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Thrombin, a pleiotropic enzyme involved in coagulation, plays a crucial role in both procoagulant and anticoagulant pathways. Thrombin converts fibrinogen into fibrin, initiates platelet activation, and promotes clot formation. Thrombin also activates anticoagulant pathways, indirectly inhibiting factors involved in coagulation. Tissue factor triggers thrombin generation, and the overexpression of thrombin in various cancers suggests that it is involved in tumor growth, angiogenesis, and metastasis. Increased thrombin generation has been observed in cancer patients, especially those with metastases. Thrombin exerts its effects through protease-activated receptors (PARs), particularly PAR-1 and PAR-2, which are involved in cancer progression, angiogenesis, and immunological responses. Thrombin-mediated signaling promotes angiogenesis by activating endothelial cells and platelets, thereby releasing proangiogenic factors. These functions of thrombin are well recognized and have been widely described. However, in recent years, intriguing new findings concerning the association between thrombin activity and cancer development have come to light, which justifies a review of this research. In particular, there is evidence that thrombin-mediated events interact with the immune system, and may regulate its response to tumor growth. It is also worth reevaluating the impact of thrombin on thrombocytes in conjunction with its multifaceted influence on tumor progression. Understanding the role of thrombin/PAR-mediated signaling in cancer and immunological responses is crucial, particularly in the context of developing immunotherapies. In this systematic review, we focus on the impact of the thrombin-related immune system response on cancer progression., Competing Interests: None declared., (Thieme. All rights reserved.)

Although cancer remains a challenging disease to treat, early detection and removal of primary tumors through surgery or chemotherapy/radiotherapy can offer hope for patients. The privilege paradigm in cancer biology suggests that cell-autonomous mechanisms play a central role in tumorigenesis. According to this paradigm, these cellular mechanisms are the primary focus for the prevention and treatment of cancers. However, this point of view does not present a comprehensive theory for the initiation of cancer and an effective therapeutic strategy. Having an incomplete understanding of the etiology of cancer, it is essential to re-examine previous assumptions about carcinogenesis and develop new, practical theories that can account for all available clinical and experimental evidence. This will not only help to gain a better understanding of the disease, but also offer new avenues for treatment. This review provides evidence suggesting a shift in focus from a cell-autonomous mechanism to systemic mechanisms, particularly the immune system, that are involved in cancer formation., (© 2024 Wiley‐VCH GmbH.)

Autoimmune disorders have risen to be among the most prevalent chronic diseases across the globe, affecting approximately 5-7% of the population. As autoimmune diseases steadily rise in prevalence, so do the number of potential therapeutic strategies to combat them. In recent years, fundamental research investigating autoimmune pathologies has led to the emergence of several cellular targets that provide new therapeutic opportunities. However, key challenges persist in terms of accessing and specifically combating the dysregulated, self-reactive cells while avoiding systemic immune suppression and other off-target effects. Fortunately, the continued advancement of nanomedicines may provide strategies to address these challenges and bring innovative autoimmunity therapies to the clinic. Through precise engineering and rational design, nanomedicines can possess a variety of physicochemical properties, surface modifications, and cargoes, allowing for specific targeting of therapeutics to pathological cell and organ types. These advances in nanomedicine have been demonstrated in cancer therapies and have the broad potential to advance applications in autoimmunity therapies as well. In this review, we focus on leveraging the power of nanomedicine for prevalent autoimmune disorders throughout the body. We expand on three key areas for the development of autoimmunity therapies - avoiding systemic immunosuppression, balancing interactions with the immune system, and elevating current platforms for delivering complex cargoes - and emphasize how nanomedicine-based strategies can overcome these barriers and enable the development of next-generation, clinically relevant autoimmunity therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Endometriosis is a debilitating gynecological disease defined as the presence of endometrium-like epithelium and/or stroma outside the uterine cavity. The most commonly affected sites are the pelvic peritoneum, ovaries, uterosacral ligaments, and the rectovaginal septum. The aberrant tissue responds to hormonal stimulation, undergoing cyclical growth and shedding similar to appropriately located endometrial tissue in the uterus. Common symptoms of endometriosis are painful periods and ovulation, severe pelvic cramping, heavy bleeding, pain during sex, urination and bowel pain, bleeding, and pain between periods. Numerous theories have been proposed to explain the pathogenesis of endometriosis. Sampson's theory of retrograde menstruation is considered to be the most accepted. This theory assumes that endometriosis occurs due to the retrograde flow of endometrial cells through the fallopian tubes during menstruation. However, it has been shown that this process takes place in 90% of women, while endometriosis is diagnosed in only 10% of them. This means that there must be a mechanism that blocks the immune system from removing endometrial cells and interferes with its function, leading to implantation of the ectopic endometrium and the formation of lesions. In this review, we consider the contribution of components of the Major Histocompatibility Complex (MHC)-I-mediated antigen-processing pathway, such as the ERAP, TAP, LMP, LNPEP, and tapasin, to the susceptibility, onset, and severity of endometriosis. These elements can induce significant changes in MHC-I-bound peptidomes that may influence the response of immune cells to ectopic endometrial cells., (© 2024 Izabela Nowak et al., published by Sciendo.)

The world's largest extant carnivorous marsupial, the Tasmanian devil, is challenged by Devil Facial Tumor Disease (DFTD), a fatal, clonally transmitted cancer. In two decades, DFTD has spread across 95% of the species distributional range. A previous study has shown that factors such as season, geographic location, and infection with DFTD can impact the expression of immune genes in Tasmanian devils. To date, no study has investigated within-individual immune gene expression changes prior to and throughout the course of DFTD infection. To explore possible changes in immune response, we investigated four locations across Tasmania that differed in DFTD exposure history, ranging between 2 and >30 years. Our study demonstrated considerable complexity in the immune responses to DFTD. The same factors (sex, age, season, location and DFTD infection) affected immune gene expression both across and within devils, although seasonal and location specific variations were diminished in DFTD affected devils. We also found that expression of both adaptive and innate immune genes starts to alter early in DFTD infection and continues to change as DFTD progresses. A novel finding was that the lower expression of immune genes MHC-II, NKG2D and CD8 may predict susceptibility to earlier DFTD infection. A case study of a single devil with regressed tumor showed opposite/contrasting immune gene expression patterns compared to the general trends observed across devils with DFTD infection. Our study highlights the complexity of DFTD's interactions with the host immune system and the need for long-term studies to fully understand how DFTD alters the evolutionary trajectory of devil immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Raven, Klaassen, Madsen, Jones, Hamilton, Ruiz-Aravena, Thomas, Hamede and Ujvari.)

Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68 + microglia (brain) and CD8 + T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII + microglia and CD11b + CD4 + T cells (brain) and (2) higher CD11b + CD4 + T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery., (© 2024. The Author(s).)

Oropharyngeal squamous cell carcinoma (OPSCC), a subset of head and neck squamous cell carcinoma (HNSCC), involves the palatine tonsils, soft palate, base of tongue, and uvula, with the ability to spread to adjacent subsites. Personalized treatment strategies for Human Papillomavirus-associated squamous cell carcinoma of the oropharynx (HPV + OPSCC) are yet to be established. In this article, we summarise our current understanding of the pathogenesis of HPV + OPSCC, the intrinsic role of the immune system, current ICI clinical trials, and the potential role of small molecule immunotherapy in HPV + OPSCC.

Having been involved in complex cellular regulatory networks and cell-to-cell communications, non-coding RNAs (lncRNAs) have become functional carriers that transmit information between cells and tissues, modulate tumor microenvironments, encourage angiogenesis and invasion, and make tumor cells more resistant to drugs. Immune cells' exosomal lncRNAs may be introduced into tumor cells to influence the tumor's course and the treatment's effectiveness. Research has focused on determining if non-coding RNAs affect many target genes to mediate regulating recipient cells. The tumor microenvironment's immune and cancer cells are influenced by lncRNAs, which may impact a treatment's efficacy. The lncRNA-mediated interaction between cancer cells and immune cells invading the tumor microenvironment has been the subject of numerous recent studies. On the other hand, tumor-derived lncRNAs' control over the immune system has not gotten much attention and is still a relatively new area of study. Tumor-derived lncRNAs are recognized to contribute to tumor immunity, while the exact mechanism is unclear., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Helicobacter pylori (H. pylori) is one of the most prevalent human pathogens and the leading cause of chronic infection in almost half of the population in the world (~59%). The bacterium is a major leading cause of chronic gastritis, gastric and duodenal ulcers, and two type of malignancies, gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. Despite the immune responses mounted by the host, the bacteria are not cleared from the body resulting in a chronic infection accompanied by a chronic inflammation. Herein, a review of the literature discussing H. pylori antigens modulating the immune responses is presented. The mechanisms that are involved in the modulation of innate immune response, include modulation of recognition by pattern recognition receptors (PRRs) such as modulation of recognition by toll like receptors (TLR)4 and TLR5, modulation of phagocytic function, and modulation of phagocytic killing mediated by reactive oxygen species (ROS) and nitric oxide (NO). On the other hands, H. pylori modulates acquired immune response by the induction of tolerogenic dendritic cells (DCs), modulation of apoptosis, induction of regulatory T cells, modulation of T helper (Th)1 response, and modulation of Th17 response., (© 2024 John Wiley & Sons Ltd.)

Cancer cell dissemination involves invasion, migration, resistance to stressors in the circulation, extravasation, colonization, and other functions responsible for macroscopic metastases. By enhancing invasiveness, motility, and intravasation, the epithelial-to-mesenchymal transition (EMT) process promotes the generation of circulating tumor cells and their collective migration. Preclinical and clinical studies have documented intensive crosstalk between the gut microbiome, host organism, and immune system. According to the findings, polymorphic microbes might play diverse roles in tumorigenesis, cancer progression, and therapy response. Microbial imbalances and changes in the levels of bacterial metabolites and toxins promote cancer progression via EMT and angiogenesis. In contrast, a favorable microbial composition, together with microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), can attenuate the processes of tumor initiation, disease progression, and the formation of distant metastases. In this review, we highlight the role of the intratumoral and gut microbiomes in cancer cell invasion, migration, and metastatic ability and outline the potential options for microbiota modulation. As shown in murine models, probiotics inhibited tumor development, reduced tumor volume, and suppressed angiogenesis and metastasis. Moreover, modulation of an unfavorable microbiome might improve efficacy and reduce treatment-related toxicities, bringing clinical benefit to patients with metastatic cancer.

Influenza A virus is a negative-sense single-stranded RNA virus that belongs to Orthomyxoviridae family. Based on the antigenic characteristics of hemagglutinin (HA) and neuraminidase (NA) influenza viruses are classified into multiple subtypes. H9N2 belongs to the low pathogenic Avian Influenza Viruses (AIVs) and is one of the widely spread viruses in poultry, which can pose a threat to humans by directly infecting or providing internal genes for various zoonotic avian influenza strains. It has the potential to directly or indirectly participate in becoming an AIV that causes a human pandemic. When the virus enters a host, the innate immune system is activated first by pattern recognition receptors. The cytokines produced at the site of infection recruit innate immune cells and antigen-presenting cells and those cells subsequently transmit antigenic signals to adaptive immune cells (i.e. B cells and T cells), to trigger specific humoral and cellular immune responses. As a result, humoral and cellular immunity can clear virus and infected cells via antibody-mediated neutralization and cytotoxicity, respectively. Understanding how chicken immune systems respond to H9N2 is a top priority for effectively controlling the virus's spread and designing vaccines. In this review, we comprehensively discuss the role of the chicken immune system in defending against H9N2, and clarify the current limitations in understanding chicken immune responses to H9N2 virus, thereby providing potential directions for future research as research on the chicken respiratory mucosal immune system has been stagnant for more than 20 years especially on how the mucosal immune system in chicken responds to avian influenza.

Modulating the immune system to treat diseases, including myeloid malignancies, has resulted in the development of a multitude of novel therapeutics in recent years. Myelodysplastic syndromes or neoplasms (MDS) and acute myeloid leukemia (AML) are hematologic malignancies that arise from defects in hematopoietic stem and progenitor cells (HSPCs). Dysregulated immune responses, especially in innate immune and inflammatory pathways, are highly associated with the acquisition of HSPC defects in MDS and AML pathogenesis. In addition to utilizing the immune system in immunotherapeutic interventions such as chimeric antigen receptor T cell therapy, vaccines, and immune checkpoint inhibitors, mitigating dysregulation of innate immune and inflammatory responses in MDS and AML remains a priority in slowing the initiation and progression of these myeloid malignancies. This review provides a comprehensive summary of the current progress of diverse strategies to utilize or modulate the immune system in the treatment of MDS and AML., Competing Interests: The authors have no competing interests to disclose.

Inflammation and immune system activation are key pathologic events in the onset and escalation of diabetic retinopathy (DR). Both are driven by cytokines and complement originating from the retinal pigment epithelium (RPE). Despite the RPE's pivotal role, there is no therapeutic tool to specifically interfere with the RPE-related pathomechanism. A therapy that addresses RPE cells and counteracts inflammation and immune response would be of paramount value for the early treatment of DR, where currently are no specific therapies available. Here, we utilized lipoprotein-mimetic lipid nanocapsules to deliver the anti-inflammatory and immunosuppressive drug cyclosporin A (CsA) to RPE cells. Using a mouse model of DR that mirrors all pathologic aspects of human DR, we demonstrate that intravenously applied CsA-loaded lipid nanocapsules comprehensively counteract inflammation and immune system activation. One single injection suppressed the expression of pro-inflammatory cytokines, dampened macrophage infiltration, and prevented macrophage and microglia activation in eyes with DR. This work shows that CsA-loaded lipid nanocapsules can offer new avenues for the treatment of DR., (© 2023. The Author(s).)

Background: Maintenance of immune system integrity is a vital requirement to protect human body against pathogens/cancers. Natural compounds have long been used due to their benefits for the immune system. One of which is bee venom that contains a peptide called melittin having antimicrobial and anticancer effects. Since a limited number of studies regarding the effects of melittin on the immune system have been carried out, we aimed to evaluate the effects of melittin on BALB/c mice immune system parameters., Methods: Female BALB /c mice were treated intraperitoneally (i.p) with 0.75 and 1.5 mg/kg doses of melittin for 14 days (5 doses per week). The negative control group received i.p normal saline whereas the positive controls received i.p 20 mg/kg cyclophosphamide (CYP). Immunological parameters such as hematological parameters, delayed-type hypersensitivity (DTH), hemagglutination titer (HA), spleen cellularity, splenocytes proliferation, as well as spleen and bone marrow histopathological assessment were evaluated., Results: Our findings showed that melittin has no gross pathological effect on the spleen and bone marrow. It was also demonstrated that melittin has no any significant effect on hematological parameters. Melittin did not cause any significant changes to proliferation response of splenocytes to PHA and LPS, spleen cellularity, DTH response, as well as the production of anti-SRBC antibodies. According to our results, melittin at 0.75 and 1.5 mg/kg doses could not induce significant changes on immune parameters and as a result, melittin was found to be safe for the mice immune system., (© 2023. BioMed Central Ltd., part of Springer Nature.)

As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 He, Lan, Jin and Liu.)

Objectives: Although the effects of estimated dose of radiation to immune cells (EDRIC) in stage III NSCLC, LA-NSCLC, LS-SCLC and esophageal cancer on clinical outcomes have been studied, its impact in early-stage non-small cell lung cancer (ES-NSCLC) is unknown. In this study, we evaluated the role of EDRIC and identified the factors influencing EDRIC in this population., Methods and Materials: We retrospectively analyzed 211 pathologically confirmed ES-NSCLC patients who were treated with SBRT between 2007 and 2020. EDRIC was calculated based on the model developed by Jin et al. and improved by Ladbury et al. Kaplan-Meier method and Cox proportional hazards regression were adopted to estimate CSS, PFS, LPFS, and DMFS. Pearson correlation was used to assess the correlation between variables. We further validated our findings in an independent cohort of 119 patients with ES-NSCLC., Results: A total of 211 patients were included with median follow-up of 48 months in the training cohort. The median EDRIC was 2.178 Gy (range: 0.426-6.015). GTV showed a positive correlation with EDRIC (r = 0.707, P = 0.000). In multivariate analysis, higher EDRIC was significantly associated with worse CSS (HR = 1.468, P = 0.009) and DMFS (HR = 1.491, P = 0.016). Considering each EDRIC quartile, there was a significant difference in CSS between 1st and 4th and 1st and 3rd quartile (P = 0.000, P = 0.004, respectively); and DMFS between 1st and 4th,1st and 3rd, and 1st and 2nd quartile (P = 0.000, P = 0.000, P = 0.008, respectively). In the subgroup and validation cohort, EDRIC was also the important prognostic predictor of CSS and DMFS using multivariate analysis., Conclusion: EDRIC was an independent predictor of CSS and DMFS in ES-NSCLC, and it was affected by GTV and tumor location. Though EDRIC is a critical determinant of treatment outcomes, it is quantifiable and potentially modifiable. Additional researches exploring the feasibility of achieving lower EDRIC while maintaining adequate tumor coverage during radiotherapy are warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Canine distemper virus (CDV) causes systemic infection resulting in severe and often fatal disease in a large spectrum of animal host species. The virus is closely related to measles virus and targets myeloid, lymphoid, and epithelial cells, but CDV is more virulent and the infection spreads more rapidly within the infected host. Here, we aimed to study the pathogenesis of wild-type CDV infection by experimentally inoculating ferrets with recombinant CDV (rCDV) based on an isolate directly obtained from a naturally infected raccoon. The recombinant virus was engineered to express a fluorescent reporter protein, facilitating assessment of viral tropism and virulence. In ferrets, this wild type-based rCDV infected myeloid, lymphoid, and epithelial cells, and the infection resulted in systemic dissemination to multiple tissues and organs, especially those of the lymphatic system. High infection percentages in immune cells resulted in depletion of these cells both from circulation and from lymphoid tissues. The majority of CDV-infected ferrets reached their humane endpoints within 20 d and had to be euthanized. In that period, the virus also reached the central nervous system in several ferrets, but we did not observe the development of neurological complications during the study period of 23 d. Two out of 14 ferrets survived CDV infection and developed neutralizing antibodies. We show for the first time the pathogenesis of a non-adapted wild type-based rCDV in ferrets. IMPORTANCE Infection of ferrets with recombinant canine distemper virus (rCDV) expressing a fluorescent reporter protein has been used as proxy to understand measles pathogenesis and immune suppression in humans. CDV and measles virus use the same cellular receptors, but CDV is more virulent, and infection is often associated with neurological complications. rCDV strains in current use have complicated passage histories, which may have affected their pathogenesis. Here, we studied the pathogenesis of the first wild type-based rCDV in ferrets. We used macroscopic fluorescence to identify infected cells and tissues; multicolor flow cytometry to determine viral tropism in immune cells; and histopathology and immunohistochemistry to characterize infected cells and lesions in tissues. We conclude that CDV often overwhelmed the immune system, resulting in viral dissemination to multiple tissues in the absence of a detectable neutralizing antibody response. This virus is a promising tool to study the pathogenesis of morbillivirus infections., Competing Interests: The authors declare no conflict of interest.

According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.

Women worldwide are more likely to develop breast cancer (BC) than any other type of cancer. The treatment of BC depends on the subtype and stage of the cancer, such as surgery, radiotherapy, chemotherapy, and immunotherapy. Although significant progress has been made in recent years, advanced or metastatic BC presents a poor prognosis, due to drug resistance and recurrences. During embryonic development, myeloid-derived suppressor cells (MDSCs) develop that suppress the immune system. By inhibiting anti-immune effects and promoting non-immune mechanisms such as tumor cell stemness, epithelial-mesenchymal transformation (EMT) and angiogenesis, MDSCs effectively promote tumor growth and metastasis. In various BC models, peripheral tissues, and tumor microenvironments (TME), MDSCs have been found to amplification. Clinical progression or poor prognosis are strongly associated with increased MDSCs. In this review, we describe the activation, recruitment, and differentiation of MDSCs production in BC, the involvement of MDSCs in BC progression, and the clinical characteristics of MDSCs as a potential BC therapy target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Wang, Zhou and Yang.)

Pathological scars are the result of over-repair and excessive tissue proliferation of the skin injury. It may cause serious dysfunction, resulting in psychological and physiological burdens on the patients. Currently, mesenchymal stem cells-derived exosomes (MSC-Exo) displayed a promising therapeutic effect on wound repair and scar attenuation. But the regulatory mechanisms are opinions vary. In view of inflammation has long been proven as the initial factor of wound healing and scarring, and the unique immunomodulation mechanism of MSC-Exo, the utilization of MSC-Exo may be promising therapeutic for pathological scars. However, different immune cells function differently during wound repair and scar formation. The immunoregulatory mechanism of MSC-Exo would differ among different immune cells and molecules. Herein, this review gave a comprehensive summary of MSC-Exo immunomodulating different immune cells in wound healing and scar formation to provide basic theoretical references and therapeutic exploration of inflammatory wound healing and pathological scars., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Zhao et al.)

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells' role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage.

The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is attractive, although to date, under-exploited. In this review we discuss the importance of co-stimulatory members of the TNFRSF in optimal immune response generation, the rationale behind targeting these receptors for immunotherapy, the success of targeting them in pre-clinical studies and the challenges in translating this success into the clinic. The efficacy and limitations of the currently available agents are discussed alongside the development of next generation immunostimulatory agents designed to overcome current issues, and capitalize on this receptor class to deliver potent, durable and safe drugs for patients., Competing Interests: MC acts as a consultant for a number of biotech companies, being retained as a consultant for BioInvent International and has received research funding from BioInvent International, GSK, UCB, iTeos, and Roche and receives institutional payments and royalties from patents and licenses relating to antibody immunotherapy. OD has received research funding from BioInvent International, outside of the current work. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dadas, Ertay and Cragg.)

Coeliac disease (CeD) is an immune-mediated disorder triggered by the ingestion of gluten and an as yet unidentified environmental factor in genetically predisposed individuals. The disease involves a major autoimmune component that primarily damages the intestinal mucosa; although, it also has systemic involvement. The Th1 inflammatory response is one of the main events leading to mucosal damage; although, enterocytes and the innate immune response also participate in the pathological mechanism. In this study, we performed an analysis of the gene expression profile of the intestinal mucosa of patients with active disease and compared it with that of patients who do not suffer from gluten-related disorders but report dyspeptic symptoms. This analysis identified 1781 differentially expressed (DE) genes, of which 872 were downregulated and 909 upregulated. Gene Ontology and pathway analysis indicated that the innate and adaptive immune response, in particular the Th1 pathway, are important pathogenetic mechanisms of CeD, while the key cytokines are IL27, IL21, IL2, IL1b, TNF, CSF2 and IL7, as well as type I (IFNA1, IFNA2) and type II (IFNG) interferons. Finally, the comparison between the DE genes identified in this study and those identified in our previous study in the intestinal mucosa of patients with non-celiac gluten sensitivity (NCGS) revealed a high degree of molecular overlap. About 30% of the genes dysregulated in NCGS, most of which are long non-coding RNAs, are also altered in CeD suggesting that these diseases may have a common root (dysregulated long non-coding RNAs) from which they develop towards an inflammatory phenotype of variable degree in the case of CeD and NCGS respectively.

Duchenne muscular dystrophy (DMD) is a progressive severe muscle-wasting disease caused by mutations in DMD, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of Prevotella. Furthermore, the absence of gut microbes through the generation of mdx germ-free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

The effects of irradiation on tumor tissue and the host immune system are interrelated. The antitumor effect of irradiation is attenuated in the immunocompromised hosts. In addition, radiation alone positively and negatively influences the host immune system. The positive effects of radiation are summarized by the ability to help induce and enhance tumor-antigen-specific immune responses. The cancer-immunity cycle is a multistep framework that illustrates how the tumor-antigen-specific immune responses are induced and how the induced antigen-specific immune cells exert their functions in tumor tissues. Irradiation affects each step of this cancer-immunity cycle, primarily in a positive manner. In contrast, radiation also has negative effects on the immune system. The first is that irradiation has the possibility to kill irradiated effector immune cells. The second is that irradiation upregulates immunosuppressive molecules in the tumor microenvironment, whereas the third is that irradiation to the tumor condenses immunosuppressor cells in the tumor microenvironment. When used in conjunction with radiotherapy, immune checkpoint inhibitors can further leverage the positive effects of radiation on the immune system and compensate for the negative effects of irradiation, which supports the rationale for the combination of radiotherapy and immune checkpoint inhibitors. In this review, we summarize the preclinical evidence for the reciprocal effects of radiation exposure and the immune system, and up-front topics of the combination therapy of immune checkpoint inhibitors and radiotherapy., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), is a heterogeneous state of chronic intestinal inflammation with no exact known cause. Intestinal innate immunity is enacted by neutrophils, monocytes, macrophages, and dendritic cells (DCs), and innate lymphoid cells and NK cells, characterized by their capacity to produce a rapid and nonspecific reaction as a first-line response. Innate immune cells (IIC) defend against pathogens and excessive entry of intestinal microorganisms, while preserving immune tolerance to resident intestinal microbiota. Changes to this equilibrium are linked to intestinal inflammation in the gut and IBD. IICs mediate host defense responses, inflammation, and tissue healing by producing cytokines and chemokines, activating the complement cascade and phagocytosis, or presenting antigens to activate the adaptive immune response. IICs exert important functions that promote or ameliorate the cellular and molecular mechanisms that underlie and sustain IBD. A comprehensive understanding of the mechanisms underlying these clinical manifestations will be important for developing therapies targeting the innate immune system in IBD patients. This review examines the complex roles of and interactions among IICs, and their interactions with other immune and non-immune cells in homeostasis and pathological conditions.

Sarcomas are heterogeneous and aggressive malignant tumors with variable responses to current standard treatments being usually incurable for those patients with metastatic and unresectable diseases. The lack of curative strategies has led to develop new therapies in the treatment of sarcomas where the role of immune system is an evolving field. Most sarcomas often exhibit an immunosuppressive microenvironment, which reduces their capacity to trigger an immune response. Therefore, sarcomas are broadly considered as an "immune cold" tumor, although some studies have described a great immune heterogeneity across sarcoma subtypes. Sarcoma cells, like other tumors, evade their immune destruction through a variety of mechanisms, including expansion and recruitment of myeloid derived suppressor cells (MDSCs). MDSCs are immature myeloid cells that have been correlated with a reduction of the therapeutic efficacy, including immunotherapy, tumor progression and worst prognosis. Consequently, different strategies have been developed in recent years to target MDSCs in cancer treatments. This chapter discusses the role of MDSCs in sarcomas and their current potential as a therapeutic target in these malignancies., Competing Interests: Conflicts of interest The authors declare no conflict of interest. The authors have designed and conceived both figures. These figures have not copyright permission for any thirds., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diabetic retinopathy is one of the most common complications of diabetes mellitus and the leading cause of low vision and blindness worldwide. Mounting evidence demonstrates that inflammation is a key mechanism driving diabetes-associated retinal disturbance, yet the pathophysiological process and molecular mechanisms of inflammation underlying diabetic retinopathy are not fully understood. Cytokines, chemokines, and adhesion molecules interact with each other to form a complex molecular network that propagates the inflammatory and pathological cascade of diabetic retinopathy. Therefore, it is important to understand and elucidate inflammation-related mechanisms behind diabetic retinopathy progression. Here, we review the current understanding of the pathology and pathogenesis of inflammation in diabetic retinopathy. In addition, we also summarize the relevant clinical trials to further suggest inflammation-targeted therapeutics for prevention and management of diabetic retinopathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yue, Shi, Luo, Weng, Wu and Zheng.)

Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of patient morbidity. Idiopathic nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches., (Copyright © 2022 by the American Society of Nephrology.)

Background: The response of solid tumors such as papillary thyroid cancer (PTC) to immune checkpoint inhibitors (ICIs) is highly variable. The biological basis of this variability remains unknown., Methods: To test the hypothesis that preconditioning of the immune system modulates the therapeutic effect of ICIs, we used a murine model where PTC and iodine exacerbated thyroiditis (IET) can be induced in a temporally predictable fashion. A total of 122 mice were divided into 3 experimental groups. In the first one, named concomitant IET and PTC (No.=40), IET, and PTC were induced at the same time; in the second one, named pre-existing IET (No.=44), IET was induced prior to the induction of PTC; in the third one, named no IET (No.=38), only PTC was induced. Following disease induction, mice of each group were treated with anti-PD-1 antibody, anti-lymphocyte activation gene 3 antibody (anti-Lag3), anti-T-cell immunoglobulin and mucin domain 3 antibody (anti-Tim3), or IgG control. Ten weeks after the initial ICI injection, mice were sacrificed to collect the thyroid gland for histological analysis, to quantify the incidence and burden of PTC, and to perform high-throughput single-cell RNA sequencing of infiltrating CD45 + cells., Results: In the concomitant IET and PTC group, ICI treatment reduced PTC incidence (p=0.002 comparing treatment with any ICI vs control), while it had no effect in the pre-existing IET and no IET groups. Single-cell sequencing of thyroidal CD45 + cells showed that the different ICIs tested had both specific and shared effects on all the components of the thyroidal immune cell infiltrate. The shared effect of the tested ICIs was dependent on the presence of pre-existing versus concomitant IET. In the context of concomitant IET, ICI treatment resulted in the modulation of a greater number of pathways related to both innate and adaptive immunity., Conclusions: Response to ICIs depends on the status of the immune system of the treated individual. Modulation of the immune system should be explored as a tool to improve response to ICIs in patients with PTC or other forms of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Lymphomatoid papulosis (LyP) is a very rare disease that belongs to the group of CD30+ lymphoproliferative skin diseases. LyP is localized or generalized and usually presents as isolated or clustered red/brown-red lesions in the form of nodules and/or papules. The course of the disease is in most cases mild; however, depending on concomitant risk factors and history, it may progress to lymphoma, significantly reducing the survival rate and prognosis. Importantly, the clinical picture of the disease remains somewhat ambiguous, leading to a large number of misdiagnoses that result in inappropriate treatment, which is usually insufficient to alleviate symptoms. In addition to clinical manifestations, the histological characteristics vary widely and usually overlap with other conditions, especially those belonging to the group of lymphoproliferative disorders. Although diagnosis remains a challenge, several recommendations and guidelines have been introduced to standardize and facilitate the diagnostic process. This article reviews the available literature on the most important aspects of etiopathogenesis, clinical and histopathological features, diagnostic criteria, and possible treatment strategies for LyP, with particular emphasis on the role of the immune system.

Protective immunity relies on the interplay of innate and adaptive immune cells with complementary and redundant functions. Innate lymphoid cells (ILCs) have recently emerged as tissue-resident, innate mirror images of the T cell system, with which they share lineage-specifying transcription factors and effector machinery 1 . Located at barrier surfaces, ILCs are among the first responders against invading pathogens and thus could potentially determine the outcome of the immune response 2 . However, so far it has not been possible to dissect the unique contributions of ILCs to protective immunity owing to limitations in specific targeting of ILC subsets. Thus, all of the available data have been generated either in mice lacking the adaptive immune system or with tools that also affect other immune cell subsets. In addition, it has been proposed that ILCs might be dispensable for a proper immune response because other immune cells could compensate for their absence 3-7 . Here we report the generation of a mouse model based on the neuromedin U receptor 1 (Nmur1) promoter as a driver for simultaneous expression of Cre recombinase and green fluorescent protein, which enables gene targeting in group 2 ILCs (ILC2s) without affecting other innate and adaptive immune cells. Using Cre-mediated gene deletion of Id2 and Gata3 in Nmur1-expressing cells, we generated mice with a selective and specific deficiency in ILC2s. ILC2-deficient mice have decreased eosinophil counts at steady state and are unable to recruit eosinophils to the airways in models of allergic asthma. Further, ILC2-deficient mice do not mount an appropriate immune and epithelial type 2 response, resulting in a profound defect in worm expulsion and a non-protective type 3 immune response. In total, our data establish non-redundant functions for ILC2s in the presence of adaptive immune cells at steady state and during disease and argue for a multilayered organization of the immune system on the basis of a spatiotemporal division of labour., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body's immune response, causing tumor cells to escape the "surveillance" of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.

Glutamine is a conditionally essential amino acid consumed by rapidly proliferating cancer cells, which deprives the same fuel from immune cells and contributes to tumor immune evasion. As such, the broad antagonism of glutamine in tumors and the tumor microenvironment may lead to direct antitumor activity and stimulation of antitumoral immune responses. DRP-104 (sirpiglenastat) was designed as a novel prodrug of the broad-acting glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). DRP-104 is an inactive form that is preferentially converted to DON within tumors. Metabolomic profiling of tumors treated with DRP-104 revealed widespread changes indicative of the disruption of tumor anabolism and canonical cancer metabolism pathways; including altered glutamine metabolism while several immunosuppressive metabolites were decreased. Gene expression profiling revealed broad immunological modulation, confirmed by flow cytometry indicating that DRP-104 treatment resulted in substantial and broad changes in various immune cell infiltrates, such as increased TIL, T, NK, and NK T cells. Functionally, T cells became more proliferative and less exhausted; tumor-associated macrophages were polarized to the M1 phenotype; MDSCs and protumorigenic proteins were decreased in TME. Finally, DRP-104 demonstrated significant antitumor activity as a monotherapy, which was further enhanced in combination with checkpoint blockade therapies, leading to improved survival and long-term durable cures. In summary, DRP-104 broadly remodels the tumor microenvironment by inducing extensive tumor metabolism effects and enhancing the infiltration and function of multiple immune cells distinct from those obtained by checkpoint inhibitor therapy. This unique mechanism of action supports the ongoing clinical development of DRP-104 alone and in combination with checkpoint inhibitors., (©2022 American Association for Cancer Research.)

Allogeneic hematopoietic stem cell transplantation (aHSCT) is a putative curative treatment for malignant hematologic disorders. During transplantation, the immune system is suppressed/eradicated through a conditioning regimen (non-myeloablative or myeloablative) and replaced with a donor immune system. In our previous study, we showed changes in gut taxonomic profiles and a decrease in bacterial diversity post-transplant. In this study, we expand the cohort with 114 patients and focus on the impact of the conditioning regimens on taxonomic features and the metabolic functions of the gut bacteria. This is, to our knowledge, the first study to examine the metabolic potential of the gut microbiome in this patient group. Adult aHSCT recipients with shotgun sequenced stool samples collected day -30 to +28 relative to aHSCT were included. One sample was selected per patient per period: pre-aHSCT (day -30-0) and post-aHSCT (day 1-28). In total, 254 patients and 365 samples were included. Species richness, alpha diversity, gene richness and metabolic richness were all lower post-aHSCT than pre-aHSCT and the decline was more pronounced for the myeloablative group. The myeloablative group showed a decline in 36 genera and an increase in 15 genera. For the non-myeloablative group, 30 genera decreased and 16 increased with lower fold changes than observed in the myeloablative group. For the myeloablative group, 32 bacterial metabolic functions decreased, and one function increased. For the non-myeloablative group, three functions decreased, and two functions increased. Hence, the changes in taxonomy post-aHSCT caused a profound decline in bacterial metabolic functions especially in the myeloablative group, thus providing new evidence for associations of myeloablative conditioning and gut dysbiosis from a functional perspective .

Cancer immunotherapy has fundamentally altered cancer treatment; however, its efficacy is limited to a subset of patients in most clinical settings. The immune system plays a key role in cancer progression from tumor initiation to the metastatic state. Throughout the treatment course, communications between the immune cells in the tumor microenvironment and the immune macroenvironment, as well as interactions between the immune system and cancer cells, are dynamic and constantly evolving. To improve the clinical benefit for patients who do not respond completely to immunotherapy, the molecular mechanisms of resistance to immunotherapy must be elucidated in order to develop effective strategies to overcome resistance. In an attempt to improve and update the current understanding of the molecular mechanisms that hinder immunotherapy, we discuss the molecular mechanisms of cancer resistance to immunotherapy and the available treatment strategies.

The term osteoimmunology describes an interdisciplinary research field that links the investigation of osteology (bone cells) with immunology. The crosstalk between innate and adaptive immune cells and cells involved in bone remodeling, mainly bone-resorbing osteoclasts and bone-forming osteoblasts, becomes particularly obvious in the inflammatory autoimmune disease rheumatoid arthritis (RA). Besides striking inflammation of the joints, RA causes bone loss, leading to joint damage and disabilities as well as generalized osteoporosis. Mechanistically, RA-associated immune cells (macrophages, T cells, B cells etc.) produce high levels of pro-inflammatory cytokines, receptor activator of nuclear factor κB ligand (RANKL) and autoantibodies that promote bone degradation and at the same time counteract new bone formation. Today, antirheumatic therapy effectively ceases joint inflammation and arrests bone erosion. However, the repair of established bone lesions still presents a challenging task and requires improved treatment options. In this review, we outline the knowledge gained over the past years about the immunopathogenesis of RA and the impact of a dysregulated immune system on bone metabolism., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the most common form of dementia affecting millions of people worldwide. While different immunotherapies are imminent, currently only disease-modifying medications are available and a cure is lacking. Over the past decade, immunological interfaces of the central nervous system (CNS) and their role in neurodegenerative diseases received increasing attention. Specifically, emerging evidence shows that subsets of circulating CD8 + T cells cross the brain barriers and associate with AD pathology. To gain more insight into how the adaptive immune system is involved in disease pathogenesis, we here provide a comprehensive overview of the contribution of T cells to AD pathology, incorporating changes at the brain barriers. In addition, we review studies that provide translation of these findings by targeting T cells to combat AD pathology and cognitive decline. Importantly, these data show that immunological changes in AD are not confined to the CNS and that AD-associated systemic immune changes appear to affect brain homeostasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer represents the leading global driver of death and is recognized as a critical obstacle to increasing life expectancy. In recent years, with the development of precision medicine, significant progress has been made in cancer treatment. Among them, various therapies developed with the help of the immune system have succeeded in clinical treatment, recognizing and killing cancer cells by stimulating or enhancing the body's intrinsic immune system. However, low response rates and serious adverse effects, among others, have limited the use of immunotherapy. It also poses problems such as drug resistance and hyper-progression. Fortunately, thanks to the rapid development of nanotechnology, engineered multifunctional nanomaterials and biomaterials have brought breakthroughs in cancer immunotherapy. Unlike conventional cancer immunotherapy, nanomaterials can be rationally designed to trigger specific tumor-killing effects. Simultaneously, improved infiltration of immune cells into metastatic lesions enhances the efficiency of antigen submission and induces a sustained immune reaction. Such a strategy directly reverses the immunological condition of the primary tumor, arrests metastasis and inhibits tumor recurrence through postoperative immunotherapy. This paper discusses several types of nanoscale biomaterials for cancer immunotherapy, and they activate the immune system through material-specific advantages to provide novel therapeutic strategies. In summary, this article will review the latest advances in tumor immunotherapy based on self-assembled, mesoporous, cell membrane modified, metallic, and hydrogel nanomaterials to explore diverse tumor therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Yue, Wang, Yang and Li.)

Metastasis, the major cause of cancer death, represents one of the major challenges in oncology. Scientists are still trying to understand the biological basis underlying the dissemination and outgrowth of tumor cells, why these cells can remain dormant for years, how they become resistant to the immune system or cytotoxic effects of systemic therapy, and how they interact with their new microenvironment. We asked experts to discuss some of the unknowns, advances, and areas of opportunity related to cancer metastasis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

People living with HIV and who receive antiretroviral therapy have a significantly improved lifespan, compared to the early days without therapy. Unfortunately, persisting viral replication in the lungs sustains chronic inflammation, which may cause pulmonary vascular dysfunction and ultimate life-threatening Pulmonary Hypertension (PH). The mechanisms involved in the progression of HIV and PH remain unclear. The study of HIV-PH is limited due to the lack of tractable animal models that recapitulate infection and pathobiological aspects of PH. On one hand, mice with humanized immune systems (hu-mice) are highly relevant to HIV research but their suitability for HIV-PH research deserves investigation. On another hand, the Hypoxia-Sugen is a well-established model for experimental PH that combines hypoxia with the VEGF antagonist SU5416. To test the suitability of hu-mice, we combined HIV with either SU5416 or hypoxia. Using right heart catheterization, we found that combining HIV+SU5416 exacerbated PH. HIV infection increases human pro-inflammatory cytokines in the lungs, compared to uninfected mice. Histopathological examinations showed pulmonary vascular inflammation with arterial muscularization in HIV-PH. We also found an increase in endothelial-monocyte activating polypeptide II (EMAP II) when combining HIV+SU5416. Therefore, combinations of HIV with SU5416 or hypoxia recapitulate PH in hu-mice, creating well-suited models for infectious mechanistic pulmonary vascular research in small animals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodriguez-Irizarry, Schneider, Ahle, Smith, Suarez-Martinez, Salazar, McDaniel Mims, Rasha, Moussa, Moustaïd-Moussa, Pruitt, Fonseca, Henriquez, Clauss, Grisham and Almodovar.)

Background: Although B-acute lymphoblastic leukemia (B-ALL) patients' survival has been improved dramatically, some cases still relapse. This study aimed to explore the prognosis-related novel differentially expressed genes (DEGs) for predicting the overall survival (OS) of children and young adults (CAYAs) with B-ALL and analyze the immune-related factors contributing to poor prognosis., Methods: GSE48558 and GSE79533 from Gene Expression Omnibus (GEO) and clinical sample information and mRNA-seq from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database were retrieved. Prognosis-related key genes were enrolled to build a Cox proportional model using multivariate Cox regression. Five-year OS of patients, clinical characteristic relevance and clinical independence were assessed based on the model. The mRNA levels of prognosis-related genes were validated in our samples and the difference of immune cells composition between high-risk and low-risk patients were compared., Results: One hundred and twelve DEGs between normal B cells and B-ALL cells were identified based on GSE datasets. They were mainly participated in protein binding and HIF-1 signaling pathway. One hundred and eighty-nine clinical samples were enrolled in the study, both Kaplan-Meier (KM) analysis and univariate Cox regression analysis showed that CYBB, BCL2A1, IFI30, and EFNB1 were associated with prognosis, CYBB, BCL2A1, and EFNB1 were used to construct prognostic risk model. Moreover, compared to clinical indicators, the three-gene signature was an independent prognostic factor for CAYAs with B-ALL. Finally, the mRNA levels of CYBB, BCL2A1, and EFNB1 were significantly lower in B-ALL group as compared to controls. The high-risk group had a significantly higher percentage of infiltrated immune cells., Conclusion: We constructed a novel three-gene signature with independent prognostic factor for predicting 5-year OS of CAYAs with B-ALL. Additionally, we discovered the difference of immune cells composition between high-risk and low-risk groups. This study may help to customize individual treatment and improve prognosis of CAYAs with B-ALL., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Down syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the innate immune system stimulating cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), which has both pro- and anti-inflammatory activities, improved cognition and reduced brain pathology in a mouse model of Alzheimer's disease (AD), another inflammatory disorder, and improved cognition and reduced biomarkers of brain pathology in a phase II trial of humans with mild-to-moderate AD. To investigate the effects of GM-CSF treatment on DS/ID in the absence of AD, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that subcutaneous GM-CSF treatment (5 μg/day, five days/week, for five weeks) improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology, increased percent area of GFAP staining in the hippocampus, clustering of astrocytes in the hippocampus, and reduced numbers of calretinin-positive interneurons in the entorhinal cortex and subiculum, and all of these brain pathologies were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) describes a spectrum of progressive liver diseases ranging from simple steatosis to steatohepatitis and fibrosis. Globally, NAFLD is the leading cause of morbidity and mortality associated with chronic liver disease, and NAFLD patients are at a higher risk of developing cirrhosis and hepatocellular carcinoma. While there is a consensus that inflammation plays a key role in promoting NAFLD progression, the underlying mechanisms are not well understood. Recent clinical and experimental evidence suggest that increased hepatic translocation of gut microbial antigens, secondary to diet-induced impairment of the intestinal barrier may be important in driving hepatic inflammation in NAFLD. Here, we briefly review various endogenous and exogenous factors influencing the intestinal barrier and present recent advances in our understanding of cellular and molecular mechanisms underlying intestinal barrier dysfunction in NAFLD., Competing Interests: The authors declare no conflicts of interest., (Thieme. All rights reserved.)

The ultimate cause of Alzheimer's disease (AD) is still unknown and no disease-modifying treatment exists. Emerging evidence supports the concept that the immune system has a key role in AD pathogenesis. This awareness leads to the idea that specific parts of the immune system must be engaged to ward off the disease. Immunotherapy has dramatically improved the management of several previously untreatable cancers and could hold similar promise as a novel therapy for treating AD. However, before potent immunotherapies can be rationally designed as treatment against AD, we need to fully understand the dynamic interplay between AD and the different parts of our immune system. Accordingly, here we review the most important aspects of both the innate and adaptive immune system in relation to AD pathology., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Noncoding cis-regulatory variants have gained interest as cancer drivers, yet progress in understanding their significance is hindered by the numerous challenges and limitations of variant prioritization. To overcome these limitations, we focused on active cis-regulatory elements (aCRE) to design a customized panel for the deep sequencing of 56 neuroblastoma tumor and normal DNA sample pairs. To search for driver mutations, aCREs were defined by reanalysis of H3K27ac chromatin immunoprecipitation sequencing peaks in 25 neuroblastoma cell lines. These regulatory genomic regions were tested for an excess of somatic mutations and assessed for statistical significance using a global approach that accounted for chromatin accessibility and replication timing. Additional validation was provided by whole genome sequence analysis of 151 neuroblastomas. Analysis of HiC data determined the presence of candidate target genes interacting with mutated regions. An excess of somatic mutations in aCREs of diverse genes were identified, including IPO7, HAND2, and ARID3A. CRISPR-Cas9 editing was utilized to assess the functional consequences of mutations in the IPO7-aCRE. Patients with noncoding mutations in aCREs showed inferior overall and event-free survival independent of age at diagnosis, stage, risk stratification, and MYCN status. Expression of aCRE-interacting genes correlated strongly with negative prognostic markers and low survival rates. Moreover, a convergence between the biological functions of aCRE target genes and transcription factors with mutated binding motifs was associated with embryonic development and immune system response. Overall, this strategy enabled the identification of somatic mutations in regulatory elements that collectively promote neuroblastoma tumorigenesis., Significance: Assessment of noncoding cis-regulatory variants and long-range interaction data highlight the combined effect of somatic mutations in regulatory elements in driving neuroblastoma., (©2022 American Association for Cancer Research.)