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PubMed2025

The X-Linked TLR7 rs179008 T Allele Is Associated with an Increased Risk of Severe Multisystem Inflammatory Syndrome in Children/Kawasaki-like Syndrome in SARS-CoV-2-Infected Boys.

The X-linked TLR7 rs179008 T allele has been associated with altered antiviral immunity. Given their shared inflammatory pathways and higher pediatric mortality rates in Brazil during the pandemic, we investigated their association with multisystem inflammatory syndrome in children (MIS-C) together with Kawasaki disease (KS) following SARS-CoV-2 infection. A cross-sectional study (2021-2022) analyzed 73 hospitalized children (<13 years) with confirmed COVID-19. Genotyping for TLR7 rs179008, TLR8 (rs3764879, rs2407992), and TLR3 rs3775291 was performed via PCR and Sanger sequencing. MIS-C/KS cases were identified using CDC criteria, with severity classified by the need for ICU care. Statistical analysis included Fisher's exact test and relative risk (RR) calculations. Hemizygous boys carrying the TLR7 T allele had a 1.87-fold higher risk of MIS-C/KS (p = 0.007) and a 1.75-fold increased risk of severe or critical outcomes. The T allele frequency was 2.6× higher in MIS-C/KS cases versus other COVID-19 presentations. All fatalities occurred in boys (3/8 MIS-C cases) with one T-allele carrier. No associations were found for TLR8 or TLR3 variants. The TLR7 rs179008 T allele is a potential genetic risk factor for severe post-COVID-19 inflammatory syndromes in boys, likely due to impaired immune signaling. These findings highlight its utility as a biomarker for risk stratification in pediatric populations.

Humans↗

PubMed2026

Antibody repertoire associated with clinically diverse presentations of pediatric SARS-CoV-2 infection.

Pediatric SARS-CoV-2 infection can give rise to a range of clinical presentations, from asymptomatic or mild cases to severe pulmonary COVID-19, and to multisystem inflammatory syndrome in children (MIS-C). The latter is characterized by hyperinflammation and involvement of multiple organs. Although various aspects of antibody responses to pediatric SARS-CoV-2 infection have been reported, there has been limited research on the parallel antibody responses to both viral and self-antigens. We examined whether clinical phenotypes were linked to particular antiviral antibody and autoantibody profiles. By using custom arrays, we discovered that all manifestations of SARS-CoV-2 infection were linked to increased autoantibody production when compared to uninfected subjects, suggesting that pediatric SARS-CoV-2 infection may predispose to immune dysregulation. We observed subtle differences in autoantibody patterns among infection groups, with some autoantibodies being more associated with mild symptoms and others linked to severe disease manifestations. In particular, subsets of subjects with MIS-C and/or severe COVID-19 exhibited elevated autoreactive antibody responses against thyroperoxidase, IL-13, and IFN-epsilon, although differences across clinical groups did not reach statistical significance. When we compared subjects with MIS-C to those with severe COVID-19, we noted differences in the abundance of IgG (primarily IgG1), but no differences in Fc-mediated effector functions. Our study shows that the antibody repertoire in children varies with the clinical presentation of SARS-CoV-2. Moreover, MIS-C may be linked to abnormal antibody function, indicating that this syndrome-and potentially other post-acute sequelae of SARS-CoV-2 infection-could be related to antibody dysfunction.

Humans↗

PubMed1977

Bypass enteropathy: an inflammatory process in the excluded segment with systemic complications.

Evidence is presented that many of the enteric and systemic manifestations after jejunoileal bypass can be related to an inflammatory process within the bypassed small bowel rather than to the surgically induced sequelae of a short bowel syndrome with malabsorption. Invasion of the excluded segment by fecal flora was associated with a histologically demonstrable inflammatory response of the mucosa. The disorder was of variable severity and duration and occurred in the majority of 28 bypass patients. Progression to a clinical syndrome resembling an acute abdomen occurred in about 15% of the patients. Small bowel ileus and, in some patients, obstruction of the colon were suggested by physical signs and x-ray findings. Surgical exploration in such instances demonstrated an inflammaotry process of the excluded small bowel loops with severe distention of this segment and of the colon, but not organic obstruction. Pneumatosis cystoides intestinalis was a sequal in two patients. Exudative protein loss was documented in the severe cases. Most of the systemic sequelae are comparable to those seen with inflammatory diseases of the bowel such as Crohn's disease. Fever, excessive weight and lean tissue loss, and the involvement of skin, blood vessels, joints and possibly, the liver suggest an immune response as a common factor in the pathogenesis. The clinical improvement with antibiotics such as metronidazole or with restitution of normal bowel continuity indicates that the bacterial flora in the excluded small bowel segment or its byproducts are causally related to the systemic complications. Hyperoxaluria may be primarily the sequela of steatorrhea and not of the inflammatory process.

Adult↗

PubMed1975

Elevated salivary and synovial fluid beta2-microglobulin in Sjogren's syndrome and rheumatoid arthritis.

Beta2-Microglobulin is normally present in low concentrations in serum and other bodily fluids. By use of a radioimmunoassay, elevated concentrations of beta2--microglobulin were found in saliva and synovial fluid from patients with Sjogren's syndrome and rheumatoid arthritis, autoimmune inflammatory diseases that attack and destroy the salivary glands and articular tissues, respectively. Elevated beta2-microglobulin concentrations decreased in the saliva of two patients who simultaneously showed a clinical response to systemic treatment. Measurement of beta2-microglobulin in inflammatory fluids may offer a simple method of quantifying local activity in autoimmune states.

Arthritis, Rheumatoid↗

PubMed2022

Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with TRAF3 mutations.

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients' B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4+ T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.

Autoimmunity↗

PubMed1978

Salivary immunoglobulins in diseases affecting salivary glands.

Inflammatory disorders of the salivary glands cause marked abnormalities in secretion of immunoglobulins. The changes are reversible, however, in a relatively short period of time. More subtle changes in immunoglobulin transport are present in such diseases as Sjogren's syndrome and diabetes. No changes are discernable in alcoholic cirrhosis. Apparently salivary gland basement membranes are much more resistant to derangement than plasma membranes and the secretory IgA system can continue to operate in the face of numerous affronts. If nothing else these findings suggest that vaccination procedures in the region of the salivary glands may produce an inflammatory response, but it would be readily reversible. In addition, one could anticipate a functioning s-IgA system even in salivary glands with alterations in electrolyte transport. It is difficult to anticipate the situation in immunologically compromised patients, such as those on hemodialysis. Fortunately these patients represent a small population and for them at least, caries is a relatively minor concern.

Albumins↗

PubMed2026

Fasudil induces anti-inflammatory transcriptomic changes and increased proliferation in human trisomy 21 neural progenitor cells.

Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here, we report the results of preclinical studies evaluating 24 candidate therapies. RNA sequencing analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglial model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.

Down Syndrome↗

PubMed1978

Diffuse fasciitis with eosinophilia.

The recently described syndrome of diffuse fasciitis with eosinophilia consists of scleroderma-like cutaneous changes in the absence of Raynaud's phenomenon and without visceral involvement. Peripheral blood eosinophilia and hypergammaglobulinemia occur in the majority of patients. The biopsy specimen is characteristic and shows a diffusely thickened fascia with a noticeable inflammatory infiltrate. The etiology and pathogenesis of the entity are unknown. The majority of the cases have been reported to respond to corticosteroids. Pulmonary function abnormalities and rheumatoid factor elevation in one of our patients suggests that this syndrome may be a variant scleroderma or may have previously unrecognized systemic manifestations. The patients' objective responses to corticosteroids were minimal.

Adrenal Cortex Hormones↗

PubMed2025

AI-driven multi-omics modeling of myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic illness with a multifactorial etiology and heterogeneous symptomatology, posing major challenges for diagnosis and treatment. Here we present BioMapAI, a supervised deep neural network trained on a 4-year, longitudinal, multi-omics dataset from 249 participants, which integrates gut metagenomics, plasma metabolomics, immune cell profiling, blood laboratory data and detailed clinical symptoms. By simultaneously modeling these diverse data types to predict clinical severity, BioMapAI identifies disease- and symptom-specific biomarkers and classifies ME/CFS in both held-out and independent external cohorts. Using an explainable AI approach, we construct a unique connectivity map spanning the microbiome, immune system and plasma metabolome in health and ME/CFS adjusted for age, gender and additional clinical factors. This map uncovers altered associations between microbial metabolism (for example, short-chain fatty acids, branched-chain amino acids, tryptophan, benzoate), plasma lipids and bile acids, and heightened inflammatory responses in mucosal and inflammatory T cell subsets (MAIT, γδT) secreting IFN-γ and GzA. Overall, BioMapAI provides unprecedented systems-level insights into ME/CFS, refining existing hypotheses and hypothesizing unique mechanisms-specifically, how multi-omics dynamics are associated to the disease's heterogeneous symptoms.

Humans↗

PubMedDate not supplied

Retardation of colony growth of in vitro bone marrow culture using sera from patients with Felty's syndrome, disseminated lupus erythematosus (SLE), rheumatoid arthritis, and other disease states.

Whole sera and serum fractions from 24 patients with Felty's syndrome, 42 patients with systemic lupus erythematosus (SLE), and 48 patients with rheumatoid arthritis (RA), as well as 30 patients with miscellaneous acute and chronic disease states, were studied for their effect on numbers of mouse bone marrow colonies grown on soft agar in the presence of human colony stimulating factor. Significant early retardation of mouse bone marrow colony counts was recorded in 87.5 percent of Felty's sera, 43 percent of SLE sera, and 12.5 percent of sera from patients with uncomplicated RA. Forty percent of 30 other control patients with acute or chronic inflammatory diseases also showed this activity. No diminution was noted with any of 40 normal control sera. Degree of marrow colony retardation could be directly correlated to amounts of test serum added. No single serum fraction isolated by ion exchange chromatography, gel filtration, or electrophoresis was identified as solely responsible for marrow growth retardation; however lipoprotein fractions including chylomicrons, LDL and HDL showed inhibiting activity in various sera.

Animals↗

PubMed1977

Direct immunofluorescence in the diagnosis of scleroderma syndromes.

Immunofluorescent study of the skin of nine patients with mesenchymal, inflammatory scleroderma (mixed connective tissue disease) revealed immunoglobulin and complement deposition at the basement membrane or within blood vessel walls. The skin specimens of ten patients with systemic scleroderma were negative for immunofluorescence. It is proposed that basement membrane or vascular (or both) immunofluorescence is an excellent means of identifying the infrequent patient who has scleroderma and myositis or lupus erythematosus in whom a corticosteroid response may occur.

Adolescent↗

PubMed2026

Developing Highly Effective Nanoparticle mRNA Therapeutic for Pediatric Acute Respiratory Distress Syndrome.

Sepsis-induced pediatric acute lung injury (ALI) and pediatric acute respiratory distress syndrome (PARDS) are life-threatening conditions with high mortality rates and no current cure. Most ALI/ARDS studies focus on adults, albeit the pediatric population has unique challenges often underrepresented. ALI/PARDS severely impacts pulmonary endothelial cells (ECs), causing endothelial dysfunction and vascular leakage. FOXF1 is a transcription factor critical for lung repair after injury, representing a viable target for ALI/PARDS. This study developed and tested a novel nanoparticle system for precise delivery of FOXF1 mRNA into lung ECs to reduce endothelial damage and improve lung function in mouse model of PARDS. Systemic inflammatory response was induced in neonatal mice after intraperitoneal administration of lipopolysaccharide (LPS). Specifically designed nanoparticles (NP) were used to intravenously deliver stabilized FOXF1 mRNA (FOXF1 NP) after LPS injury to restore FOXF1 expression in injured lung endothelial cells. FOXF1 NP selectively targeted pulmonary ECs without affecting other cell types or organs. FOXF1 NP treatment reduced vascular leakage, enhanced endothelial barrier function, and improved survival of neonatal mice after injury. FOXF1 NP decreased EC apoptosis by restoring the expression of BCL2, an anti-apoptotic FOXF1 target gene. Nanoparticle-based rescue of lung ECs has promise for future treatments of human ALI/PARDS.

endothelial cells↗

PubMed2025

Sex differences in cerebrospinal fluid proteomics of patients with restless legs syndrome.

STUDY OBJECTIVES: The pathobiology of restless legs syndrome (RLS) remains poorly understood, complicating effective treatment. This observational cross-sectional study aimed to identify a cerebrospinal fluid proteomic signature of RLS and to explore sex-specific differences in cerebrospinal fluid proteomics. METHODS: Cerebrospinal fluid samples were collected from 22 untreated RLS patients and 18 controls, matched for age, body mass index, and sex. Proteomic analysis was conducted using the SOMAscan platform, assessing over 7000 peptides. RESULTS: Eight proteins were differentially abundant between patients and controls, with CRP and JAML increased, and TAPBPL and IL1RL1 decreased. Pathway analysis highlighted significant involvement in immune response, coagulation, and cytoskeletal regulation. Analyses were then carried out using sex stratification, comparing men and women separately. Sex-specific analyses revealed more pronounced proteomic alterations in males (68 differentially abundant proteins vs. control males) than in females (17 proteins). Gene enrichment analysis revealed that men with RLS had more involvement in gene regulation and epigenetic factors than control males and women with restless legs syndrome had greater involvement in systemic inflammatory and vascular processes than control females. CONCLUSIONS: This study identified a cerebrospinal fluid proteomic signature in RLS, implicating immune and inflammatory pathways in the disease's pathophysiology. Significant sex differences in protein level suggest potential sex-specific mechanisms in RLS, warranting further investigation. These findings contribute to the current understanding of RLS and could inform future therapeutic strategies.

Humans↗

PubMed2026

Spatially Distinct Bone Marrow Sites Are Asymmetrically Impacted by Inflammatory Cardiovascular Disease.

Cardiovascular disease, a leading cause of mortality globally, is increasingly recognized to involve complex bone marrow-driven inflammatory mechanisms, yet the impact on spatially distinct bone marrow sites and comorbidities remains poorly understood. To address this, we developed MarrowMet, a methodology for whole-body, site-specific quantification of bone marrow activity. The approach involves intravenously injecting the metabolic tracer 18F-fluorodeoxyglucose (18F-FDG) in mice, followed by bone excision to quantify site-specific bone marrow activity, with values then superimposed on a whole-body mouse atlas. After establishing that 18F-FDG bone marrow uptake strongly correlated with inflammatory activity, we applied MarrowMet to map site-specific activation patterns across diverse cardiovascular pathologies, including mouse models of inflammatory atherosclerosis, acute ischemic events, acute respiratory distress syndrome, metabolic syndrome, and aging. MarrowMet guided the selection of bone marrow regions of interest for in-depth mass cytometric analyses, with the skull and sternum emerging as critical sites exhibiting distinct immune and metabolic profiles in cardiovascular disease. These results challenge the prevailing view that femoral marrow represents systemic activity. Together, this work lays a foundation for whole-body exploration of bone marrow heterogeneity, yielding critical insights into cardiovascular disease and associated inflammatory responses, and MarrowMet can be readily adopted to profile other immune mechanisms in a variety of pathologies, including cancer and autoimmune diseases.

(18)F-FDG↗

PubMed1977

Angiolymphoid hyperplasia with eosinophilia: report of 3 cases.

Angiolymphoid hyperplasia with eosinophilia is reported in 3 patients. This lesion is an uncommon reactive vasoproliferative disorder which presents with swellings in the dermis and subcutis. The aetiological agent which produces this tissue response is unknown. Clinically the disease follows a benign prolonged course without evidence of systemic involvement. The histological features consist of a prominent fibroblastic and proliferative vascular reaction associated with an inflammatory infiltrate in which lymphoid aggregates with germinal centres and eosinophils are conspicuous.

Adult↗

PubMed1978

Iron deficiency, infections, and immune function: a reassessment.

Many physicians believe that patients with iron deficiency have an increased susceptibility to infections. Data in the literature, however, are contradictory, and in many instances the reports are vulnerable to critical review. Literature available through 1976 was analyzed in an attempt to define possible relationships between infections, immune function, and states of iron imbalance, both iron deficiency and overload. Critical points that must be considered for an accurate interpretation were emphasized. It seems clear that the inflammatory response, when assessed by skin reactivity, is diminished in iron deficiency. The precise molecular defect remains undefined, but the abnormality is detected by several assays measuring cell-mediated immunity. Normal function is usually restored following iron repletion.

Anemia, Hypochromic↗

PubMed1976

The effect oa a new anti-inflammatory drug, flurbiprofen, on the respiratory, haemodynamic and metabolic responses to E. coli endotoxin shock in the cat.

1 The intravenous administration of E. coli endotoxin (2.0 mg/kg) in cats anaesthetized with sodium pentobarbitone resulted in immediate pulmonary hypertension and reductions in lung compliance and systemic arterial PO2. These effects were abolished, or greatly reduced, by the prior intravenous administration of flurbiprofen in doses (100 and 250 mug/kg and 1.0 mg/kg) which were devoid of cardiovascular or metabolic effects. Flurbiprofen is thus the most active antipyretic-analgesic drug so far examined in this experiment model. 2 Production of lactate, characteristic of the severe, secondary endotoxin shock phase, was delayed only by the highest dose of flubiprofen; hypotension, hypoglycaemia and the reduction in cardiac output which occurs during this phase, were unaffected. 3 These findings are discussed with reference to the treatment of the (shocked lung" syndrome of human septicaemia.

Animals↗

PubMed2026

Integrated multi-omics analyses identify an RAS-SLC11A2-associated molecular framework linking iron metabolism with PCOS-related cardiometabolic risk.

INTRODUCTION: PCOS is a common endocrine disorder with elevated cardiometabolic risk, yet the role of the renin-angiotensin system (RAS)-iron metabolism axis in this comorbidity remains unclear. We explored its underlying mechanisms and evaluated the therapeutic potential of gentiopicroside. METHODS: Integrated multi-omics analyses combining transcriptomics, single-cell RNA sequencing, Mendelian randomization, machine learning, molecular docking, and in vitro functional assays were performed to identify shared molecular pathways and therapeutic targets across PCOS, hypertension, NAFLD, and T2DM. RESULTS: SLC11A2 was consistently dysregulated in PCOS transcriptomic datasets, and associated with iron metabolism, inflammatory response and oxidative stress pathways. Genetic analyses validated RAS-related regulation in hypertension susceptibility and revealed shared genetic architecture between PCOS and cardiometabolic traits. Network and single-cell analyses characterized SLC11A2-associated molecular patterns in disease-relevant cell types; machine learning identified disease-classifying molecular signatures. Gentiopicroside alleviated inflammatory and oxidative stress phenotypes, including reduced IL-6 expression and reactive oxygen species accumulation. CONCLUSION: This study defines an RAS-SLC11A2 molecular framework linking iron metabolism dysregulation to PCOS-related cardiometabolic risk, elucidating the mechanisms connecting ovarian dysfunction, inflammation, oxidative stress and hypertension, and supports gentiopicroside as a promising therapeutic candidate.

Humans↗