Potential Immunological Mechanisms Research Articles

Novel Immunologic Mechanisms for Fontan-Associated Liver Disease

IntroductionSingle ventricle congenital heart disease resulting in Fontan palliation has led to improved survival, however, Fontan-associated liver disease (FALD) is ubiquitous in this population by adulthood. While lymphopenia has been associated with the degree of FALD, potential immunologic mechanisms remain unstudied, and were the focus of this study. MethodsSingle-nuclei RNA-seq (snRNA-seq) data from liver samples of adolescent Fontan and control patients were analyzed with specific focus on lymphocytes and natural killer (NK) and T-cell fractions. ResultsLiver samples from Fontan patients demonstrated upregulation of endothelial cells (ECs: 4.2 + 1.0 vs. 13.6 + 3.4%, p = 0.037) and total lymphocytes (0.7 + 0.1 vs. 3.6 + 0.7%, p = 0.007), more specifically in NK and T-cells (NK: 0.29 ± 0.16 vs. 1.40 ± 0.64%, p = 0.028 and T-cell: 0.28 ± 0.04 vs. 1.80 ± 1.01%, p = 0.034). Enhanced genes important in T-cell activation and differentiation were demonstrated, as well as those involved in cell-to-cell adhesion and lymphocyte migration. Supporting lymphocyte trafficking, ECs demonstrated amplification of critical chemotactic and lymphocyte recruitment genes. Increased time from Fontan palliation was associated with more dramatic lymphocytic transcriptomic changes. ConclusionsHepatic changes in adolescent Fontan patients suggest that T-cells are contributing to the early development and possible progression of FALD.

The Role of NK and T Cells in Endometriosis.

Endometriosis, a debilitating condition, affects one in ten women of reproductive age. Its pathophysiology remains unclear, though deficiencies in immune surveillance are thought to create an environment conducive to the evasion of ectopic endometrial cells from the immune system. Our research explores the immunological impact of endometriosis both locally and systemically, emphasizing natural killer (NK) and T cell subpopulations. We incorporated 62 female patients who underwent laparoscopic surgery; of those, 47 had endometriosis, and 15 were controls. We collected peritoneal fluid (PF) and peripheral blood (PB) samples which were tagged with monoclonal antibodies and subsequently scrutinized using flow cytometry. Our findings revealed significant differences in immunological profiles based on demographic factors and symptomatology. In the endometriosis cohort, there was an increase in PB CD56HiCD16dim and PF CD8+ CD56dimCD16Hi NK cells. CD16+ CD4 T cell levels were significantly lower in the PB of endometriosis patients who smoke. Individuals with more severe disease displayed significantly higher levels of PB CD16+ CD8 T cells, which also increased in those with non-menstrual pelvic pain. Dysmenorrhea severity correlated with a progressive increase in PF CD8+ CD56dimCD16Hi NK cells. These variations in specific lymphocyte subsets, namely, within NK and T cells, suggest potential immunological mechanisms in the evolution and clinical presentation of endometriosis.

Testosterone and estradiol reduce inflammation of human macrophages induced by anti-SARS-CoV-2 IgG.

COVID-19, the disease caused by SARS-CoV-2, particularly causes severe inflammatory disease in elderly, obese, and male patients. Since both aging and obesity are associated with decreased testosterone and estradiol expression, we hypothesized that decreased hormone levels contribute to excessive inflammation in the context of COVID-19. Previously, we and others have shown that hyperinflammation in severe COVID-19 patients is induced by the production of pathogenic anti-spike IgG antibodies that activate alveolar macrophages. Therefore, we developed an in vitro assay in which we stimulated human macrophages with viral stimuli, anti-spike IgG immune complexes, and different sex hormones. Treatment with levels of testosterone reflecting young adults led to a significant reduction in TNF and IFN-γ production by human macrophages. In addition, estradiol significantly attenuated the production of a very broad panel of cytokines, including TNF, IL-1β, IL-6, IL-10, and IFN-γ. Both testosterone and estradiol reduced the expression of Fc gamma receptors IIa and III, the two main receptors responsible for anti-spike IgG-induced inflammation. Combined, these findings indicate that sex hormones reduce the inflammatory response of human alveolar macrophages to specific COVID-19-associated stimuli, thereby providing a potential immunological mechanism for the development of severe COVID-19 in both older male and female patients.

Clinical and Immunological Features of Bronchial Asthma Comorbid Chronic Urticaria: A Retrospective Study.

Asthma and chronic urticaria (CU) are two high prevalent diseases and often coexist. The underlying relationship and potential immunological mechanism between the two diseases are still unclear. The objective of this study was to investigate the clinical and immunological feature of asthma comorbid with CU. A retrospective study was conducted. Fifty patients with asthma comorbid CU, 50 patients with asthma, and 50 patients with CU alone were included. Age and sex of the patients enrolled were matched. Data of demographic characteristics, clinical manifestations including disease severity (frequency of symptoms, age of onset, disease duration, symptom score, complication with allergic rhinitis) as well as serum immunological index including total IgE (tIgE), allergen-specific IgE (sIgE), and food-specific IgG4 (FS-IgG4), were collected and analyzed. No significant differences in the frequency of symptoms, age of onset, and disease duration were found among the three groups. The score of asthma control test (ACT) in patients with asthma comorbid CU was significantly lower than that of asthma (p = 0.005); however, compared with patients with CU, the 7-day urticaria activity score (UAS7) of patients with asthma comorbid CU did not show obvious differences. Immunological index showed that the positive rates of tIgE, house dust mite (HDM)-sIgE, and FS-IgG4 were different among the three groups (p < 0.05). Patients with asthma comorbid CU had the highest rate of positive tIgE, moderate and severe positive sIgE to HDM. Egg-specific IgG4 (egg-sIgG4) had the highest positive rate in all groups. Patients of asthma comorbid CU obtained the highest rate of severe positive of egg-sIgG4. Our results demonstrated that patients with asthma comorbid CU have lower control level of asthma symptoms, higher tIgE and HDM-sIgE level, and highest rate of severe positive egg-sIgG4. These results indicate that comorbidity of CU in asthma obviously increases the severity of allergens.

Causal association between blood leukocyte counts and vascular dementia: a two-sample bidirectional Mendelian randomization study

While previous observational studies have suggested a link between leukocyte counts and vascular dementia (VD), the causal relationship between leukocyte counts and various subtypes of VD remains elusive. This study aimed to investigate the causal relationship between five types of leukocyte counts and VD, with the goal of improving prevention and treatment strategies. In this study, leukocyte counts were used as the exposure variable, with genome-wide association study (GWAS) data sourced from both the UK Biobank and the Blood Cell Consortium. Additionally, GWAS data for five subtypes of vascular dementia were obtained from the FinnGen database. We conducted rigorous statistical analysis and visualization using Mendelian randomization (MR) to elucidate the potential causal relationship between leukocyte counts and vascular dementia. This study, utilizing MR analysis with data from the UK Biobank and Blood Cell Consortium, identified significant causal associations between increased lymphocyte counts and VD. Specifically, lymphocyte counts were found to be causally related to multiple and mixed VD subtypes. Sensitivity analyses, including MR-Egger regression and MR-PRESSO tests, confirmed the robustness of these findings, with no evidence of reverse causality or significant horizontal pleiotropy detected. The results underscore a potential inflammatory or immunological mechanism in the pathogenesis of VD, highlighting lymphocytes as a key component in their etiology. This investigation establishes a robust association between elevated lymphocyte and leukocyte counts and an increased risk of VD, emphasizing the roles of inflammation, immune activation, and hematological factors in disease pathogenesis.

The potential immunological mechanisms of sepsis.

Sepsis is described as a life-threatening organ dysfunction and a heterogeneous syndrome that is a leading cause of morbidity and mortality in intensive care settings. Severe sepsis could incite an uncontrollable surge of inflammatory cytokines, and the host immune system's immunosuppression could respond to counter excessive inflammatory responses, characterized by the accumulated anti-inflammatory cytokines, impaired function of immune cells, over-proliferation of myeloid-derived suppressor cells and regulatory T cells, depletion of immune effector cells by different means of death, etc. In this review, we delve into the underlying pathological mechanisms of sepsis, emphasizing both the hyperinflammatory phase and the associated immunosuppression. We offer an in-depth exploration of the critical mechanisms underlying sepsis, spanning from individual immune cells to a holistic organ perspective, and further down to the epigenetic and metabolic reprogramming. Furthermore, we outline the strengths of artificial intelligence in analyzing extensive datasets pertaining to septic patients, showcasing how classifiers trained on various clinical data sources can identify distinct sepsis phenotypes and thus to guide personalized therapy strategies for the management of sepsis. Additionally, we provide a comprehensive summary of recent, reliable biomarkers for hyperinflammatory and immunosuppressive states, facilitating more precise and expedited diagnosis of sepsis.

Bacterial vaginosis-driven changes in vaginal T cell phenotypes and their implications for HIV susceptibility.

Bacterial vaginosis (BV) is a dysbiosis of the vaginal microbiome that is prevalent in reproductive-age women worldwide. Adverse outcomes associated with BV include an increased risk of sexually acquired Human Immunodeficiency Virus (HIV), yet the immunological mechanisms underlying this association are not well understood. To investigate BV driven changes to cervicovaginal tract (CVT) and circulating T cell phenotypes, participants with or without BV provided vaginal tract (VT) and ectocervical (CX) tissue biopsies and peripheral blood mononuclear cells (PBMC). Immunofluorescence analysis of genital mucosal tissues revealed a reduced density of CD3+CD4+CCR5+ cells in the VT lamina propria of individuals with compared to those without BV (median 243.8 cells/mm2 BV- vs 106.9 cells/mm2 BV+, p=0.043). High-parameter flow cytometry of VT biopsies revealed an increased frequency in individuals with compared to those without BV of dysfunctional CD39+ conventional CD4+ T cells (Tconv) (median frequency 15% BV- vs 30% BV+, padj=0.0331) and tissue-resident CD69+CD103+ Tconv (median frequency 24% BV- vs 38% BV+, padj=0.0061), previously reported to be implicated in HIV acquisition and replication. Our data suggests that BV elicits diverse and complex VT T cell alterations and expands on potential immunological mechanisms that may promote adverse outcomes including HIV susceptibility.

A Search for New Biological Pathways in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy by Proteomic Research.

Background/Objectives: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease leading to significant morbidity and mortality. Despite advances in genetic diagnosis, the underlying pathophysiology remains incompletely understood. Proteomic studies offer insights into disease mechanisms by identifying altered protein expression patterns. Here, we conducted a proteomic analysis to elucidate molecular pathways associated with CADASIL. Methods: We enrolled genetically diagnosed CADASIL patients and healthy, genetically related controls. Plasma samples were subjected to proteomic analysis using the Olink platform, measuring 552 proteins across six panels. The data were analyzed from several approaches by using three different statistical methods: Exploratory Principal Component Analysis (PCA) and Partial Least Squares-Discriminant Analysis (PLS-DA), differential expression with moderated t-test, and gene set enrichment analysis (GSEA). In addition, bioinformatics analysis, including volcano plot, heatmap, and Variable Importance on Projection (VIP) scores from the PLS-DA model were drawn. Results: Significant differences in protein expression were observed between CADASIL patients and controls. RSPO1 and FGF-19 exhibited elevated levels (p < 0.05), while PPY showed downregulation (p < 0.05) in CADASIL patients, suggesting their involvement in disease pathogenesis. Furthermore, MIC-A/B expression varied significantly between patients with mutations in exon 4 versus exon 11 of the NOTCH3 gene (p < 0.05), highlighting potential immunological mechanisms underlying CADASIL. We identified altered pathways using GSEA, applied after ranking the study data. Conclusions: Our study provides novel insights into the proteomic profile of CADASIL, identifying dysregulated proteins associated with vascular pathology, metabolic dysregulation, and immune activation. These findings contribute to a deeper understanding of CADASIL pathophysiology and may inform the development of targeted therapeutic strategies. Further research is warranted to validate these biomarkers and elucidate their functional roles in disease progression.

Berberine alleviates diabetic retinopathy by regulating the Th17/Treg ratio

BackgroundDiabetic retinopathy (DR) stands as a prominent complication of diabetes. Berberine (BBR) has reported to be effective to ameliorate the retinal damage of DR. Studying the potential immunological mechanisms of BBR on the streptozotocin (STZ) induced DR mouse model will explain the therapeutic mechanisms of BBR and provide theoretical basis for the clinical application of this drug. MethodsC57BL/6 J mice were induced into a diabetic state using a 50 mg/(kg·d) dose of STZ over a 5-day period. Subsequently, they were subjected to a high-fat diet (HFD) for one month. Following a 5-week treatment with 100 mg/(kg·d) BBR, the concentrations of inflammatory factors in the mice's peripheral blood were determined using an enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin staining was employed to scrutinize pathological changes in the mice's retinas, while flow cytometry assessed the proportions of T-lymphocyte subsets and the activation status of dendritic cells (DCs) in the spleen and lymph nodes. CD4+T cells and DC2.4 cell lines were utilized to investigate the direct and indirect effects of BBR on T cells under high glucose conditions in vitro. ResultsFollowing 5 weeks of BBR treatment in the streptozotocin (STZ) mouse model of DR, we observed alleviation of retinal lesions and a down-regulation in the secretion of inflammatory cytokines, namely TNF-α, IL-1β, and IL-6, in the serum of these mice. And in the spleen and lymph nodes of these mice, BBR inhibited the proportion of Th17 cells and promoted the proportion of Treg cells, thereby down-regulating the Th17/Treg ratio. Additionally, in vitro experiments, BBR directly inhibited the expression of the transcription factor RORγt and promoted the expression of the transcription factor Foxp3 in T cells, resulting in a down-regulation of the Th17/Treg ratio. Furthermore, BBR indirectly modulated the Th17/Treg ratio by suppressing the secretion of TNF-α, IL-1β, and IL-6 by DCs and enhancing the secretion of indoleamine 2,3-dioxygenase (IDO) and transforming growth factor-beta (TGF-β) by DCs. This dual action inhibited Th17 cell differentiation while promoting Treg cells. ConclusionOur findings indicate that BBR regulate T cell subpopulation differentiation, reducing the Th17/Treg ratio by directly or indirectly pathway. This represents a potential therapeutic avenue of BBR for improving diabetic retinopathy.

Decreased exercise-induced natural killer cell redistribution in multiple sclerosis

BackgroundExercise may have beneficial effects in MS, remaining controversial its possible disease-modifying effects and which mechanisms might be involved. We evaluated whether exercise-induced lymphocyte redistribution differ in MS patients as compared to controls. MethodsExercise was assessed in 12 relapsing-remitting MS patients and 11 controls in a cycle ergometer, obtaining blood samples before exercise, at maximal exercise capacity (T1), and after resting (T2). Peripheral lymphocytes were evaluated by flow cytometry, assessing chemokine receptor expression to study cell trafficking properties. ResultsLymphocyte subsets in all cases increased after exercise and decreased at resting. However, total natural killer (NK) cells in patients as compared to controls had a lower exercise-induced redeployment at T1 (696 ± 581 cells/µL vs.1502 ± 641 cells/µL, p < 0.01). Evaluating NK cell subsets, CD56bright NK cells numbers decreased in peripheral blood in MS patients after resting (T2), contrasting with values remaining above baseline in healthy controls. NK cells mobilized after exercise at T1 in controls, as compared to patients, had a higher CX3CR1 expression (1402 ± 564/µL vs. 615 ± 548 cell//µL, p < 0.01). ConclusionExercise-induced redeployment of NK cells may be reduced in MS patients, as well as their migration capabilities, pointing to potential immunological mechanisms to be enhanced by exercise training programs.

Exploring Chronic Hypocalcemia: Insights into Autoimmune Polyglandular Syndrome Type 1-A Case Study and Literature Review.

Hypocalcemia is a common occurrence in pediatric patients, attributed to various causes and presenting with diverse clinical manifestations. A prompt evaluation is necessary to determine its underlying cause, whether it presents acutely or chronically, and to tailor treatment based on its severity. Among the potential causes of chronic hypocalcemia, primary hypoparathyroidism stands out. The case of a seven-year-old male patient with hypocalcemia reported in this article serves as an illustration, wherein targeted next-generation sequencing revealed a homozygous p.R257X mutation in the AIRE gene, indicative of autoimmune polyendocrine syndrome type 1 (APS-1). It poses challenges due to its multisystemic nature and involvement of specific autoantibodies, often leading to underdiagnosis, owing to its rarity, varied manifestations, and incomplete penetrance. A comprehensive review of the APS-1 literature was conducted to provide insights into the clinical manifestations, genetic spectrum, potential immunological mechanisms, and current medical strategies. Additionally, the recognition of AIRE gene mutations is crucial for facilitating genetic diagnosis, prognosis, and potential treatment strategies for APS-1. The management of such cases involves individualized approaches to treatment, regular monitoring, medication adjustments, and the early identification of associated conditions.

Prognostic implication of UBE2C + CD8 + T cell in neoadjuvant immune checkpoint blockade plus chemotherapy for locally advanced esophageal cancer

BackgroundImmune checkpoint blockers (ICBs) plus chemotherapy as neoadjuvant therapy for patients with esophageal cancer (EC) has gained substantial attention. This study aimed to investigate the early and mid-term outcome of neoadjuvant ICBs plus chemotherapy and discover immune-associated predictors of major pathological response (MPR) for locally advanced EC. MethodPatients with locally advanced EC who received neoadjuvant ICBs plus chemotherapy were retrospectively included between June 2019 to December 2021. Conjoint analysis of Bulk-RNA seq (GSE165252) and scRNA seq (GSE188900) were used to investigate potential prognostic factors and immunological mechanisms, then multiplexed immunofluorescence was applied to validate. Results76 patients were included. A total of 21 (27.6 %) patients achieved MPR, with 13 (17.1 %) attaining a pathological complete response. Over a median follow-up of 1.8 years, 6 (7.9 %) patients died and 21 (27.6 %) experienced disease recurrence within 0.6 to 2.1 years after surgery. The overall survival rate and recurrence-free survival rate were 93.3 + 2.9 % and 84.8 + 4.2 % at 12 months, 90.8 + 3.7 % and 67.1 + 6.4 % at 24 months, and 90.8 + 3.7 % and 62.9 + 7.2 % at 36 months, respectively. Patients achieving MPR had a significantly lower risk of recurrence compared to non-responders (9.5 % vs 34.5 %, P = 0.017). Analysis of bulk-RNA seq and scRNA-seq revealed that UBE2C and UBE2C + CD8 + T cells were adverse prognostic factors. Immunohistochemistry demonstrated that the non-MPR group had a higher infiltration of UBE2C + immune cells than MPR group after neoadjuvant treatment. Multiplexed immunofluorescence confirmed that infiltrating UBE2C + CD8 + T cells in MPR group were significantly fewer than non-MPR group after neoadjuvant treatment, indicating their poor prognostic role for EC. ConclusionsNeoadjuvant ICBs plus chemotherapy shows promising efficacy in locally advanced EC, with MPR being a significant predictor of lower recurrence risk. Immunological analyses identified UBE2C + CD8 + T cells as adverse prognostic factors, suggesting their potential as biomarkers for patient stratification and treatment response.

PD-L1 Blockade Improves Survival in Sepsis by Reversing Monocyte Dysfunction and Immune Disorder

Monocyte dysfunction is critical to sepsis-induced immunosuppression. Programmed death ligand-1 (PD-L1) has shown a close relationship with inflammatory disorder among animal models and patients. We aimed to investigate the potential beneficial immunologic mechanisms of anti-PD-L1 on monocyte dysfunction of mice with sepsis. Firstly, we assessed the potential association between PD-L1 expression on monocyte subsets and sepsis severity as well as 28-day mortality. In this study, 52 septic patients, 28 septic shock patients, and 40 healthy controls were enrolled and their peripheral whole blood was examined by flow cytometry. Then, cecal ligation and puncture (CLP) were performed for establishing the mouse sepsis model. Subsequently, effects of anti-PD-L1 antibody on monocyte subset, major histocompatibility complex II (MHC II) expression, cytokine production, and survival were investigated. PD-L1 expression on the classical monocytes (CD14 + + CD16 −) was significantly upregulated among septic shock patients and the 28-day death group than non-septic shock group and 28-day survival group (P < 0.05). Compared to septic mice, anti-PD-L1-treated mice had significantly elevated percentages of major histocompatibility complex (MHC) II on peripheral Ly6chi monocyte at 24 h after CLP. Our results showed that the anti-PD-L1 antibody markedly decreased the level of serum inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 in sepsis mice at 24 h, 48 h, and 72 h, respectively (P < 0.05). The survival rate of CLP mice was significantly improved by anti-PD-L1 antibody treatment. Classical monocytes with high expression of PD-L1 were thought to be connected with sepsis progression. The PD-L1 blockade protects from sepsis, at least partially by inhibiting the reversal of monocyte dysfunction.

Therapeutic hyperthermia for the treatment of infection-a narrative review.

Modulating body temperature, mostly through the use of antipyretics, is a commonly employed therapeutic intervention in medical practice. However, emerging evidence suggests that hyperthermia could serve as an adjuvant therapy for patients with infection. We performed a narrative review to explore the application of therapeutic hyperthermia in the treatment of infection. A number of studies have been performed in the pre-antibiotic era, enrolling patients with neurosyphilis and gonococcal infections, with reported cure rates at around 60%-80%. We have outlined the potential molecular and immunological mechanisms explaining the possible beneficial effects of therapeutic hyperthermia. For some pathogens increased temperature exerts a direct negative effect on virulence; however, it is presumed that temperature driven activation of the immune system is probably the most important factor affecting microbial viability. Lastly, we performed a review of modern-era studies where modulation of body temperature has been used as a treatment strategy. In trials of therapeutic hypothermia in patients with infection worse outcomes have been observed in the hypothermia group. Use of antipyretics has not been associated with any improvement in clinical outcomes. In modern-era therapeutic hyperthermia achieved by physical warming has been studied in one pilot trial, and better survival was observed in the hyperthermia group. To conclude, currently there is not enough data to support the use of therapeutic hyperthermia outside clinical trials; however, available studies are in favor of at least a temperature tolerance strategy for non-neurocritical patients.

Emerging Insights Into the Pathophysiology of Multisystem Inflammatory Syndrome Associated With COVID-19 in Children.

Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare delayed hyperinflammatory response to SARS-CoV-2 infection and causes severe morbidity in the pediatric age group. Although MIS-C shares many clinical similarities to Kawasaki disease (KD), important differences in epidemiologic, clinical, immunologic, and potentially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemiologic features include male predominance, peak age of 6 to12 years, and specific racial or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and neurologic complaints, and patients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnormalities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein-as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens-are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that underlie the pathogenesis of MIS-C vs both acute SARS-CoV-2 infection and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine-associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac complications, provide insights into the underlying immunologic pathophysiology, and define similarities and differences with KD.

Sex-biased immunological processes drive hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can manifest with abscesses, sinus tracts, and scarring in the intertriginous areas of the body. HS is characterized by immune dysregulation, featuring elevated levels of myeloid cells, T helper (Th) cells, and pro-inflammatory cytokines, particularly those involved in Th1- and Th17-mediated immunity. In most epidemiological studies, HS shows a strong female sex bias, with reported female-to-male ratios estimated at roughly 3:1, suggesting that sex-related factors contribute to HS pathophysiology. In this article, we review the role of intrinsic and extrinsic factors that contribute to immunological differences between the sexes and postulate their role in the female sex bias observed in HS. We discuss the effects of hormones, X chromosome dosage, genetics, the microbiome, and smoking on sex-related differences in immunity to postulate potential immunological mechanisms in HS pathophysiology. Future studies are required to better characterize sex-biased factors that contribute to HS disease presentations.

Impact of diabetes mellitus on immunity to latent tuberculosis infection.

Tuberculosis (TB) is an infectious disease that poses a major health threat and is one of the leading causes of death worldwide. Following exposure to Mycobacterium tuberculosis (M.tb) bacilli, hosts who fail to clear M.tb end up in a state of latent tuberculosis infection (LTBI), in which the bacteria are contained but not eliminated. Type 2 diabetes mellitus (DM) is a noncommunicable disease that can weaken host immunity and lead to increased susceptibility to various infectious diseases. Despite numerous studies on the relationship between DM and active TB, data on the association between DM and LTBI remains limited. Immunological data suggest that LTBI in the presence of DM leads to an impaired production of protective cytokines and poly-functional T cell responses, accounting for a potential immunological mechanism that could leads to an increased risk of active TB. This review highlights the salient features of the immunological underpinnings influencing the interaction between TB and DM in humans.

Type I interferon signaling promotes radioresistance in head and neck cancer.

Despite the promise of concurrent radiotherapy (RT) and immunotherapy in head and neck cancer (HNC), multiple randomized trials of this combination have had disappointing results. To evaluate potential immunologic mechanisms of RT resistance, we compared pre-treatment HNCs that developed RT resistance to a matched cohort that achieved curative status. Gene set enrichment analysis demonstrated that a pre-treatment pro-immunogenic tumor microenvironment (TME), including type II interferon [interferon gamma (IFNγ)] and tumor necrosis factor alpha (TNFα) signaling, predicted cure while type I interferon [interferon alpha (IFNα)] enrichment was associated with an immunosuppressive TME found in tumors that went on to recur. We then used immune deconvolution of RNA sequencing datasets to evaluate immunologic cell subset enrichment. This identified M2 macrophage signaling associated with type I IFN pathway expression in RT-recurrent disease. To further dissect mechanism, we then evaluated differential gene expression between pre-treatment and RT-resistant HNCs from sampled from the same patients at the same anatomical location in the oral cavity. Here, recurrent samples exhibited upregulation of type I IFN-stimulated genes (ISGs) including members of the IFN-induced protein with tetratricopeptide repeats (IFIT) and IFN-induced transmembrane (IFITM) gene families. While several ISGs were upregulated in each recurrent cancer, IFIT2 was significantly upregulated in all recurrent tumors when compared with the matched pre-RT specimens. Based on these observations, we hypothesized sustained type I IFN signaling through ISGs, such as IFIT2, may suppress the intra-tumoral immune response thereby promoting radiation resistance.

Computational analysis to define efficacy & molecular mechanisms of 7, 4'- Dihydroxyflavone on eosinophilic esophagitis: Ex-vivo validation in human esophagus biopsies.

Eosinophilic Esophagitis (EoE) is a chronic condition characterized by eosinophilic inflammation of the esophagus which leads to esophageal dysfunction with common symptoms including vomiting, feeding difficulty, dysphagia, abdominal pain. Current main treatment options of EoE include dietary elimination and swallowed steroids. Diet elimination approach could lead to identifying the trigger food(s), but it often requires repeated upper endoscopy with general anesthesia and potentially could negatively affect nutrition intake and growth of the child and individuals' quality of life. Although the swallowed steroid treatment of effective, the EoE will universally recur after discontinuation of the treatment. Digestive Tea formula (DTF) has been used by the Traditional Chinese Medicine (TCM) practice to improve GI symptoms in EoE patients, including abdominal pain, GE reflux, and abnormal bowel movement. Previously, a flavonoid small molecule compound 7, 4 dihydroxy flavone (DHF) from Glycyrrhiza uralensis in DTF inhibited eotaxin, Th2 cytokine and IgE production in vitro and in vivo. This study comprehensively evaluates the potential therapeutic and immunological mechanisms underlying DHF improvement of symptoms related to EoE using computational modeling, including target mining, gene ontology enrichment, pathway analyses, protein-protein interaction analyses, in silico molecular docking and dynamic simulation followed by ex-vivo target validation by qRT-PCR using cultured human esophagus biopsy specimen with or without DHF from patients with EoE. Computational analyses defined 29 common targets of DHF on EoE, among which TNF-α, IL-6, IL1β, MAPK1, MAPK3 and AKT1 were most important. Docking analysis and dynamic simulation revealed that DHF directly binds TNF-α with a free binding energy of -7.7 kcal/mol with greater stability and flexibility. Subsequently, in the human esophagus biopsy culture system, significant reduction in levels of TNF-α, IL-6, IL-8 and IL1-β was found in the supernatant of biopsy sample cultured with DHF. Furthermore, the gene expression profile showed significant reduction in levels of TNF-α, IL1-β, IL-6, CCND and MAPK1 in the esophagus biopsy sample cultured with DHF. Taken together, the current study provides us an insight into the molecular mechanisms underlying multi-targeted benefits of DHF in the treatment of EoE and paves the way for facilitating more effective EoE therapies.

Triptolide Inhibits Th17 Response by Upregulating microRNA-204-5p and Suppressing STAT3 Phosphorylation in Psoriasis.

Psoriasis is an immune and inflammation-related skin disease. Triptolide with immunosuppressive and anti-inflammatory properties has been utilized for psoriasis treatment. However, the potential immunological mechanisms of triptolide have not been fully elucidated. Using an imiquimod (IMQ)-induced psoriatic mouse model, we detected the effects of triptolide on psoriasis-like lesions including scales, thickening, and erythema. Methyl thiazol tetrazolium (MTT) cytotoxicity assay was performed for evaluating the influence of triptolide on cell viability. Gene expression at mRNA and protein levels were examined by reverse transcription-quantitative polymerase chain reaction and Western blot analysis, respectively. The combination between microRNA-204-5p (miR-204-5p) and signal transduction and transcription activator-3 (STAT3) was confirmed by luciferase reporter assay. Enzyme-linked immunosorbent assay was conducted to examine interleukin (IL)-17 and interferon-γ (IFN-γ) levels using corresponding kits. Hematoxylin and eosin staining was used for the visualization of epidermal thickness. Flow cytometry analysis was employed for examining T helper (Th) 17 cells. Triptolide ameliorated IMQ-induced psoriatic skin lesions manifested by the decreased psoriasis area and severity indexes (PASI) scores. Triptolide inhibited Th17 cell differentiation from splenocytes. Additionally, triptolide elevated miR-204-5p expression, whereas it downregulated STAT3 expression levels both in vitro and in vivo. Moreover, miR-204-5p directly targeted STAT3 in HaCaT cells. Furthermore, triptolide repressed the expression of proinflammatory cytokines in IMQ-evoked psoriasis-like mice. Triptolide inhibits STAT3 phosphorylation via upregulating miR-204-5p and thus suppressing Th17 response in psoriasis.