The pathology of concomitant burn and traumatic brain injury remains poorly defined, despite their frequent co-occurrence in military settings and the potential for deleterious synergy. To address this gap, we combined established models of blast-induced mild traumatic brain injury and 15% total body surface area flame burn to approximate a common combat-related trauma and examined how the injuries interact to shape systemic inflammation and brain transcriptional programs. Burn injury induced systemic G-CSF and IL-6 secretion and hematopoietic reprioritization, whereas overlapping brain injury did not substantially alter these systemic effects but magnified brain transcriptional responses relative to single injuries. Bulk RNA-seq profiling at 6 h post-injury revealed enriched gene sets associated with inflammation and endocrine stress in the combined injury group, alongside elevated systemic cytokines and corticosterone; thereby suggesting concurrent immune-endocrine activation. Since our prior work demonstrated burn wound-associated IL-1 signaling induces G-CSF and IL-6 secretion, we tested IL-1 neutralizing antibodies and anakinra as therapies. Treatment reduced G-CSF and IL-6 secretion, improved erythropoiesis, and selectively modulated brain transcriptional changes. Single-nucleus RNA-seq projection mapping predicted that the transcripts altered by combined injury were broadly enriched across vascular and glial cell types. Targeted expression profiling identified a shared brain-liver signature characterized by an IL-1/6-dependent inflammatory response alongside an interleukin-independent stress response. These findings highlight IL-1-responsive inflammatory signals and endocrine stress interactions within a multi-organ network that shapes the early brain transcriptional response to the combined injury.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory disorder characterised by excessive immune activation. It may be primary or secondary, with secondary HLH associated with a range of triggers; the most common are infections, autoimmune and autoinflammatory conditions, haematological malignancies and other immune‑dysregulatory states. We present a case of a man in his 70s who presented with a two-week history of exertional dyspnoea, profound fatigue and anorexia. Initial investigations demonstrated marked hyperferritinaemia, thrombocytopenia, mild anaemia, cholestatic liver dysfunction and disproportionately elevated lactate without acidosis. Despite intravenous fluids, lactate remained persistently elevated, consistent with type B hyperlactataemia. Computed tomography (CT) of the abdomen and pelvis demonstrated appearances suggestive of hepatitis but no organomegaly, significant lymphadenopathy or biliary obstruction. Despite empirical antibiotics and fluid resuscitation, he developed progressive pancytopenia, worsening liver dysfunction and rising lactate. Further investigations supported secondary HLH, with an HScore of 186, hypertriglyceridaemia and markedly elevated lactate dehydrogenase. Initial treatment with corticosteroids and anakinra resulted in limited response. An autoimmune trigger was initially considered given his Raynaud's phenomenon and ongoing connective tissue disease investigation. However, bone marrow biopsy subsequently confirmed diffuse large B-cell lymphoma (DLBCL). Reduced-dose rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone (R-mini-CHOP) was commenced, resulting in the resolution of hyperlactataemia, normalisation of blood counts and liver function and improvement in performance status. PET-CT after two cycles demonstrated a complete metabolic response. This case highlights the importance of considering secondary HLH in patients with unexplained cytopenias, hyperferritinaemia, liver dysfunction and persistent hyperlactataemia. Persistent hyperlactataemia despite adequate fluid resuscitation should prompt the consideration of systemic causes beyond tissue hypoperfusion. Bone marrow biopsy is crucial for identifying occult malignancy when conventional imaging fails to show overt malignancy. The early recognition of HLH and investigation for an underlying aetiology may facilitate timely definitive treatment.

Macrophage activation syndrome (MAS), a form of secondary hemophagocytic lymphohistiocytosis (HLH), is an uncommon but life-threatening complication of autoimmune disease and may occasionally represent the first clinical manifestation of systemic lupus erythematosus (SLE). We describe the case of a previously healthy 15-year-old girl who initially presented with persistent fever, mucocutaneous ulcerations, fatigue, and pancytopenia. Her evaluation revealed low complement levels, elevated lactate dehydrogenase, and splenomegaly, and subsequent serologic testing confirmed new-onset SLE with features of mixed connective tissue disease and Class II lupus nephritis. Although she showed early improvement after receiving corticosteroids and hydroxychloroquine, her condition unexpectedly deteriorated with rising ferritin, hypertriglyceridemia, worsening cytopenias, and progressive liver enzyme elevation, raising concern for an evolving hyperinflammatory syndrome. She ultimately fulfilled five HLH-2004 criteria and had an HScore of 261, indicating a very high probability of HLH/MAS, despite the absence of hemophagocytosis on bone marrow biopsy. Targeted immunomodulatory therapy with anakinra was initiated promptly and resulted in rapid clinical and biochemical improvement. This case highlights the diagnostic challenges of MAS when it emerges in parallel with newly diagnosed SLE, emphasizes the importance of distinguishing MAS from SLE flare or infection, and introduces interleukin-1 blockade as a potential therapeutic option. Early recognition and timely introduction of targeted anti-inflammatory therapy may contribute to rapid stabilization and to be lifesaving when corticosteroids alone are insufficient to halt the cytokine-driven inflammatory cascade.

The interleukin-1 receptor antagonist (IL-1Ra) is a key anti-inflammatory cytokine that inhibits interleukin-1 signaling by competitively binding to IL-1 receptors. However, recombinant IL-1Ra, currently produced in Escherichia coli, exhibits limited pharmacokinetics and requires frequent administration due to its short plasma half-life and absence of glycosylation. To overcome these limitations, we designed a novel IL-1Ra-Fc fusion protein consisting of human IL-1Ra fused to a human IgG1 Fc fragment via a flexible linker and transiently expressed in Nicotiana benthamiana to enhance protein yield, stability, and enable glycosylation. The recombinant protein accumulated to approximately 340 mg/kg fresh leaf biomass and achieved an overall DSP recovery of 45% protein yield, with a characteristic high α-helical secondary structure, as confirmed by CD spectroscopy. Receptor-binding analysis shows that rhIL-1Ra-Fc exhibited significantly enhanced IL-1 receptor binding activity, showing approximately 17% higher activity than that of commercial IL-1Ra. Overall, this is the first study to demonstrate the feasibility of producing functionally active IL-1Ra-Fc in plants for potential therapeutic applications in inflammatory diseases.

To report a rare case of irreversible paraplegia due to transverse myelitis as a severe neurotoxic complication of chimeric antigen receptor (CAR) T-cell therapy.

Myocardial infarction (MI) remains a major cause of death and heart failure despite advances in reperfusion and secondary prevention. Sterile inflammation triggered by ischemic myocardial injury is increasingly recognized as a determinant of infarct expansion, adverse ventricular remodeling, and subsequent clinical outcomes. The NOD-like receptor protein 3 (NLRP3) inflammasome integrates danger-associated molecular patterns, mitochondrial dysfunction, ionic disturbance, metabolic stress, and innate immune signaling. Following activation, caspase-1 processes interleukin-1β and interleukin-18 and cleaves gasdermin D to generate the pore-forming GSDMD-N fragment, thereby promoting pyroptosis and inflammatory amplification. After MI, NLRP3 activity is shaped by extracellular adenosine triphosphate and P2X7 signaling, potassium efflux, reactive oxygen species, mitochondrial DNA release, lysosomal and endoplasmic reticulum stress, and cyclic GMP-AMP synthase-stimulator of interferon genes signaling. Importantly, these responses are temporally and cell-type dependent: cardiomyocytes, macrophages, endothelial cells, and fibroblasts contribute differently to injury, debris clearance, vascular dysfunction, scar formation, and repair. This review differs from earlier pathway-centered summaries by integrating temporal regulation and cell-specific biology with emerging crosstalk among mitochondrial quality control, STING signaling, ferroptosis, pyroptosis, and immunometabolism. Translational evidence is considered alongside mechanism, including interleukin-1-directed studies such as CANTOS and the Virginia Commonwealth University Anakinra Remodeling Trial program, while emphasizing that clinical benefit from selective NLRP3 inhibition itself remains to be established. Direct inflammasome inhibitors, colchicine, metabolic modulators, RNA-based approaches, targeted delivery systems, and traditional Chinese medicine-derived compounds are critically discussed with attention to evidence level and limitations. We further examine biomarker-guided patient selection and unresolved questions concerning therapeutic timing, cell specificity, long-term safety, and preservation of reparative inflammation.

IL-10 receptor deficiency is a life-threatening inborn error of immunity associated with early-onset inflammatory bowel disease. Hematopoietic cell transplantation (HCT) using treosulfan-based conditioning resulted in excellent survival with full donor engraftment. Importantly, anakinra effectively served as a bridge to HCT.

Preterm birth is associated with breakdown of maternal-fetal tolerance and remains the leading cause of global mortality in young children. However, the role of self-reactive antibodies has been limited to a handful of pathogenic allo- and autoantibodies linked to pregnancy complications. Here we identify a shared autoreactive signature of pregnancy in pregnant sera (n = 2,719) relative to never-pregnant controls (n = 130), using proteome-wide autoantibody profiling. Across eight human pregnancy cohorts, we define autoreactivities associated with preterm birth by comparing preterm (n = 688) and term (n = 1,505) pregnancies. Within the signature, antibodies to IL1 receptor antagonist (IL1RA) induce resorption, inflammation and vascular malperfusion in pregnant mice. IL1RA localizes to placental endothelial adherens junctions, suggesting a role in vascular integrity. These findings identify a term pregnancy humoral immune program and shared changes preceding preterm delivery, including anti-IL1RA, which may have direct pathogenic consequences.