Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive bone destruction in which immune dysregulation plays a central role. Recent evidence has highlighted the gut-bone axis as a critical framework linking gut microbiota to skeletal and immune homeostasis. Gut microbiota dysbiosis disrupts intestinal barrier integrity by altering tight junction proteins and increasing intestinal permeability, facilitating microbial translocation and triggering systemic inflammatory responses. Microbiota-derived metabolites, including short-chain fatty acids, bile acids, and tryptophan metabolites, act as key mediators along the gut-bone axis. These metabolites regulate multiple signaling pathways and immune cell functions, particularly by modulating the balance between T helper 17 and regulatory T cells, suppressing B-cell hyperactivation, promoting macrophage M2 polarization, and inhibiting dendritic cell maturation. These actions may contribute to immune homeostasis and bone metabolism associated with RA. This review systematically summarizes the role of gut microbiota dysbiosis, intestinal barrier dysfunction, and microbial metabolites in RA pathogenesis within the framework of the gut-bone axis. Furthermore, microbiota-targeted therapeutic strategies, including probiotics, prebiotics, dietary interventions, fecal microbiota transplantation, and traditional Chinese medicine, are discussed as potential approaches to restore host-microbiota balance. However, most current evidence is derived from preclinical studies, highlighting the need for further clinical validation. Despite these limitations, a deeper understanding of microbiota-driven mechanisms along the gut-bone axis may provide novel insights into RA pathogenesis and facilitate the development of targeted and personalized therapeutic strategies.
To evaluate intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for stratifying early response to neoadjuvant immune checkpoint inhibitor and tyrosine kinase inhibitor (ICI-TKI) therapy in renal cell carcinoma (RCC) and explore correlations between IVIM‑DWI parameters and tumor immune cell infiltration. This retrospective exploratory analysis utilized prospectively collected data from a single‑center study enrolling patients with advanced, metastatic or unresectable RCC scheduled for neoadjuvant ICI‑TKI therapy. Two radiologists independently segmented primary tumors on baseline IVIM‑DWI to obtain the true diffusion coefficient (D), pseudo‑diffusion coefficient (D*), perfusion fraction (f), and standard apparent diffusion coefficient (ADCstandard). Response was assessed per iRECIST. Baseline parameters were compared between responders and nonresponders; subgroup analysis was conducted for clear cell RCC (ccRCC). Diagnostic performance was evaluated using the area under the curve (AUC). Immune infiltration was analyzed from RNA‑sequencing data, and correlations were assessed with the Spearman's test. Among 58 patients (44 ccRCC), 33 (56.9%) were responders. Responders showed higher baseline D*, D, f, and ADCstandard values than nonresponders in both the whole cohort and ccRCC subgroup (all P < 0.05). A combined parameter incorporating these variables achieved the highest AUC (whole cohort: 0.903; ccRCC subgroup: 0.979). Nonresponders exhibited higher infiltration of CD8⁺ T cells and follicular helper T cells (all P < 0.05). CD8⁺ T‑cell infiltration correlated negatively with the baseline D (P = 0.015) but not with the ADCstandard (P = 0.062). IVIM‑DWI parameters show promise as a non‑invasive tool for early response stratification of neoadjuvant ICI‑TKI therapy in RCC. The inverse correlation between D values and CD8⁺ T‑cell infiltration suggests that restricted diffusion may reflect a tumor microenvironment associated with treatment resistance.
Immune checkpoint inhibitor (ICI)-induced thyroiditis is a common immune-related adverse event (irAE) linked to improved survival. Polygenic risk scores (PRSs) for autoimmune hypothyroidism predict thyroid irAEs in European-ancestry patients; performance in non-European populations is unclear. In the Veterans Affairs Million Veteran Program (2011-2023), we identified ICI-treated patients with germline genotyping and a chemotherapy-treated control cohort, excluding those with thyroid disease or prior thyroid-directed treatments. Harmonized ancestry and race (HARE) defined Non-Hispanic White (NHW) and Black (NHB) groups. Thyroid irAEs within one year were defined using laboratory criteria capturing both hyperthyroid and hypothyroid phases. We compared two PRSs: a published European-derived PRS, and an updated PRS selected across multiple GWAS sources and methods (including MVP multi-ancestry GWAS) to maximize discrimination in African-ancestry individuals in a held-out test set. HARE-stratified multivariable Cox models estimated time to thyroiditis; a 6-month landmark analysis assessed overall survival. The ICI cohort included 4,289 patients (3,473 NHW; 816 NHB). The baseline PRS was associated with thyroiditis in NHW (adjusted hazard ratio [aHR] per SD 1.33, 95% CI 1.19-1.50) but not NHB patients or controls. The updated PRS improved risk stratification in NHW (aHR 1.45, 1.28-1.63) and predicted thyroiditis in NHB patients (aHR 1.48, 1.11-1.98), but not in controls. Thyroiditis within 6 months was associated with improved survival, but neither PRS was. Germline polygenic liability to hypothyroidism predicts ICI-induced thyroiditis in NHW and NHB patients when PRSs are selected via ancestry-stratified validation. Careful exploration of the dataset-method space is critical for equitable PRS development.
The intrinsic low immunogenicity of tumors remains a major limitation for cancer immunotherapy. Herein, a Bifidobacterium breve lw01-based bioreactor (lw01@Pd) was engineered to facilitate the intracellular in situ biosynthesis of palladium nanocrystals (Pd NCs) via carbon monoxide (CO) reduction to alleviate the immunosuppression of cold tumors. The intrinsic hypoxic targeting capability of lw01 in solid tumors enables the selective tumor colonization of lw01@Pd and synchronously minimizes off-target effects. Once within the tumor microenvironment (TME), the engineered lw01@Pd release Pd NCs via Xenophagy-mediated degradation within tumor cells, which then induce oxidative damage to both tumor cells and lw01 carrier. This oxidative stress not only induces the immunogenic cell death (ICD) of tumor cells, but also triggers the lysis of lw01, resulting in the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). The concurrent presence of DAMPs and PAMPs promotes the maturation of dendritic cells (DCs) and facilitates antigen presentation, which in turn activates CD8+ T cells-mediated adaptive immune response. This probiotic nano-catalytic system demonstrates significant immunotherapeutic potential, offering new perspectives on overcoming the immune tolerance of cold tumors.
Rotavirus is a highly contagious pathogen and a leading cause of severe diarrhea cases in children under 5 y of age worldwide. Although effective oral rotavirus vaccines have been developed and implemented globally, their performance varies substantially by setting. In high-income countries (HICs), these oral vaccines exhibit 85-90% efficacy in preventing rotavirus-associated hospitalizations, with protection lasting until at least 2 y of age. In contrast, vaccine efficacy in low- and middle-income countries (LMICs) is considerably lower, ranging from approximately 45% to 65%. To address this disparity, efforts are underway to develop next-generation rotavirus vaccines. In this review, we critically examine the immune responses elicited by natural rotavirus infection and by oral vaccination in both HICs and LMICs. The goal is to identify immunological factors associated with durable protection and to define key characteristics that an improved rotavirus vaccine should possess to achieve sustained high efficacy in LMICs. 1. Need of a good CoP: IgA correlate with protection after natural infection and after ORV in the first year of life (especially in low child mortality setting)do not capture a true clinical endpoint and is not a mechanistic CoPdo not predict individual level of protectionstandardization and comparison across studies remain a challengeunsuitable for parenterally administered vaccinesIgG: could be suitable for parenterally administered vaccinescould be mechanistic since passive transfer of IgG suppresses or delays viral infection in a primate model and IgA-deficient individuals are still able to recover from RV infectionmaternally derived transplacental IgG are protective but it may be important to differentiate between infant IgG and acquired IgG (maternal)Neutralizing Antibodies: correlate with protection after natural infectionnot clear correlation with protection after vaccinationCellular response: Need for further studies on T- and B-cell activationNeed for further studies at the mucosal levels2. Identification of the right vaccine targets / delivery platform / adjuvants Outer layer antigens (VP4 and VP7) – more variable, target of neutralizing antibodiesInner capsid antigen (VP6) – more conservative, intracellular viral inhibitionDifferent technologies – Subunit, VLP, nanoparticles, mRNA, Inactivated whole virus3. Use of more suitable infection models Animal models: mice for immunogenicity – do not recapitulate human immune responsepigs for challenge – dependent on IgAHuman model: challenge with ORV not reliableHuman intestinal enteroids: could help for a better characterization of neutralizing antibodies, and intracellular neutralizing antibodies, transmigration of IgG and IgA antibodies from sera.
Immune checkpoint inhibitor (ICI)-myopathy-myocarditis is an immune-related adverse event, with high mortality despite first-line immunosuppression. Emerging data suggest upregulation of the interleukin-6 (IL-6) pathway in ICI-myopathy, raising interest in IL-6 receptor blockade as escalation therapy. We aimed to characterize acute and long-term functional and oncologic outcomes for severe ICI-myopathy-myocarditis, with focus on those treated with tocilizumab after failure of first-line therapy. We performed a retrospective cohort study of patients admitted with severe (Common Terminology Criteria for Adverse Events [CTCAE] grade 3 or 4) ICI-myopathy-myocarditis managed at a Canadian tertiary referral center. Clinical characteristics, investigations, treatment, and functional and long-term cancer outcomes were summarized. Patients were stratified by treatment with tocilizumab after first-line therapy. Primary outcomes were in-hospital mortality and acute-phase survival. Secondary outcomes included functional status at last follow-up, final CTCAE grade, and oncologic response. Eleven patients were identified. Eight patients received second-line tocilizumab at a median of 13 days after admission; weakness improved in all, but only 4 survived hospitalization. Among acute-phase survivors, median follow-up was 8.1 months, with final median CTCAE grade of 1. Limb strength normalized before oculobulbar weakness. Most survivors demonstrated partial oncologic response, followed by later disease progression at a median 8 months. No patients were rechallenged with ICI therapy. In severe ICI-myopathy-myocarditis refractory to first-line therapy, escalation with IL-6 receptor blockade was temporally associated with limb muscle strength improvement and favorable long-term functional outcomes among survivors. These findings support further evaluation of tocilizumab as second-line therapy in this high-risk population.
To evaluate the impact of the COVID-19 pandemic on physical growth, nutritional intake, and immune function in children aged 12-24 months. A cross-sectional analysis was conducted utilizing data from the National Health and Nutrition Examination Survey (NHANES). Pre-pandemic (2017-2018) and pandemic (2021-2023) cohorts were compared. Nationally representative data from the United States. Children aged 12-24 months (pre-pandemic: n = 3,904,863; pandemic: n = 3,496,904). No significant differences were observed in physical growth (weight, length, BMI) or macronutrient intake between cohorts. Pandemic-born children had lower vitamin A (437.0 vs. 540.0 mcg/day, p = 0.006) and B12 (2.7 vs. 3.4 mcg/day, p = 0.009) intake but higher vitamin C intake (87.0 vs. 62.8 mg/day, p < 0.001). Inflammatory markers (NLR, PLR, SII) showed minor age- and sex-specific variations but remained within normal ranges. Environmental toxin exposure (cadmium, mercury) was significantly reduced during the pandemic. The COVID-19 pandemic did not substantially alter growth, nutrition, or immune function in infants and toddlers, though micronutrient intakes and toxin exposure shifted. Long-term monitoring is warranted.
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Precision plant protection requires carriers that couple crystalline order with context-responsive release. Hydrogen-bonded organic frameworks (HOFs) offer ordered, metal-free porosity and programmable host-guest interactions to realize this goal. We therefore built a multi-stimuli-responsive system (PYR@PFC-1-F@HACC) using the fluorinated HOF PFC-1-F as a pesticide carrier and label-free in planta fluorescent marker. Pyraclostrobin (PYR) was encapsulated in PFC-1-F with ∼30 wt.% loading, and the resulting composite was surface-coated with chitosan quaternary ammonium salt (HACC). The HACC shell imparts leaf adhesion and biointerface compatibility, thereby enabling enzyme/reactive oxygen species (ROS)/pH-triggered, site-specific release of the fungicide while suppressing leakage near neutrality. Under pathogen-mimicking conditions, the composite shows hierarchically programmed, multi-stimuli-responsive release with diffusion-dominated kinetics. Antifungal activity follows a dual pathway-membrane disruption together with ROS-associated oxidative stress-accompanied by host-defense remodeling. In planta, the platform curtails lesion development, reduces pathogen adhesion/invasion, and exhibits robust foliar retention with acropetal transport. Standard biosafety assays show no significant adverse effects at working doses on peanut seed germination, zebrafish, earthworms, or silkworms. Overall, this study delivers a generalizable, sustainable nanocarrier for precision management of soil-borne crop diseases.
In the gut, the immune system is exposed to self and dietary antigens and antigens from microbes including potential pathogens. How the immune system distinguishes between this wide array of substances to mount appropriate responses that range from tolerance to immunity is not well understood. Accumulating evidence suggests that intestinal goblet cells may play a central role in the ability of the immune system to mount appropriate responses and to discriminate between innocuous substances and potential pathogens. Intestinal goblet cells can form goblet cell-associated antigen passages (GAPs), which acquire luminal substances and deliver them to the immune system. GAPs are closely regulated to not only control where and when antigen delivery to the immune system occurs but also to shape downstream immune outcomes. More recent studies suggest roles for GAPs in health and for GAP dysregulation as a contributor to disease. Here, we review emerging studies and concepts on the role of goblet cells and GAPs, highlighting implications of these observations on the pathogenesis of, and potential therapies for, disease.
To clarify the potential anticancer role of celecoxib and its immune-related mechanisms. We confirmed the antitumor effects of celecoxib using Cell Counting Kit-8, wound-healing, colony-formation, and transwell assays. Network pharmacology and enrichment analyses were performed to identify pathways linking celecoxib to cervical cancer. Based on these results, two-sample and two-step Mendelian randomization (MR) analyses using blood expression quantitative trait loci instruments were conducted to evaluate the causal effect of NEU1 inhibition-the key celecoxib target-on cervical cancer risk and to assess immune cell mediation. Celecoxib significantly inhibited cervical cancer cell proliferation, migration, colony formation, and invasion. Network pharmacology and enrichment analyses consistently highlighted T-cell-related immune pathways. MR revealed that genetically proxied NEU1 inhibition reduced cervical cancer risk (OR = 0.736, 95% CI: 0.566-0.958), with CD25 on CD45RA+ CD4+ non-regulatory T cells mediating 28.458% of the total effect. By integrating genetic causal inference, in vitro experiments, and network pharmacology, our study systematically reveals that celecoxib may exert therapeutic effects by targeting against cervical cancer by targeting NEU1 and modulating CD25 on CD45RA+ CD4+ non-regulatory T cell-related immune pathways. This finding highlights both the novelty and the translational potential of this approach.
Bacteriophage adhesion to intestinal mucus has been proposed as an important mechanism for preventing bacterial infection. However, whether differences in adhesion capacity among closely related phages translate into distinct protective outcomes remains unclear. In this study, we compared two T4-like bacteriophages, S143_2 and W143, to investigate how variation in mucosal adhesion influences antibacterial efficacy and host responses. Both phages exhibited comparable lytic activity against enteropathogenic Escherichia coli (EPEC143) but differed in adhesion capacity to intestinal epithelium. In vitro assays demonstrated that phages adhered to mucus-secreting IPEC-1 cells via a reversible mucus association, with S143_2 displaying significantly stronger adhesion than W143. This difference was further confirmed in vivo, where S143_2 showed higher mucosal retention and a significantly greater mucosa-to-digesta ratio of phage titers in the small intestine. Functionally, enhanced adhesion was associated with improved protective efficacy. In a prophylactic mouse model, pretreatment with S143_2 resulted in reduced body weight loss and lower intestinal pathogen load compared to W143. Furthermore, S143_2 induced a more robust systemic immune response evidenced by elevated serum cytokines and the enrichment of immune-related signaling pathways in the intestinal transcriptome. Together, these findings demonstrate that mucosal adhesion capacity is a critical determinant of phage performance in vivo. Our results highlight that, beyond host range and bactericidal capacity, adhesion properties should be considered a key criterion in the rational selection of bacteriophages for preventing and treating mucosa-associated infections.IMPORTANCEPhages are among the most promising antibiotic alternatives, yet their evaluation has largely focused on bacterial host range and lytic activity. Our findings highlight mucosal adhesion as a previously overlooked but decisive factor in phage efficacy when targeting mucosa-associated infections. Phages with stronger epithelial adhesion exhibit superior protection and immune modulation in the gut, underscoring that adhesion capacity should be integrated as a key criterion in the rational selection and engineering of therapeutic phages.
Cryoglobulinemia comprises heterogeneous disorders caused by immunoglobulins that precipitate at low temperatures, leading to vascular occlusion and immune-mediated tissue injury. Type I disease is typically linked to monoclonal gammopathies, whereas mixed forms (Type II or III) are characterized by immune complex-mediated vasculitis, rheumatoid factor activity, and renal involvement. The immune complexes are generally composed of IgM rheumatoid factor and IgG. We describe a 67-year-old woman with marginal zone lymphoma who developed an unusual cryoglobulinemia phenotype combining monoclonal IgM-κ cryoglobulins with clinical features characteristic of mixed disease, including purpura, transient rheumatoid factor positivity, and renal impairment. Diagnosis was delayed due to initial false-negative cryoglobulin testing and atypical presentation. Despite rituximab therapy, subsequent R-CVP, and intensive plasmapheresis, the patient's condition progressed, ultimately requiring bendamustine-rituximab, after which she deteriorated and died shortly after discharge. The exceptional nature of this case lies the concomitant clinical manifestation of Type I and Type II cryoglobulinemia, which complicated the diagnostic process and therapeutic management. This case underscores a significant diagnostic challenge in hematology.
Comprehensive genomic profiling has prognostic and predictive value for patients with pancreatic adenocarcinoma. We reviewed clinical and molecular data from 4,009 samples from patients who had undergone the BostonGene Tumor Portrait test between 28.10.2021 and 08.10.2024, and 2,181 samples from the BostonGene pancreatic adenocarcinoma meta-cohort, collected from various data hosts and processed by BostonGene automated pipelines. In this high-purity pancreatic adenocarcinoma cohort, 24% harbor homozygous MTAP deletion, and the co-occurrence of KRAS mutations and MTAP loss was common (18.9% of all pancreatic adenocarcinomas). This association identified a subgroup with worse survival outcomes. MTAP-deficient tumors harbor more fibrotic, less immune-enriched microenvironments and have shorter survival. Within the co-mutated tumors, the most frequently detected KRAS variants were G12D, G12V, and G12R, with the last one slightly more related to immune-enriched TME features than the other KRAS variants. Comprehensive genomic profiling is essential for patients with PAAD and carries both prognostic and predictive value. MTAP loss KRAS-mutant PAAD represents a subgroup of immune-excluded PAADs with a poor prognosis.
The effects of time-restricted feeding (TRF) on immune responses during bacterial infection are not well-studied. Here, we subjected mice (6-8 weeks, male) to 8 h of TRF for 30 days and then infected them with a low dose of Mycobacterium tuberculosis (Mtb) H37Rv. During the first 15 days, TRF improved glucose tolerance with marginal weight loss. However, global serum and liver metabolomics alongside liver proteomics indicated that TRF perturbed fatty acid biosynthesis and degradation, steroid hormone biosynthesis, and tyrosine metabolism. Together, these results indicate that TRF potentially affected the distribution and functionality of host immune cells. TRF mice had similar mycobacterial burdens in lungs and spleen at 21 days postinfection but had significantly lower CD3+ T cells in bone marrow and CD4+ T cells in both bone marrow and lungs. Ultimately, we show that TRF induced changes in amino acid and lipid metabolism persist during Mtb infection.
Gastric cancer remains a leading cause of cancer-related mortality worldwide, with high metastatic potential being a critical factor for poor prognosis. Notably, the objective response rate (ORR) of current immunotherapies, such as immune checkpoint inhibitors (ICIs), remains below 20%. Within the tumor microenvironment (TME), the dynamic interactions among immune cells profoundly regulate tumor progression, in which the remarkable plasticity of tumor-associated macrophages (TAMs) plays a pivotal role. Under the induction of microenvironmental signals, TAMs can polarize into either the anti-tumor M1 phenotype or the pro-tumor M2 phenotype. This review summarizes the research progress of macrophage polarization in distant metastasis of gastric cancer, with a specific focus on the regulatory mechanisms of core signaling pathways, including STAT3, PI3K/AKT, and exosomal ncRNA regulatory networks, in macrophage functional reprogramming and metastatic niche formation. Furthermore, we discuss potential immunotherapy strategies centered on modulating macrophage phenotypes, such as CSF1R inhibitors, CD47 blockers, and their combination with ICIs. These findings provide a significant foundation for developing macrophage-targeted therapeutic interventions, screening translational biomarkers, and improving the prognosis of patients with metastatic gastric cancer.
This investigation seeks to determine their potential efficacy in reducing parasite load and mitigating disease progression in immunocompromised hosts. The green synthesis of copper nanoparticles (CNPs) was performed using an extract from Rumex vesicarius. The chronic toxoplasmosis model was developed using the ME49 strain of Toxoplasma gondii. RT in the mice was achieved using dexamethasone (0.25 mg/kg) for 30 days. Then, mice were randomly assigned to 10 distinct groups, which were orally treated with CNP alone (10 and 20 mg/kg) and in combination with pyrimethamine (PM, 5 mg/kg) for 28 days. Next, parasite burden, spleen cell proliferation, and cytokine analysis, molecular analysis of inflammatory and apoptosis gene expression, oxidative/antioxidative biomarkers, and biochemical analysis were evaluated. CNP exhibits a uniform distribution and spherical morphology with an average diameter of 40 nm. CNP, mainly in combination with PM, significantly enhanced the survival rate in RT mice (P < 0.001), whereas it markedly yielded the most substantial reduction in parasite burden across all organs assessed (P < 0.001). The CNP 20 mg/kg + PM 5 mg/kg group demonstrated the highest increases in the gene expression of immune factors (3.78- to 5.79-fold change) (P < 0.001), whereas it reduced the expression of pro-apoptotic markers (P < 0.01). CNP + PM indicated a synergistic interaction in mitigating liver and kidney damage associated with reactivated toxoplasmosis. The combined administration of CNP and PM significantly decreased the parasitic load in cases of reactivated toxoplasmosis, concurrently augmenting antioxidant capacity and innate immune function. These results indicate that CNP holds potential as a valuable adjunctive therapy to enhance treatment efficacy in reactivated toxoplasmosis.
IntroductionOnasemnogene abeparvovec is an adeno-associated virus serotype 9 (AAV9) gene therapy for spinal muscular atrophy (SMA) that is frequently associated with immune-mediated hepatotoxicity. Previous studies have suggested that older age and higher body weight may increase the risk or severity of hepatic enzyme elevation; however, interpretation is limited by heterogeneous immunosuppression strategies across centers.MethodWe conducted a retrospective cohort study of children with SMA who received onasemnogene abeparvovec between 2020 and 2025 and were managed using a unified, protocol-driven immunomodulation strategy. Peak alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values (upper limit of normal [ULN] 35 U/L), as well as the timing of peak transaminase elevations, were analyzed in relation to age and weight at infusion.ResultsAmong 152 children with adequate biochemical follow-up, hepatic enzyme elevation was common: 63.2% had peak ALT ≥2× ULN and 29.6% had peak ALT ≥5× ULN. Weight demonstrated a statistically significant but modest correlation with peak ALT magnitude (r = 0.184, p = 0.023), whereas age was not associated with transaminase severity. In contrast, age correlated with delayed timing of peak ALT (r = 0.229, p = 0.005) and AST (r = 0.283, p < 0.001). All hepatic enzyme abnormalities resolved under protocol-based immunomodulation, and no cases of hepatic failure or synthetic dysfunction occurred.ConclusionWhen managed with a structured, proactive immunomodulation protocol, hepatotoxicity following onasemnogene abeparvovec is predictable and manageable. Weight modestly influences ALT severity, while age primarily affects the timing rather than the magnitude of hepatic immune activation, supporting safe administration across a broad pediatric age and weight spectrum.
Psoriasis is a chronic, systemic inflammatory disease associated with cardiovascular and metabolic comorbidities. It is driven by a sustained immune response in the skin, orchestrated by keratinocytes and both innate and adaptive immune cells. The initial phase of the pathology remains largely unclear. It likely involves the activation of dendritic cells by stress signals from keratinocytes with the NLRP3 inflammasome potentially acting as a key innate sensor. Here we investigate the effects of the topical administration of the selective NLRP3 inhibitor MCC950, in the imiquimod-induced psoriasis-like inflammation model with the aim to achieve the inhibition of both cutaneous and systemic manifestations. Topical MCC950 effectively suppressed NLRP3 inflammasome activation by preventing pro-caspase-1 cleavage and generation of the active p20 subunit in the skin. Gene expression analysis showed that inhibition of NLRP3 suppressed the expression of psoriasis hallmark genes, including Il17, Tnf, S100a8/a9 and Il1b. Furthermore, network analysis identified NLRP3 as a central hub in the psoriasis-associated inflammatory module, supporting the concept that inflammasome inhibition dampens multiple downstream inflammatory pathways. In psoriasis-like condition, MCC950 reduced the skin infiltration of CD3+ T cells, CD11b+ myeloid and CD11c+ dendritic cells. Notably, MCC950 also prevented the systemic effects of psoriasis-like inflammation. Analysis in the spleen shows that it effectively prevented the phenotypic changes induced by psoriasis-like inflammation including the increased frequency of IL-17 A+ T cells. Finally, MCC950 prevented the systemic increase of serum IL-6. These findings highlight that upstream targeting of the NLRP3 inflammasome by MCC950 represents a promising strategy to inhibit both initiation and the systemic spread of psoriasis-like inflammation.
Profound immune suppression in people living with HIV/AIDS predisposes to multiple opportunistic and endemic infections. While HIV/tuberculosis (TB) and HIV/hepatitis C virus (HCV) coinfections are well recognized, simultaneous infection with Mycobacterium tuberculosis, HCV, and Brucella spp. is exceptionally rare. Such triple infection poses substantial diagnostic and therapeutic challenges, especially in endemic settings where overlapping febrile syndromes may obscure multiple concurrent etiologies. We describe a complex case of HIV/TB/HCV/brucellosis coinfection from northwestern China and summarize the diagnostic approach, staged treatment strategy, and long-term outcome. A 43-year-old man with a history of intravenous drug use and poorly controlled HIV infection presented with fatigue and progressive left scrotal swelling. He was found to have advanced HIV disease (CD4+ T-cell count 128/μL; HIV RNA 15,000 copies/mL), pulmonary TB confirmed by bronchoalveolar lavage fluid culture, chronic hepatitis C virus infection, and systemic brucellosis confirmed by blood culture and serology. Baseline liver biochemistry was within normal limits, although imaging suggested underlying chronic hepatic vulnerability. Initial treatment consisted of an individualized anti-tuberculosis regimen with isoniazid, rifampin, ethambutol, and levofloxacin, a 12-week rifampin-levofloxacin regimen for brucellosis, and ART with tenofovir disoproxil fumarate/lamivudine/efavirenz. HCV treatment was deferred because of concern about cumulative hepatotoxicity and contraindication between rifampin and direct-acting antivirals. Poor ART adherence subsequently led to virologic failure and resistance, prompting intensification to bictegravir/emtricitabine/tenofovir alafenamide. After completion of rifampin-based therapy, sofosbuvir/velpatasvir was initiated for HCV. The patient's course was marked by early treatment interruption, delayed virologic suppression, and later recovery under a simplified, multidisciplinary treatment strategy. At month 33, HIV RNA remained 83,500 copies/mL with a CD4+ T-cell count of 80/μL. By month 35, resistance-associated mutations had been detected and ART was intensified. At month 43, HIV RNA had declined to 79 copies/mL, allowing initiation of HCV treatment. By month 48, HIV RNA was 76 copies/mL, HCV RNA was < 25 IU/mL, and the CD4+ T-cell count had risen to 147/μL. At month 54, the patient had achieved substantial immune recovery (CD4+ T-cell count 520/μL) and durable HIV suppression (HIV RNA < 20 copies/mL), with no clinical or radiologic evidence of relapsed TB or brucellosis. This case highlights the diagnostic complexity of overlapping infectious syndromes in an immunocompromised host from an endemic region and demonstrates that even highly complex coinfections can be successfully managed through timely microbiologic confirmation, individualized sequencing of anti-infective and antiretroviral therapies, careful management of drug-drug interactions, and sustained adherence support.