Prospective Variation of Cytokine Trends during COVID-19: A Progressive Approach from Disease Onset until Outcome.

COVID-19 is characterized by pronounced hypercytokinemia. The cytokine switch, marked by an imbalance between pro-inflammatory and anti-inflammatory cytokines, emerged as a focal point of investigation throughout the COVID-19 pandemic. However, the kinetics and temporal dynamics of cytokine release remain contradictory, making the development of new therapeutics difficult, especially in severe cases. This study collected serum samples from SARS-CoV-2 infected patients at 72 h intervals and monitored them for various cytokines at each timepoint until hospital discharge or death. Cytokine levels were analyzed based on time since symptom onset and patient outcomes. All cytokines studied prospectively were strong predictors of mortality, particularly IL-4 (AUC = 0.98) and IL-1ß (AUC = 0.96). First-timepoint evaluations showed elevated cytokine levels in the mortality group (p < 0.001). Interestingly, IFN-γ levels decreased over time in the death group but increased in the survival group. Patients who died exhibited sustained levels of IL-1ß and IL-4 and increased IL-6 levels over time. These findings suggest cytokine elevation is crucial in predicting COVID-19 mortality. The dynamic interplay between IFN-γ and IL-4 highlights the balance between Th1/Th2 immune responses and underscores IFN-γ as a powerful indicator of immune dysregulation throughout the infection.

From the mechanism of action to clinical management: A review of cardiovascular toxicity in adult treated with CAR-T therapy.

Chimeric antigen receptor T-cell therapy represents an innovative approach to immunotherapy and currently stands out, particularly for oncohematological patients refractory to traditional treatments. Ongoing trials are further expanding its clinical use for new oncological and non-oncological indications, potentially leading to newer treatment options soon. This new approach, however, also presents challenges, including cardiovascular toxicity. Little is reported in pivotal studies, and some recent retrospective observations suggest a non-negligible incidence of side effects with presentation ranging from mild adverse cardiovascular events to fatal complications in which, in most cases, there is a direct or indirect association with cytokine release syndrome. In this literature review, the hypotheses of an important interface between cytokine release syndrome and cardiotoxicity by chimeric antigen receptor T-cell therapy will be addressed, as will current knowledge about risk factors for cardiotoxicity and recommendations for pre-therapy evaluation, post-infusion monitoring and clinical management of these complications.

Monnieriside A from Evolvulus linarioides promotes antinociceptive effects in models of inflammatory and postoperative pain in male mice.

Monnieriside A (MoA) is a chromone isolated from Evolvulus linarioides. This study investigated the antinociceptive potential of MoA in mice. MoA (0.01-100 mg/kg, i.p.) inhibited nociception in the inflammatory phase of the formalin test without causing motor impairment. MoA (0.1-100 mg/kg, i.p.) also reduced hindpaw mechanical allodynia caused by either intraplantar injection of Complete Freund's Adjuvant (CFA) or surgical paw incision to simulate postoperative pain. Postoperative antinociception was accompanied by reduced IL-1ß levels in the incised paw, assessed by ELISA. The antinociceptive action of MoA (100 mg/kg, i.p.) was preserved in IL-10 knockout mice submitted to paw incision, indicating that IL-10 is not essential to the antinociceptive effect. Interestingly, MoA (100 mg/kg, i.p.) increased the expression of TGF-ß in IL-10 knockout mice, which could be a compensation mechanism leading to an antinociceptive effect in the absence of IL-10.

Resolvin D5 Protects Female Hairless Mouse Skin from Pathological Alterations Caused by UVB Irradiation.

Resolvin D5 (RvD5) is a lipid mediator that has been reported to present anti-inflammatory and pro-resolution properties. Evidence also supports its capability to enhance reactive oxygen species (ROS) production during bacterial infections, which would be detrimental in diseases driven by ROS. The biological activity of RvD5 and mechanisms against UVB irradiation skin pathology have not been investigated so far. Female hairless mice were treated intraperitoneally with RvD5 before UVB stimulus. RvD5 reduced skin edema in a dose-dependent manner as well as oxidative stress by increasing antioxidants (endogenous tissue antioxidant scavenging of cationic radical, iron reduction, catalase activity and reduced glutathione levels) and decreasing pro-oxidants (superoxide anion and lipid peroxidation). RvD5 antioxidant activity was accompanied by enhancement of Nrf2, HO-1 and NQO1 mRNA expression. RvD5 reduced the production of IL-1ß, TNF-α, TGF-ß, and IL-10. RvD5 also reduced the inflammatory cell counts, including mast cells and neutrophils/macrophages. The reduction of oxidative stress and inflammation resulted in diminished matrix metalloproteinase 9 activity, collagen degradation, epidermal thickening and sunburn cell development. Therefore, this study demonstrates, to our knowledge, the first body of evidence that RvD5 can be used to treat UVB skin pathology and unveils, at least in part, its mechanisms of action.

Microglia and Systemic Immunity.

Microglia are specialized immune cells that reside in the central nervous system (CNS) and play a crucial role in maintaining the homeostasis of the brain microenvironment. While traditionally regarded as a part of the innate immune system, recent research has highlighted their role in adaptive immunity. The CNS is no longer considered an immune-privileged organ, and increasing evidence suggests bidirectional communication between the immune system and the CNS. Microglia are sensitive to systemic immune signals and can respond to systemic inflammation by producing various inflammatory cytokines and chemokines. This response is mediated by activating pattern recognition receptors (PRRs), which recognize pathogen- and danger-associated molecular patterns in the systemic circulation. The microglial response to systemic inflammation has been implicated in several neurological conditions, including depression, anxiety, and cognitive impairment. Understanding the complex interplay between microglia and systemic immunity is crucial for developing therapeutic interventions to modulate immune responses in the CNS.

Neutrophil-to-Lymphocyte Ratio and Cytokine Profiling as Predictors of Disease Severity and Survival in Unvaccinated COVID-19 Patients.

BACKGROUND: During the COVID-19 pandemic, identifying reliable biomarkers for predicting disease severity and patient outcomes in unvaccinated individuals is essential. This study evaluates the efficacy of key hematological markers, including leukocyte and neutrophil counts, Neutrophil-to-Lymphocyte Ratio (NLR), and cytokine profiles (IL-6, INF-γ, TNF-α, IL-17A, CCL2, and CXCL10) for predicting the necessity for mechanical ventilation and assessing survival probabilities. METHODS: We conducted an in-depth analysis on a cohort of COVID-19 patients, emphasizing the relationship between NLR, cytokine profiles, and clinical outcomes, utilizing routine leukocyte counting and cytokine quantification by flow cytometry. RESULTS: Elevated leukocyte and neutrophil counts, increased NLR, and significant cytokine elevations such as IL-6 and IL-10 were strongly associated with the need for mechanical ventilation, reflecting a pronounced systemic inflammatory response indicative of severe disease outcomes. CONCLUSION: Integrating hematological markers, particularly NLR and cytokine profiles, is crucial in predicting mechanical ventilation needs and survival in non-vaccinated COVID-19 patients. Our findings provide critical insights into the pathophysiology of COVID-19, supporting the development of more targeted clinical interventions and potentially informing future strategies for managing infectious disease outbreaks.

Current treatment of Psoriasis triggered by Cytokine Storm and future immunomodulation strategies.

Psoriasis is a chronic condition caused by an inflammation mediated mainly by cytokines and T cells. In COVID-19, the same type of imbalance is common, generating the Cytokine Storm and promoting a worsening in the skin conditions of patients with autoimmune disorders, such as Psoriasis. In this context, one of the main mediators of immune responses presented by SARS-CoV-2 infected patients is the Purinergic System. This immunological resource is capable of stimulating the hyperinflammatory state presented by infected individuals, mainly by the activity of the P2X7 receptor, culminating in the Cytokine Storm and consequently in the Psoriasis crisis. Currently, different drugs are used for patients with Psoriasis, such as immunosuppressants and small molecules; however, the safety of these drugs in infected patients has not been analyzed yet. In this context, studies are being developed to evaluate the possible administration of these traditional drugs to COVID-19 patients with Psoriasis crisis. Along with that, researchers must evaluate the potential of administrating P2X7 antagonists to these patients as well, improving both the systemic and the dermatological prognostics of patients, by reducing the Cytokine Storm and its general effects, but also avoiding the provocation of Psoriasis crisis.

Cytokine release syndrome after chimeric antigen receptor T cell therapy in patients with diffuse large B-cell lymphoma: a systematic review.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapy is an innovative technology that has shown promising results in clinical trials. Treatment is based on modifying the patient's own T cells to express artificial surface receptors to specifically recognize and attack the tumor cells. OBJECTIVE: To synthesize available evidence on the incidence and management strategies of cytokine release syndrome in patients with diffuse large B-cell lymphoma who received CAR-T cell therapy. METHODS: This is a systematic literature review. The search was conducted in the PubMed, Scopus, and Web of science databases. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database under number CRD42022359258. RESULTS: Nineteen studies were included with a total of 1193 patients who received CAR-T cell therapy. Of these patients, 804 (67%) developed some degree of cytokine release syndrome. The frequencies of Grade 3 and 4 cytokine release syndrome were 10% and 3%, respectively. The regimen most used in the management of the syndrome included tocilizumab and/or glucocorticoids. CONCLUSION: The results obtained in this review demonstrate high rates of cytokine release syndrome in patients with diffuse large B-cell lymphoma treated with CAR-T cell therapy, however these events are manageable, supporting the conclusion that this therapy is safe in these patients.

Potential use of stem cell therapies for treating osteoarthritis and rheumatoid arthritis.

Arthritis, defined as a chronic inflammation often accompanied by swelling of one or more joints, encompasses more than 100 conditions that affect the joints, tissues around them as well as other connective tissues. This condition causes severe discomfort compromising the quality of life drastically, and thereby inflicts severe financial and social impact on the people affected. The incidence rate of arthritis is increasing all around the globe including the United States every year. In general, osteoarthritis (OA) affects more people in comparison to rheumatoid arthritis (RA). In the USA itself, more than 14 million people are affected by OA in comparison to 1.4 million people suffering from RA. In both conditions, elevated levels of proinflammatory cytokines have been recorded, this incidence generally precedes the cartilage degradation observed in the patients. The use of mesenchymal stem cells (MSCs) has proven to be a safe and efficient therapeutic option for treating many inflammation-rooted pathological conditions. Evidence suggests that MSCs down-regulate the effects of proinflammatory cytokines including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1B, IL-2, and IL-17, and help restore the functions of immune cells. In addition, these cells promote the polarization of M2 phenotype macrophages, thus contributing to the suppression of the inflammatory process and consequentially to cartilage regeneration. Preclinical and clinical trials have proven the safety and effectiveness of this therapy, supported by the fact that these do not provoke any host immune response, and their influence on the cytokine profiles. An attempt to survey the results of stem cell therapy for treating arthritis has been carried out in this review.

Repeated saline injections reduce the pulmonary allergic inflammatory response in rats by inducing short-term stress.

Purpose: Asthma is characterized by pulmonary cell infiltration and hyper-responsiveness of the airways. Short-term stress reduces airway inflammation. Thus, in the present study, we examined the effects of short-term stress induced by repeated treatment with saline injections on the pulmonary allergic inflammatory response in rats. Methods: Adult male rats were divided into three groups: Naïve group (non-sensitized, challenged, or treated rats), Control group (rats sensitized with ovalbumin (OVA) to induce lung inflammation), and Saline group (rats treated for five days with saline before OVA sensitization). Inhalation challenges were performed one week after the booster with aerosolized OVA. On day 18, the effect of saline injections on total and differential leukocytes in bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood was evaluated. The percentage of mucus, serum corticosterone, collagen, cytokines in lung explants, and norepinephrine levels were also measured. Results: OVA sensitization increased the circulating leukocytes and their migration to the lung, decreasing the bone marrow leukocytes. The repeated saline injections prevented this migration by decreasing the number of leukocytes in BAL and blood in the control group. Cytokine Interleukin-4 (IL-4) was higher in the control group than in the naive and saline groups; cytokines Interleukin-6 (IL-6), Interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNFα) were higher in the control and saline groups than in the naïve group; Interferon gamma (IFNγ) was higher in the saline group than in the naive and control groups; norepinephrine increased in animals sensitized with OVA and was higher only in the saline group relative to the naïve group. Conclusions: These results suggest that short-term stress could contribute to the anti-allergic airway inflammation effects of a given treatment.

Anti-IL12p40 autoantibodies in a teenage girl with multiple recurrent abscesses.

More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of anti-IL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.

Unraveling the Interaction between Inflammation and the Cardiometabolic Index in Older Men: A Pilot Study.

Both cardiometabolic and chronic inflammatory diseases pose a significant challenge to global public health, particularly among older adults. Here, we investigated the interplay between systemic inflammatory status and the cardiometabolic index (CMI) in older men with adequate weight or obesity. In this observational cross-sectional study, older men (71.79 ± 7.35 years) were separated into groups with normal weight (NW, n = 34) and obesity (O, n = 32) to assess circulating levels of pro- and anti-inflammatory cytokines and CMI. Overall, the O group showed not only a higher inflammatory status but also increased CMI (p < 0.0001) compared with the NW group. Interestingly, only positive correlations were found between pro- and anti-inflammatory cytokines in both groups. Through multivariate regression analysis, IL-6 (ß = -0.2276, p = 0.0003) and IL-10 (ß = 0.2023, p = 0.0030) significantly influenced CMI in the NW group. No significant results were found in the O group. Our findings reinforce the effects of obesity in inflammaging, as well as suggesting that the influence of cytokines in CMI occurs in older men with normal weight, since the elevated pro-inflammatory profile observed in older men with obesity can interfere in this effect.

Utility of the WHO dengue guidelines in pediatric immunological studies.

Dengue is a significant health problem due to the high burden of critical infections during outbreaks. In 1997, the World Health Organization (WHO) classified dengue as dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). It was revised in 2009 (updated in 2015), and the new guidelines recommended classifying patients as dengue without warning signs (DNS), dengue with warning signs (DWS), and severe dengue (SD). Although the utility of the revised 2009 classification for clinical studies is accepted, for immunological studies it needs to be clarified. We determined the usefulness of the 2009 classification for pediatric studies that analyze the circulating interleukin (IL)-6 and IL-8, two inflammatory cytokines. Plasma levels of IL-6 and IL-8 were evaluated in the acute and convalescent phases by flow cytometry in children with dengue classified using the 1997 and 2009 WHO guidelines. The plasma levels of IL-6 and IL-8 were elevated during the acute and decreased during convalescence, and both cytokines served as a good marker of acute dengue illness compared to convalescence. There were no differences in the plasma level of the evaluated cytokines among children with different clinical severity with any classification, except for the IL-8, which was higher in DWS than DNS. Based on the levels of IL-8, the 2009 classification identified DWS plus SD (hospital-treated children) compared to the DNS group [area under the curve (AUC): 0.7, p = 0.028]. These results support the utility of the revised 2009 (updated in 2015) classification in studies of immune markers in pediatric dengue.

Wound fluid sampling methods and analysis of cytokine mRNA expression in ulcers from patients with diabetes mellitus.

The development of diabetic foot ulcers is a common and severe complication of diabetes that can significantly affect quality of life. The physiological healing cascade does not progress tissue repair in diabetic foot ulcerations in a timely manner. Serum markers from foot ulcers have been used to characterize the healing process of the diabetic foot using various collection techniques. This study aimed to compare the use of cervical brushes and the Levine technique to collect wound fluid from foot ulcers of people with diabetes in order to determine the presence of cytokines. The collected material was used for gene expression analysis of macrophage/monocyte-associated cytokines IL1-ß, IL-6, TNF-α, regulatory cytokine IL-10 and growth factor TGFß, via quantitative polymerase chain reaction (qPCR). Both collection methods produced sufficient amounts of RNA, but significantly more RNA was collected using a cervical brush (brush 224.82 ng/µL vs. Levine 80.90 ng/µL p = 0.0001). Significantly higher levels of expression of the following cytokine genes were detected in samples collected using a cervical brush: IL1-ß (p = 0.0001), IL-6 (p = 0.0106), IL-10 (p = 0.0277) and TGFß (p = 0.0002). Understanding why some wounds are difficult to heal is important for developing more effective treatments, and biomarkers may be useful for predicting the healing trajectory. These results demonstrate that it is possible to collect material from the wound bed for RT-qPCR analysis, and the cervical brush proved to be a simple and rapid method for monitoring cytokine gene expression.

Potential Mechanisms Underlying COVID-19-Mediated Central and Peripheral Demyelination: Roles of the RAAS and ADAM-17.

Demyelination is among the most conspicuous neurological sequelae of SARS-CoV-2 infection (COVID-19) in both the central (CNS) and peripheral (PNS) nervous systems. Several hypotheses have been proposed to explain the mechanisms underlying demyelination in COVID-19. However, none have considered the SARS-CoV-2's effects on the renin-angiotensin-aldosterone system (RAAS). Therefore, our objective in this review is to evaluate how RAAS imbalance, caused by direct and indirect effects of SARS-CoV-2 infection, could contribute to myelin loss in the PNS and CNS. In the PNS, we propose that demyelination transpires from two significant changes induced by SARS-CoV-2 infection, which include upregulation of ADAM-17 and induction of lymphopenia. Whereas, in the CNS, demyelination could result from RAAS imbalance triggering two alterations: (1) a decrease in angiotensin type II receptor (AT2R) activity, responsible for restraining defense cells' action on myelin; (2) upregulation of ADAM-17 activity, leading to impaired maturation of oligodendrocytes and myelin formation. Thus, we hypothesize that increased ADAM-17 activity and decreased AT2R activity play roles in SARS-CoV-2 infection-mediated demyelination in the CNS.

Tumor Necrosis Factor-Alpha Modulates Expression of Genes Involved in Cytokines and Chemokine Pathways in Proliferative Myoblast Cells.

Skeletal muscle regeneration after injury is a complex process involving inflammatory signaling and myoblast activation. Pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) are key mediators, but their effects on gene expression in proliferating myoblasts are unclear. We performed the RNA sequencing of TNF-α treated C2C12 myoblasts to elucidate the signaling pathways and gene networks regulated by TNF-α during myoblast proliferation. The TNF-α (10 ng/mL) treatment of C2C12 cells led to 958 differentially expressed genes compared to the controls. Pathway analysis revealed significant regulation of TNF-α signaling, along with the chemokine and IL-17 pathways. Key upregulated genes included cytokines (e.g., IL-6), chemokines (e.g., CCL7), and matrix metalloproteinases (MMPs). TNF-α increased myogenic factor 5 (Myf5) but decreased MyoD protein levels and stimulated the release of MMP-9, MMP-10, and MMP-13. TNF-α also upregulates versican and myostatin mRNA. Overall, our study demonstrates the TNF-α modulation of distinct gene expression patterns and signaling pathways that likely contribute to enhanced myoblast proliferation while suppressing premature differentiation after muscle injury. Elucidating the mechanisms involved in skeletal muscle regeneration can aid in the development of regeneration-enhancing therapeutics.

Autoantibodies Neutralizing GM-CSF in HIV-Negative Colombian Patients Infected with Cryptococcus gattii and C. neoformans.

BACKGROUND: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016. METHODS: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans). RESULTS: We detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans. CONCLUSIONS: We report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.

Takotsubo syndrome as an outcome of the use of checkpoint inhibitor therapy in patients with COVID-19.

Takotsubo Syndrome (TS) is a heart disease caused by extreme exposure of the body to physical or psychological stress. In the context of COVID-19, the virus can be a significant source of stress, with particular attention being paid to the cytokine storm as a cause of damage to the body. New research shows that the production of specific cytokines is linked to the activation of immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4 on T cells. Although initially beneficial in combating infections, it can suppress defense and aid in disease progression. Therefore, checkpoint inhibitor therapy has been highlighted beyond oncological therapies, given its effectiveness in strengthening the immune system. However, this treatment can lead to excessive immune responses, inflammation, and stress on the heart, which can cause Takotsubo Syndrome in patients. Several studies investigate the direct link between this therapy and cardiac injuries in these patients, which can trigger TS. From this perspective, we must delve deeper into this treatment and consider its effects on the prognosis against SARS-CoV-2 infection.

High levels of anti-factor VIII immunoglobulin G4 and immunoglobulin G total are associated with immune tolerance induction failure in people with congenital hemophilia A and high-responding inhibitors.

Background: Immune tolerance induction (ITI) is the treatment of choice to eradicate neutralizing anti-factor (F)VIII alloantibodies (inhibitors) in people with inherited hemophilia A. However, it is not successful in 10% to 40% of the cases. The biological mechanisms and biomarkers associated with ITI outcome are largely unknown. Objectives: The aim of this study was to investigate the association of plasma cytokines (interferon-γ, tumor necrosis factor, interleukin [IL]-2, IL-4, IL-5, IL-6, IL-10, and IL-17A), chemokines (IL-8/CXCL8, RANTES/CCL5, MIG/CXCL9, MCP-1/CCL2, and IP-10/CXCL10), and anti-FVIII immunoglobulin (Ig) G total, IgG1, and IgG4 with ITI outcome. Methods: In this cross-sectional analysis of the Brazilian Immune Tolerance Study, we assessed plasma levels of anti-FVIII IgGs using an enzyme-linked immunosorbent assay with plasma-derived FVIII and recombinant FVIII as target antigens, immobilized in microplates. Results: We assayed 98 plasma samples of moderately severe and severe (FVIII activity, <2%) people with hemophilia A after completion of a first ITI course. Levels of anti-recombinant FVIII IgG total and IgG4 were higher in people with hemophilia A who failed ITI (IgG total optical density [OD], 0.37; IQR, 0.15-0.73; IgG4 OD, 2.19; IQR, 0.80-2.52) than in those who had partial (IgG total OD, 0.03; IQR, 0.00-0.14; IgG4 OD, 0.39; IQR, 0.09-1.11; P < .0001 for both) or complete success (IgG total OD, 0.04; IQR, 0.00-0.07; IgG4 OD, 0.07; IQR, 0.06-0.40; P < .0001 for both). Plasma cytokines, chemokines, and anti-FVIII IgG1 were not associated with ITI outcome. Conclusion: Our results show that high levels of plasma anti-FVIII IgG4 and IgG total are associated with ITI failure.

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans.

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.