Immune Disruption Research Articles

Toxicological effects of polystyrene nanoplastics on marine organisms

Nanoplastic (NP) is an emerging contaminant in recent years, and it has been detected in water and even in polar ice. Further verification of the toxic potential of NPs in marine organisms is needed so that the ecological threat can be minimized. This study investigated the effects of 0.1, 0.2, 0.5, and 1.0μg (g shrimp)−1 of polystyrene nanoplastics (PS-NPs) on immune and oxidative response in Litopenaeus vannamei (L. vannamei) and the survival rate was recorded everyday. After 7 days, the immune and antioxidant parameters were analyzed, and histopathology and accumulation of PS-NPs were observed. The results indicated that the survival rate of shrimp receiving > 0.5μg (g shrimp)−1 PS-NPs was remarkably decreased than that of the control. The immune response results indicated that phagocytic activity (PA) receiving different concentrations of PS-NPs was remarkably decreased than the control. Respiratory burst activity (RB) receiving different concentrations of PS-NPs was remarkably increased than the control. However, superoxide dismutase activity (SOD) receiving > 0.2μg (g shrimp)−1 of PS-NPs was remarkably decreased than the control. The oxidative response results indicated that SOD activity receiving different concentrations of PS-NPs was remarkably decreased than that of the control. The catalase (CAT) activity, SOD mRNA expression, and malondialdehyde (MDA) content receiving different concentrations PS-NPs was remarkably increased than that of the control. In addition, CAT mRNA expression receiving > 0.2μg (g shrimp)−1 of PS-NPs was remarkably increased than the control. The histopathology shows that different concentrations of PS-NPs cause muscle, hepatopancreas, midgut gland, and gill damage. These results indicate that PS-NPs cause toxicity to L. vannamei by immune disruption, increased oxidative stress, and histopathology damage.

COVID-19 as a trigger of Guillain-Barré syndrome: A review of the molecular mechanism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic with serious complications. After coronavirus disease 2019 (COVID-19), several post-acute COVID-19 syndromes (PACSs) and long-COVID sequels were reported. PACSs involve many organs, including the nervous, gustatory, and immune systems. One of the PACSs after SARS-CoV-2 infection and vaccination is Guillain-Barré syndrome (GBS). The incidence rate of GBS after SARS-CoV-2 infection or vaccination is low. However, the high prevalence of COVID-19 and severe complications of GBS, for example, autonomic dysfunction and respiratory failure, highlight the importance of post-COVID-19 GBS. It is while patients with simultaneous COVID-19 and GBS seem to have higher admission rates to the intensive care unit, and demyelination is more aggressive in post-COVID-19 GBS patients. SARS-CoV-2 can trigger GBS via several pathways like direct neurotropism and neurovirulence, microvascular dysfunction and oxidative stress, immune system disruption, molecular mimicry, and autoantibody production. Although there are few molecular studies on the molecular and cellular mechanisms of GBS occurrence after SARS-CoV-2 infection and vaccination, we aimed to discuss the possible pathomechanism of post-COVID-19 GBS by gathering the most recent molecular evidence.

Utility of Class-Switched B-Cells in Diagnosing Common Variable Immunodeficiency

Measuring the relative quantity of peripheral blood class-switched CD27 +IgD- B-cells (CSBs) has previously been proposed as useful in the subclassification of CVID diagnoses. Perhaps incautiously, this practice has been adopted widely among clinical immunologists and has even been included as supportive diagnostic criteria for CVID. Existing research has also shown lower numbers of CSBs in CVID than in IgG deficiency; however, the diagnostic utility of CSBs was not evaluated and additional cohorts have not been studied. This study aimed to determine if low peripheral blood CSB numbers accurately differentiate CVID from other forms of humoral immunodeficiency.We performed a retrospective chart review of all patients at Children's Hospital of Colorado with 8-marker comprehensive B-cell panel results from the time of the panel's implementation in 2020. Inclusion criteria included: age ≥5 years and absolute CD19 B-cell measurement within 60 days of B-cell panel results. Subjects were assigned a diagnosis of CVID based on ICON criteria and by expert opinion when the workup was incomplete, such as in cases with borderline serum immunoglobulin levels or where polysaccharide antibody responses were not available. Patients that did not meet CVID criteria but were considered to have a humoral immunodeficiency based on immunoglobulin levels were separately categorized. Of the patients included (n = 64), 3 met all ICON criteria, 10 had a diagnosis by expert opinion, and 24 had a non-CVID immunological defect. Multinomial logistic regression accounting for age and sex demonstrated no significant association between absolute or percent CSB levels and whether the patient had a known or suspected CVID diagnosis; however, binary logistic regression indicated the odds of having any humoral immunodeficiency, including CVID, increased with decreasing CSB percentage (p = 0.026). Additionally, a linear regression between percent CSBs and in vivo serum IgG levels found a statistically significant relationship (p = 0.046), which has not been demonstrated previously. This observation is consistent with peripheral blood CD27+IgD- CSBs reflecting a person's general ability to class-switch to IgG production. Ultimately these findings suggest that CSBs may have utility as a general indicator of humoral immune disruption but are not an adequately specific metric in forming a CVID diagnosis.

Chronic Mycobacterium avium infection differentially affects the cytokine expression profile of three mouse strains, but has no effect on behavior

One of the most remarkable findings in the immunology and neuroscience fields was the discovery of the bidirectional interaction between the immune and the central nervous systems. This interplay is tightly regulated to maintain homeostasis in physiological conditions. Disruption in this interplay has been suggested to be associated with several neuropsychiatric disorders. Most studies addressing the impact of an immune system disruption on behavioral alterations focus on acute pro-inflammatory responses. However, chronic infections are highly prevalent and associated with an altered cytokine milieu that persists over time. Studies addressing the potential effect of mycobacterial infections on mood behavior originated discordant results and this relationship needs to be further addressed. To increase our understanding on the effect of chronic infections on the central nervous system, we evaluated the role of Mycobacterium avium infection. A model of peripheral chronic infection with M. avium in female from three mouse strains (Balb/c, C57BL/6, and CD-1) was used. The effect of the infection was evaluated in the cytokine expression profile (spleen and hippocampus), hippocampal cell proliferation, neuronal plasticity, serum corticosterone production and mood behavior. The results show that M. avium peripheral chronic infection induces alterations not just in the peripheral immune system but also in the central nervous system, namely in the hippocampus. Interestingly, the cytokine expression profile alterations vary between mouse strains, and are not accompanied by hippocampal cell proliferation or neuronal plasticity changes. Accordingly, no differences were observed in locomotor, anxious and depressive-like behaviors, in any of the mouse strains used. We conclude that the M. avium 2447 infection-induced alterations in the cytokine expression profile, both in the periphery and the hippocampus, are insufficient to alter hippocampal plasticity and behavior.

Proopiomelanocortin (POMC) and psychodermatology.

Psychodermatology is the crossover discipline between Dermatology and Clinical Psychology and/or Psychiatry. It encompasses both Psychiatric diseases that present with cutaneous manifestations (such as delusional infestation) or more commonly, the psychiatric or psychological problems associated with skin disease, such as depression associated with psoriasis. These problems may be the result either of imbalance in or be the consequence of alteration in the homoeostatic endocrine mechanisms found in the systemic hypothalamic-pituitary-adrenal axis or in the local cutaneous corticotrophin-releasing factor-proopiomelanocortin-corticosteroid axis. Alteration in either of these systems can lead to immune disruption and worsening of immune dermatoses and vice-versa. These include diseases such as psoriasis, atopic eczema, acne, alopecia areata, vitiligo and melasma, all of which are known to be linked to stress. Similarly, stress and illnesses such as depression are linked with many immunodermatoses and may reflect alterations in the body's central and peripheral neuroendocrine stress pathways. It is important to consider issues pertaining to skin of colour, particularly with pigmentary disorders.

The potential effect of Moringa oleifera ethanolic leaf extract against oxidative stress, immune response disruption induced by abamectin exposure in Oreochromis niloticus

Abamectin (ABM), a naturally fermented product of Streptomyces avermitilis, is applied to pest control in livestock and agriculture fields. The aim of the current study is to evaluate the protective effects of Moringa oleifera leaf ethanolic extract (MOE) on biochemical changes including oxidative stress indices, immune response marker, lipid profiles as well as mRNA expression of immune related genes, and abamectin (ABM, 5% EC) residue levels in Nile tilapia (Oreochromis niloticus) exposed to a sub-lethal concentration (0.5 µg/l) for 28 days. Disturbance in liver and kidney biomarkers was markedly increased in ABM-exposed fish compared to the control group. Malondialdehyde levels in the liver and brain tissues, as well as the activities of glutathione-s-transferase, superoxide dismutase, and glutathione peroxides, all increased significantly in ABM group. Additionally, ABM exposure increased the levels of interleukin 10 beta and growth factor gene expression. On the other hand, fish exposed to ABM had significantly lower serum alkaline phosphatase, creatinine, high-density lipoprotein, glutathione peroxides in brain, glutathione in liver and brain tissues, lysozyme activity, nitric oxide, immunoglobulin M, tumor necrosis factor, and interleukin 1 beta as compared to the control group. The recorded detrimental effects of ABM on tilapia have been overcome by the addition of MOE to the diet (1%) and ameliorating hepato-renal damage and enhancing antioxidant activity, innate immune responses, and upregulating the anti-inflammatory gene expression. Therefore, it could be concluded that MOE dietary supplementation at 1% could be used to counteract the oxidative stress, immune response disruption induced by abamectin exposure in Oreochromis niloticus, and reduce its accumulation in fish tissues.

Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID

The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease's poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs' phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.

The Cell Transformation Assay: A Historical Assessment of Current Knowledge of Applications in an Integrated Approach to Testing and Assessment for Non-Genotoxic Carcinogens.

The history of the development of the cell transformation assays (CTAs) is described, providing an overview of in vitro cell transformation from its origin to the new transcriptomic-based CTAs. Application of this knowledge is utilized to address how the different types of CTAs, variously addressing initiation and promotion, can be included on a mechanistic basis within the integrated approach to testing and assessment (IATA) for non-genotoxic carcinogens. Building upon assay assessments targeting the key events in the IATA, we identify how the different CTA models can appropriately fit, following preceding steps in the IATA. The preceding steps are the prescreening transcriptomic approaches, and assessment within the earlier key events of inflammation, immune disruption, mitotic signaling and cell injury. The CTA models address the later key events of (sustained) proliferation and change in morphology leading to tumor formation. The complementary key biomarkers with respect to the precursor key events and respective CTAs are mapped, providing a structured mechanistic approach to represent the complexity of the (non-genotoxic) carcinogenesis process, and specifically their capacity to identify non-genotoxic carcinogenic chemicals in a human relevant IATA.

Angina Bullosa Haemorrhagica in COVID 19: A Diagnostic Conundrum. Case Report and Review of Literature

Oral manifestations of COVID-19 are amongst the most obscure and ill-reported. Of these, angina bullosa haemorrhagica is amongst the rarest. Only 2 cases of angina bullosa haemorrhagica in COVID-19 patients have been reported in literature. Angina bullosa haemorrhagica (ABH) is an enigmatic, abstruse condition represented by sudden onset of painful subepithelial, mucosal blood-filled vesicles and bullae in the oral cavity. It is not attributed to any systemic conditions, blood dyscracias or other well-known dermatological pathologies. The occurrence of these lesions in patients of COVID-19 suggests that the underlying pathology of the latter may predispose to ABH and thus help in shedding some light onto the pathogenesis of this obscure disease. Herein we present 2 cases of ABH in patients of COVID-19 within a few weeks of the resolution of the latter. Both patients reported that they had never had this condition before and that this was the first presentation of the symptom. A review of literature shows that the etiopathogenesis of ABH is ambiguous at best and that the pathology underlying the oral manifestation of COVID-19 may well be applicable to ABH as well. Various mechanisms have been proposed to cause oral manifestations in COVID-19 patients. These include imbalance in the RAS pathway causing mucosal disruption, immune dysregulation, deranged cellular immune mechanism and disruption of local immune mechanisms. Since ABH has been reported in COVID 19, it is plausible that some of the mechanisms underlying the pathogenesis of oral manifestations may explain the pathogenesis of ABH.

The Role of Neutrophils in Spondyloarthritis: A Journey across the Spectrum of Disease Manifestations.

Spondyloarthritis (SpA) contemplates the inflammatory involvement of the musculoskeletal system, gut, skin, and eyes, delineating heterogeneous diseases with a common pathogenetic background. In the framework of innate and adaptive immune disruption in SpA, neutrophils are arising, across different clinical domains, as pivotal cells crucial in orchestrating the pro-inflammatory response, both at systemic and tissue levels. It has been suggested they act as key players along multiple stages of disease trajectory fueling type 3 immunity, with a significant impact in the initiation and amplification of inflammation as well as in structural damage occurrence, typical of long-standing disease. The aim of our review is to focus on neutrophils' role within the spectrum of SpA, dissecting their functions and abnormalities in each of the relevant disease domains to understand their rising appeal as potential biomarkers and therapeutic targets.

Comparative toxicogenomics of benzotriazole ultraviolet stabilizers at environmental concentrations in Asian clam (Corbicula fluminea): Insight into molecular networks and behavior

Benzotriazole ultraviolet stabilizers (BUVSs) are widespread emerging pollutants, which can pose exposure risks to benthic organisms. However, the toxicity and mechanisms of BUVSs congeners in benthic clams are far from elucidated. In this study, Asian clams (Corbicula fluminea) were exposed to one of UV-234, UV-326, UV-329, or UV-P at environmentally relevant levels (0.1, 1, and 10 μg/L) for 21 days. Filtration rate (FR) was increased in clams exposed to all BUVSs and there were notable histopathologic changes, including irregular digestive lumen, lipid droplet vacuolation, and degraded epithelial cells. To determine the molecular underpinnings following BUVSs exposure, the transcriptome responses in digestive glands were compared. Differentially expressed genes shared among BUVSs treatments were associated with focal adhesion, TNF-α/NF-κB proinflammatory pathways, and apoptosis. Following this, biochemical analysis of biomarkers related to apoptosis were conducted to further validate response. Exposure to BUVSs inhibited anti-oxidant enzyme activity and induced oxidative stress. Heat shock proteins were also triggered with exposure, and there was an induction of caspase-3 and caspase-9 activity. Molecular responses were not identical in the digestive gland of C. fluminea when comparing responses to BUVSs; nevertheless conserved mechanism (impairment of the oxidative defense system, immune system disruption, and induction of apoptosis) among BUVSs congeners was noted. This study provides novel insight into the toxicity and hazards of BUVSs in benthic organisms.

Current understanding of antibiotic-associated dysbiosis and approaches for its management.

Increased exposure to antibiotics during early childhood increases the risk of antibiotic-associated dysbiosis, which is associated with reduced diversity of gut microbial species and abundance of certain taxa, disruption of host immunity, and the emergence of antibiotic-resistant microbes. The disruption of gut microbiota and host immunity in early life is linked to the development of immune-related and metabolic disorders later in life. Antibiotic administration in populations predisposed to gut microbiota dysbiosis, such as newborns, obese children, and children with allergic rhinitis and recurrent infections; changes microbial composition and diversity; exacerbating dysbiosis and resulting in negative health outcomes. Antibiotic-associated diarrhea (AAD), Clostridiodes difficile-associated diarrhea (CDAD), and Helicobacter pylori infection are all short-term consequences of antibiotic treatment that persist from a few weeks to months. Changes in gut microbiota, which persist even 2 years after antibiotic exposure, and the development of obesity, allergies, and asthma are among the long-term consequences. Probiotic bacteria and dietary supplements can potentially prevent or reverse antibiotic-associated gut microbiota dysbiosis. Probiotics have been demonstrated in clinical studies to help prevent AAD and, to a lesser extent, CDAD, as well as to improve H pylori eradication rates. In the Indian setting, probiotics (Saccharomyces boulardii and Bacillus clausii) have been shown to reduce the duration and frequency of acute diarrhea in children. Antibiotics may exaggerate the consequences of gut microbiota dysbiosis in vulnerable populations already affected by the condition. Therefore, prudent use of antibiotics among neonates and young children is critical to prevent the detrimental effects on gut health.

The Emerging Role of the Mitochondrial Respiratory Chain in Skeletal Aging.

Maintenance of mitochondrial homeostasis is crucial for ensuring healthy mitochondria and normal cellular function. This process is primarily responsible for regulating processes that include mitochondrial OXPHOS, which generates ATP, as well as mitochondrial oxidative stress, apoptosis, calcium homeostasis, and mitophagy. Bone mesenchymal stem cells express factors that aid in bone formation and vascular growth. Positive regulation of hematopoietic stem cells in the bone marrow affects the differentiation of osteoclasts. Furthermore, the metabolic regulation of cells that play fundamental roles in various regions of the bone, as well as interactions within the bone microenvironment, actively participates in regulating bone integrity and aging. The maintenance of cellular homeostasis is dependent on the regulation of intracellular organelles, thus understanding the impact of mitochondrial functional changes on overall bone metabolism is crucially important. Recent studies have revealed that mitochondrial homeostasis can lead to morphological and functional abnormalities in senescent cells, particularly in the context of bone diseases. Mitochondrial dysfunction in skeletal diseases results in abnormal metabolism of bone-associated cells and a secondary dysregulated microenvironment within bone tissue. This imbalance in the oxidative system and immune disruption in the bone microenvironment ultimately leads to bone dysplasia. In this review, we examine the latest developments in mitochondrial respiratory chain regulation and its impacts on maintenance of bone health. Specifically, we explored whether enhancing mitochondrial function can reduce the occurrence of bone cell deterioration and improve bone metabolism. These findings offer prospects for developing bone remodeling biology strategies to treat age-related degenerative diseases.

The Role of Serum Inflammation-Based Scores in Diagnosis and Assessing Remission in Cushing's Disease.

Chronic hypercortisolism causes diverse alterations in the immune system and inflammatory disruptions. Serum inflammation-based scores (SIBS) are indicators of systemic inflammatory status. This study aims to determine the role of SIBS in the diagnosis and evaluation of remission in patients with Cushing's disease (CD). This retrospective cross-sectional study was conducted on 195 participants; 52 patients diagnosed and followed up after treatment with CD, 65 patients with subclinical Cushing's syndrome (SCS), and 78 healthy individuals whose complete blood counts (CBC) were obtained for analysis. Participants with additional diseases or drug use that could affect CBC were excluded from the study. SIBS of the three groups were compared. Scores considered were neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The correlations between SIBS and initial diagnostic tests for hypercortisolism were analyzed. The SIBS of patients with CD at the diagnosis were compared with those after remission. In addition, receiver operator characteristic curve analyses were used to determine the diagnostic accuracy, specificity, and sensitivity of the scores significantly high in the CD group. MLR and SII values were significantly higher in CD patients than in the healthy group (p<0.01). NLR and SII were significantly higher in patients with CD than those with SCS (p<0.05). There were no significant differences between the SCS and the control groups in all SIBS. We determine significant, positive, and moderately correlated findings between SIBS and initial diagnostic tests for hypercortisolism in the CD group (0.30<r<0.70; p<0.05). All of the scores evaluated were significantly lower in the remission of the disease compared to the active period (p<0.001). An optimal cut-off MLR value of 0.20 showed the best diagnostic value (p=0.003; sensitivity, 78.4%; specificity, 51.4%), and an optimal cut-off SII value of 776.20 showed the best diagnostic value (p=0.017; sensitivity, 54.9%; specificity, 70.0%). The SIBS, which can be easily calculated with the data obtained from CBC and do not have additional costs, can contribute to the diagnosis and assessment of remission in patients with CD.

Regional peculiarities of specific immunity in inhabitants of different mountain heights of the Kyrgyz Republic

Kyrgyzstan’s challenging natural conditions and fragile mountain ecosystems can weaken the immune system of individuals residing permanently in high-altitude areas. Our study aimed to explore specific immune protection indicators in healthy populations from the Chui and Naryn regions at varying mountain altitudes. We assessed percentages of CD3+ (T-lymphocytes), CD20+ (B-lymphocytes), CD4+ (T-helper lymphocytes), CD8+ (cytotoxic T-lymphocytes), IRI (immunoregulatory index), CIC (circulating immune complexes), and quantified immunoglobulins of classes A, M, and G. Using immunofluorescent methods and monoclonal antibodies; we determined the percentages of CD3+, CD20+, CD4+, and CD8+. Radial immunodiffusion was used to quantify immunoglobulins of classes A, M, and G, while Falk’s method helped study CIC levels in blood sera. The participant count was based on statistical expert recommendations and G power analysis. The analysis revealed a decrease in the total number of T-lymphocytes (CD3+), primarily due to reduced T-helper and cytotoxic T-lymphocyte subpopulations. However, a significant increase in cytotoxic T-lymphocytes (CD8+) was observed among high-altitude residents. Mountain residents exhibited wide-ranging individual fluctuations for each immunoglobulin class. Our findings suggest varying degrees of immune mechanism disruptions, which maintain natural protection and internal environment constancy at different altitudes, resulting in a mixed type of cellular and humoral immunity suppression. These results emphasize the need for further research in the region and consideration of altitude when implementing disease prevention strategies related to the immune system for the local population.

Can immune gene silencing via dsRNA feeding promote pathogenic viruses to control the globally invasive Argentine ant?

Pest control methods that can target pest species with limited environmental impacts are a conservation and economic priority. Species-specific pest control using RNA interference is a challenging but promising avenue in developing the next generation of pest management. We investigate the feasibility of manipulating a biological invader's immune system using double-stranded RNA (dsRNA) in order to increase susceptibility to naturally occurring pathogens. We used the invasive Argentine ant as a model, targeting the immunity-associated genes Spaetzle and Dicer-1 with dsRNA. We show that feeding with Spaetzle dsRNA can result in partial target gene silencing for up to 28days in the laboratory and 5days in the field. Dicer-1 dsRNA only resulted in partial gene knockdown after 2days in the laboratory. Double-stranded RNA treatments were associated with significant gene expression disruptions across immune pathways in the laboratory and to a lower extent in the field. In total, 12 viruses and four bacteria were found in these ant populations. Some changes in viral loads in dsRNA-treated groups were observed. For example, Linepithema humile Polycipivirus 2 (LhuPCV2) loads increased after 2days of treatment with Spaetzle and Dicer-1 dsRNA treatments in the laboratory. After treatment with the dsRNA in the field, after 5days the virus Linepithema humile toti-like virus 1 (LhuTLV1) was significantly more abundant. However, immune pathway disruption did not result in a consistent increase in microbial infections, nor did it alter ant abundance in the field. Some viruses even declined in abundance after dsRNA treatment. Our study explored the feasibility of lowering a pest's immunity as a control tool. We demonstrate that it is possible to alter immune gene expression of pest species and pathogen loads, although in our specific system the affected pathogens did not appear to influence pest abundance. We provide suggestions on future directions for dsRNA-mediated immune disruption in pest species, including potential avenues to improve dsRNA delivery as well as the importance of pest and pathogen biology. Double-stranded RNA targeting immune function might be especially useful for pest control in systems in which viruses or other microorganisms are prevalent and have the potential to be pathogenic.

Abstract PR011: Histone demethylase KDM5D drives sex-specific differences in colorectal cancer

Abstract Gender exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible oncogenic Kras transgene (KRAS*) and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with KRAS* CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of epithelial cell tight junction and MHC class I complex components. Deletion of KDM5D in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive KDM5D expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, thus providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC. Citation Format: Jiexi Li, Zhengdao Lan, Wenting Liao, James W. Horner, Jielin Liu, Shan Jiang, Hong S. Shim, Max Slotnik, Kyle A. LaBella, Wen-Hao Hsu, Denise J. Spring, Y. Alan Wang, Ronald A. DePinho. Histone demethylase KDM5D drives sex-specific differences in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR011.

Colitis aggravated by Mrgprb2 knockout is associated with altered immune response, intestinal barrier function and gut microbiota.

What is the central question of this study? What is the role of mas-related G protein-coupled receptor X2 (MRGPRX2/Mrgprb2) in ulcerative colitis in relation to the intestinal flora, intestinal barrier and immune response? What is the main finding and its importance? Knockout of mouse Mrgprb2 aggravates dextran sulfate sodium (DSS)-induced colitis, which is associated with altered gut microbiota and immune response and disruption of the intestinal barrier. MRGPRB2 may have a protective effect on DSS-induced colitis. Ulcerative colitis (UC) is a chronic immune-related disease, and changes in the intestinal microbiota and damage to the intestinal barrier contribute to its pathogenesis. Mast cells (MCs) are widely distributed in the gastrointestinal tract and are thought to be related to the pathogenesis of UC. Human mas-related G protein-coupled receptor X2 (MRGPRX2) and its mouse homologue, Mrgprb2, are selectively expressed on MCs to recruit immune cells and modulate host defence against microbial infection. To investigate the role of Mrgprb2 in UC in mice, we compared the differences between Mrgprb2 knockout (b2KO) male mice and wild-type (WT) male mice with dextran sulfate sodium (DSS)-induced colitis in the severity of clinical symptoms, inflammatory cell infiltration, degree of intestinal barrier damage and composition of the intestinal flora. The results showed that weight loss, disease activity index score, colon shortening and colonic pathological damage were significantly increased in b2KO mice while MC activation, cytokine and chemokine secretion, and inflammatory cell infiltration were decreased. In addition, the abundance and diversity of the intestinal microbiota were reduced in b2KO mice. B2KO mice also exhibited a reduction of probiotics such as norank_f_Muribaculaceae and Lactobacillus and increase of harmful bacteria like Escherichia-Shigella. Intestinal mucosal barrier damage of b2KO mice was more severe than that of WT mice due to the attenuated expression of mucin-2 and occludin. These results demonstrated that MRGPRB2 may have a protective effect on DSS-induced colitis by altering the intestinal flora, participating in barrier repair and recruiting inflammatory cells to eliminate pathogens.

Folate Receptor-Mediated Delivery of Cas9 RNP for Enhanced Immune Checkpoint Disruption in Cancer Cells.

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associatedprotein9(Cas9)system offers great opportunities for the treatment of numerous diseases by precise modification of the genome. The functional unit of the system is represented by Cas9/sgRNA ribonucleoproteins (RNP), which mediate sequence-specific cleavage of DNA. For therapeutic applications, efficient and cell-specific transport into target cells is essential. Here, Cas9 RNP nanocarriers are described, which are based on lipid-modified oligoamino amides and folic acid (FolA)-PEG to realize receptor-mediated uptake and gene editing in cancer cells. In vitro studies confirm strongly enhanced potency of receptor-mediated delivery, and the nanocarriers enable efficient knockout of GFP and two immune checkpoint genes, PD-L1 and PVR, at low nanomolar concentrations. Compared with non-targeted nanoparticles, FolA-modified nanocarriers achieve substantially higher gene editing including dual PD-L1/PVR gene disruption after injection into CT26 tumors in vivo. In the syngeneic mouse model, dual disruption of PD-L1 and PVR leads to CD8+ T cell recruitment and distinct CT26 tumor growth inhibition, clearly superior to the individual knockouts alone. The reported Cas9 RNP nanocarriers represent a versatile platform for potent and receptor-specific gene editing. In addition, the study demonstrates a promising strategy for cancer immunotherapy by permanent and combined immune checkpoint disruption.

The Relationship between Inflammation and Hemostasis Disorders in Cardiovascular and Infectious Diseases

Thrombosis and inflammation develop concomitantly during inflammatory, cardiovascular and infectious diseases. Thrombosis induces inflammation and immune system disruption, while inflammation leads to increased hemostasis a vascular thrombosis. Combined use of anti-inflammatory and antithrombotic drugs often leads to adverse effects, for example, nonsteroidal anti-inflammatory drugs induce gastric ulcers, aggravated by bleeding. Vascular endothelial dysfunction plays an important role in the development of thrombosis and inflammation, therefore, research and development of drugs improving endothelial function is a promising approach to preventing thrombotic events arising from inflammation or infectious disease.