non-monotonic exception at 5 mg/kgBW. Macrophage yield varied across groups, while H3K18la/H3 levels were markedly elevated at LPS 15 and 20 mg/kgBW. To conclude, lactate rises early and non-uniformly across LPS doses, limiting its value as severity marker in male BALB/c endotoxemia. MSS provides a more dose-responsive indicator of clinical severity. An LPS dose of 15 mg/kg provides an optimal model for studying immunometabolic and immunoepigenetic responses in sepsis.
To perform cross-disease immunological comparison across the broader spondyloarthritis (SpA) spectrum and examine their association with disease activity. We analyzed 111 patients with active broader SpA spectrum (ankylosing spondylitis, inflammatory bowel disease-associated SpA, psoriatic arthritis, pustulotic arthro-osteitis, and chronic non-bacterial osteitis) and 24 age- and sex-matched healthy controls (HC). Serum IL-17A, IL-17F, TNFα, and Oncostatin M levels were higher in the broader SpA spectrum than in HC. These cytokines levels did not differ among the broader SpA spectrum. Activated Th17, activated Th1-17, classical and intermediate monocytes were increased in the broader SpA spectrum compared with HC. Although Kruskal-Wallis test showed differences among the spectrum for activated Th17, activated Th1-17, and classical monocytes, post hoc analyses did not identify a specific disease driving these differences. Intermediate monocytes positively correlated with CRP and MMP-3 levels. Circulating immune subsets remained unchanged following DMARDs treatment despite clinical improvement. Systemic immune alterations, including activation of IL-17 axis, elevated Oncostatin M, and expansion of intermediate monocytes, are broadly shared across the broader SpA spectrum. Although global differences among the spectrum were observed for some immune cell populations, post hoc analyses did not identify disease-specific enrichment.
