Immunological Background Research Articles

Humanized NSG Mouse Models as a Preclinical Tool for Translational Research in Inflammatory Bowel Diseases.

The development of animal models reflecting the pathologies of ulcerative colitis (UC) and Crohn's disease (CD) remains a major challenge. The NOD/SCID/IL2rγnull (NSG) mouse strain, which is immune-compromised, tolerates the engraftment of human peripheral blood mononuclear cells (PBMC) derived from patients with UC (NSG-UC) or CD (NSG-CD). This offers the opportunity to examine the impact of individual immunological background on the development of pathophysiological manifestations. When challenged with ethanol, NSG-UC mice exhibited a strong pro-inflammatory response, including the development of edemas, influx of human T cells, B cells and monocytes into the mucosa and submucosa, and elevated expression of the inflammatory markers CRP and CCL-7. Fibrotic alterations were characterized by an influx of fibroblasts and a thickening of the muscularis mucosae. In contrast, the development of pathological manifestations in NSG-CD mice developed without challenge and was signified by extensive collagen deposition between the muscularis propria and muscularis mucosae, as observed in the areas of strictures in CD patients. Vimentin-expressing fibroblasts supplanting colonic crypts and elevated expression of HGF and TGFß corroborated the remodeling phenotype. In summary, the NSG-UC and NSG-CD models partially reflect these human diseases and are powerful tools to examine the mechanism underlying the inflammatory processes in UC and CD.

The effect of lymphocyte immunotherapy (LIT) in modulating immune responses in patients with recurrent pregnancy loss (RPL).

In order to prevent miscarriage in RPL patients, the goal of this study was to determine how well lymphocyte immunotherapy (LIT) works in modifying immunological responses produced by cells, cytokines, transcription factors, and microRNAs. 200 RPL patients and 200 healthy controls were included in the study. Using flow cytometry, it was possible to compare the frequency of cells before and after lymphocyte treatment. Real-time PCR was used to assess the gene expression levels of transcription factors, cytokines, and microRNAs. ELISA method was used to evaluate the level of secretion of cytokines in the serum. Primary evaluation of the immune profile between healthy controls and RPL cases showed a higher frequency of Th17, NK, B cells and a lower frequency of Treg cells in RPL cases. Also, pro-inflammatory cytokines showed increased expression at mRNA and protein levels in the RPL group in comparison with the control group. Whereas, anti-inflammatory cytokines showed decreased expression in RPL patients. Decreased and increased frequency of Th17 and Treg lymphocytes observed in RPL cases following LIT, respectively. The same results obtained for RORγt and FoxP3 mRNA expression as transcription factor of Th17 and Treg cells, respectively. NK cell cytotoxicity decreased after LIT in RPL patients. miR-326a and miR-155 expression after LIT reduced, but miR-146a and miR-10a expression increased in RPL instances. LIT in RPL cases causes to elevation and modulation of anti-inflammatory and pro-inflammatory cytokines. Our data showed that lymphocyte therapy can be proposed as an effective therapeutic agent in RPL patients with immunological background by a modulating inflammatory condition.

Hepatitis delta virus RNA decline post-inoculation in human NTCP transgenic mice is biphasic.

Chronic infection with hepatitis B and delta viruses (HDV) is the most serious form of viral hepatitis due to more severe manifestations of an accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. We characterized early HDV kinetics post-inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics. We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor-human sodium taurocholate co-transporting polypeptide (hNTCP). Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific-binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 35 minutes (standard error, SE: 6.3), binds to non-specific cells with a rate of 0.05 per hour (SE: 0.01), and returns as free virus with a rate of 0.11 per hour (SE: 0.02). Characterizing early HDV-host kinetics elucidates how quickly HDV is either cleared or bound depending on the immunological background and hNTCP presence. IMPORTANCE The persistence phase of HDV infection has been studied in some animal models; however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post-inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics.

Analyses of tumor microenvironment affecting the survival in patients with ovarian cancer receiving intraperitoneal chemotherapy: Translational research from the phase 3 trial of intraperitoneal therapy for ovarian cancer with carboplatin (TRiPocc).

5555 Background: The iPocc trial is a randomized, global phase (P) 3 study of intraperitoneal (IP) versus intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients that demonstrated an improved progression-free survival (PFS) but not overall survival (OS) in the former. IP chemotherapy induces an antitumor immune response and increases survival in a murine xenograft model. This study aimed to assess whether immunological background affected the clinical outcomes of patients receiving IP chemotherapy. Methods: Fresh frozen tumor samples at the time of primary surgery were obtained from 116 patients who joined the iPocc P3 trial for microarray analysis. Cell-type deconvolution was performed using MCP counter. Single sample Gene Set Enrichment Analysis was performed to evaluate the tumor immune microenvironment. Clinical data were obtained from the iPocc P3 trial. We stratified 116 patients according to the high or low values of each factor determined by the median values. The Kaplan-Meier method and log-rank test were used to analyze PFS and OS. Results: A total of 116 patients were assigned to either the IP (n=59) or IV (n=57) group. The most common histologic type was serous (58.6%), followed by endometrioid (17.2%) and clear cell (12.1%). The patients who received IP therapy had longer OS than those who received IV therapy in the group with a high infiltration of T cells, NK cells, or cytotoxic lymphocytes in the MCP counter (median OS: not reached (NR) vs 75.0 months, P=0.041, NR vs. 75.0 months, P=0.042, NR vs 65.2 months, P=0.031), but not in the group with a low infiltration. Similarly, the IP therapy improved OS in the patients with high expression of immune-related genes such as CD8A, FOXP3 or PDCD1 (median OS; NR vs 65.2 months, P=0.035, NR vs 65.2 months P=0.030, NR vs 53.1 months, P=0.016), but not in the patients with low expression of those genes. In addition, a multifaceted evaluation was conducted because of the limitations of evaluating the interaction between cancer and immunity using a single factor. When the patients were divided into two groups, “Immune Hot” and “Immune Cold” based on the hierarchical clustering analysis with 4 parameters representing “Innate immunity,” “T cells,” “Interferon gamma response” and “Inhibitory molecules,” the IP therapy increased both PFS and OS compared to the IV therapy in the “Immune Hot” group (median PFS; 35.5 vs 23.4 months, P=0.024, median OS; NR vs 75.0 months, P=0.040), but not in the “Immune Cold” group. Conclusions: IP therapy may improve the survivals in EOC patients with a high immunological background. Further studies are warranted to validate this hypothesis and to clarify the impact of IP therapy on the tumor immune microenvironment. Clinical trial information: NCT01506856 / GOTIC-001/ JGOG3019.

Paraneoplastic Neurologic Syndromes

Paraneoplastic neurologic syndromes (PNS) are a group of neurological disorders that are possibly caused by immunological mechanisms triggered by an underlying tumor that involves every part of the nervous system. Autoantibodies were categorized according to the risk of cancer association. Antibodies against intracellular proteins are excellent markers for tumor detection, however, without functional roles in neuronal loss, the direct effector of neuronal damage is thought to be cytotoxic T cells. The frequently associated symptoms include limbic encephalitis, cerebellar ataxia and sensory neuronopathy. The associated tumors are mainly small-cell lung cancer, breast/ovarian/uterine cancers, and thymoma. Timely diagnosis, prompt immunotherapy, and treatment of the underlying tumor are essential for managing PNS. However, we need to be cautious about the high frequency of false-positive/negative results of antibodies using commercial antibody tests. This highlight the importance of the careful evaluation of clinical features. Recently, PNS emerged after immune check point inhibitor administration, and this became a subject of attention exploring its pathogenesis. Other basic studies to understand the immunological background of PNS have been progressing.

Microbiome Alterations Driven by Trypanosoma cruzi Infection in Two Disjunctive Murine Models.

Alterations caused by Trypanosoma cruzi in the composition of gut microbiome may play a vital role in the host-parasite interactions that shapes physiology and immune responses against infection. Thus, a better understanding of this parasite-host-microbiome interaction may yield relevant information in the comprehension of the pathophysiology of the disease and the development of new prophylactic and therapeutic alternatives. Therefore, we implemented a murine model with two mice strains (BALB/c and C57BL/6) to evaluate the impact of Trypanosoma cruzi (Tulahuen strain) infection on the gut microbiome utilizing cytokine profiling and shotgun metagenomics. Higher parasite burdens were observed in cardiac and intestinal tissues, including changes in anti-inflammatory (interleukin-4 [IL-4] and IL-10) and proinflammatory (gamma interferon, tumor necrosis factor alpha, and IL-6) cytokines. Bacterial species such as Bacteroides thetaiotaomicron, Faecalibaculum rodentium, and Lactobacillus johnsonii showed a decrease in relative abundance, while Akkermansia muciniphila and Staphylococcus xylosus increased. Likewise, as infection progressed, there was a decrease in gene abundances related to metabolic processes such as lipid synthesis (including short-chain fatty acids) and amino acid synthesis (including branched-chain amino acids). High-quality metagenomic assembled genomes of L. johnsonii and A. muciniphila among other species were reconstructed, confirming, functional changes associated with metabolic pathways that are directly affected by the loss of abundance of specific bacterial taxa. IMPORTANCE Chagas disease (CD) is caused by the protozoan Trypanosoma cruzi, presenting acute and chronic phases where cardiomyopathy, megaesophagus, and/or megacolon stand out. During the course of its life cycle, the parasite has an important gastrointestinal tract transit that leads to severe forms of CD. The intestinal microbiome plays an essential role in the immunological, physiological, and metabolic homeostasis of the host. Therefore, parasite-host-intestinal microbiome interactions may provide information on certain biological and pathophysiological aspects related to CD. The present study proposes a comprehensive evaluation of the potential effects of this interaction based on metagenomic and immunological data from two mice models with different genetic, immunological, and microbiome backgrounds. Our findings suggest that there are alterations in the immune and microbiome profiles that affect several metabolic pathways that can potentially promote the infection's establishment, progression, and persistence. In addition, this information may prove essential in the research of new prophylactic and therapeutic alternatives for CD.

Hidden Comorbidities in Asthma: A Perspective for a Personalized Approach.

Bronchial asthma is the most frequent inflammatory non-communicable condition affecting the airways worldwide. It is commonly associated with concomitant conditions, which substantially contribute to its burden, whether they involve the lung or other districts. The present review aims at providing an overview of the recent acquisitions in terms of asthma concomitant systemic conditions, besides the commonly known respiratory comorbidities. The most recent research has highlighted a number of pathobiological interactions between asthma and other organs in the view of a shared immunological background underling different diseases. A bi-univocal relationship between asthma and common conditions, including cardiovascular, metabolic or neurodegenerative diseases, as well as rare disorders such as sickle cell disease, α1-Antitrypsin deficiency and immunologic conditions with hyper-eosinophilia, should be considered and explored, in terms of diagnostic work-up and long-term assessment of asthma patients. The relevance of that acquisition is of utmost importance in the management of asthma patients and paves the way to a new approach in the light of a personalized medicine perspective, besides targeted therapies.

Immune Checkpoint Inhibitor Related Rheumatological Complications: Cooperation between Rheumatologists and Oncologists

In cancer, immune checkpoint inhibitors (ICIs) improve patient survival but may lead to severe immune-related adverse events (irAEs). Rheumatic irAEs are a distinct entity that are much more common in a real-life than in clinical trial reports due to their unspecific symptoms and them being a rare cause of hospitalization. This review focuses on an interdisciplinary approach to the management of rheumatic irAEs, including cooperation between oncologists, rheumatologists, and immunologists. We discuss the immunological background of rheumatic irAEs, as well as their unique clinical characteristics, differentiation from other irAEs, and treatment strategies. Importantly, steroids are not the basis of therapy, and nonsteroidal anti-inflammatory drugs should be administered in the front line with other antirheumatic agents. We also address whether patients with pre-existing rheumatic autoimmune diseases can receive ICIs and how antirheumatic agents can interfere with ICIs. Interestingly, there is a preclinical rationale for combining ICIs with immunosuppressants, particularly tumor necrosis factor α and interleukin 6 inhibitors. Regardless of the data, the mainstay in managing irAEs is interdisciplinary cooperation between oncologists and other medical specialties.

EAACI Molecular Allergology User's Guide 2.0.

Since the discovery of immunoglobulin E (IgE) as a mediator of allergic diseases in 1967, our knowledge about the immunological mechanisms of IgE-mediated allergies has remarkably increased. In addition to understanding the immune response and clinical symptoms, allergy diagnosis and management depend strongly on the precise identification of the elicitors of the IgE-mediated allergic reaction. In the past four decades, innovations in bioscience and technology have facilitated the identification and production of well-defined, highly pure molecules for component-resolved diagnosis (CRD), allowing a personalized diagnosis and management of the allergic disease for individual patients. The first edition of the "EAACI Molecular Allergology User's Guide" (MAUG) in 2016 rapidly became a key reference for clinicians, scientists, and interested readers with a background in allergology, immunology, biology, and medicine. Nevertheless, the field of molecular allergology is moving fast, and after 6 years, a new EAACI Taskforce was established to provide an updated document. The Molecular Allergology User's Guide 2.0 summarizes state-of-the-art information on allergen molecules, their clinical relevance, and their application in diagnostic algorithms for clinical practice. It is designed for both, clinicians and scientists, guiding health care professionals through the overwhelming list of different allergen molecules available for testing. Further, it provides diagnostic algorithms on the clinical relevance of allergenic molecules and gives an overview of their biology, the basic mechanisms of test formats, and the application of tests to measure allergen exposure.

Towards reproducible research in recurrent pregnancy loss immunology: Learning from cancer microenvironment deconvolution.

The most recent international guidelines regarding recurrent pregnancy loss (RPL) exclude most of the immunological tests recommended for RPL since they do not reach an evidence-based level. Comparisons for metanalysis and systematic reviews are limited by the ambiguity in terms of RPL definition, etiological and risk factors, diagnostic work-up, and treatments applied. Therefore, cohort heterogeneity, the inadequacy of numerosity, and the quality of data confirm a not standardized research quality in the RPL field, especially for immunological background, for which potential research application remains confined in a separate single biological layer. Innovative sequencing technologies and databases have proved to play a significant role in the exploration and validation of cancer research in the context of dataset quality and bioinformatics tools. In this article, we will investigate how bioinformatics tools born for large-scale cancer immunological research could revolutionize RPL immunological research but are limited by the nature of current RPL datasets.

The Role of Immunity in the Pathogenesis of SARS-CoV-2 Infection and in the Protection Generated by COVID-19 Vaccines in Different Age Groups.

This study aims to review the available data regarding the central role of immunity in combating SARS-CoV-2 infection and in the generation of protection by vaccination against COVID-19 in different age groups. Physiologically, the immune response and the components involved in it are variable, both functionally and quantitatively, in neonates, infants, children, adolescents, and adults. These immunological differences are mirrored during COVID-19 infection and in the post-vaccination period. The outcome of SARS-CoV-2 infection is greatly dependent on the reaction orchestrated by the immune system. This is clearly obvious in relation to the clinical status of COVID-19 infection, which can be symptomless, mild, moderate, or severe. Even the complications of the disease show a proportional pattern in relation to the immune response. On the contrary, the commonly used anti-COVID-19 vaccines generate protective humoral and cellular immunity. The magnitude of this immunity and the components involved in it are discussed in detail. Furthermore, many of the adverse effects of these vaccines can be explained on the basis of immune reactions against the different components of the vaccines. Regarding the appropriate choice of vaccine for different age groups, many factors have to be considered. This is a cornerstone, particularly in the following age groups: 1 day to 5 years, 6 to 11 years, and 12 to 17 years. Many factors are involved in deciding the route, doses, and schedule of vaccination for children. Another important issue in this dilemma is the hesitancy of families in making the decision about whether to vaccinate their children. Added to these difficulties is the choice by health authorities and governments concerning whether to make children's vaccination compulsory. In this respect, although rare and limited, adverse effects of vaccines in children have been detected, some of which, unfortunately, have been serious or even fatal. However, to achieve comprehensive control over COVID-19 in communities, both children and adults have to be vaccinated, as the former group represents a reservoir for viral transmission. The understanding of the various immunological mechanisms involved in SARS-CoV-2 infection and in the preparation and application of its vaccines has given the sciences a great opportunity to further deepen and expand immunological knowledge. This will hopefully be reflected positively on other diseases through gaining an immunological background that may aid in diagnosis and therapy. Humanity is still in continuous conflict with SARS-CoV-2 infection and will be for a while, but the future is expected to be in favor of the prevention and control of this disease.

Intralesional injection of platelet-rich plasma versus steroid in the treatment of oral lichen planus.

Oral licen planus (OLP) is a chronic inflammatory disease and may have immunological background. Both intralesional injection of PRP and steroids succeeded in treating and decreasing recurrence of the disease. Twenty-four participants with clinically diagnosed as OLP were enrolled in this study. We separated the patients in 2 groups, 12 patients in group A were treated by intralesional PRP every two weeks for 2months or stopped if healing occurred earlier. Group B (12 patients) treated by intralesional Triamcinolone Acetonide (TA) (20 mg) every two weeks for 2months or may be less if healing occurred earlier. The response of OLP lesions to treatment was evaluated by reduction of lesional areas, REU scores, and NRS scores. The patients with complete response (CR; 80%-100% reduction in the lesion area) were followed for 3months biweekly. There was a statistically significant decrease in REU and pain score in both groups after treatment compared to before. There was a statistically increase in frequency of side effects among patients received PRP especially pain compared to those treated by steroid. Also, recurrence of the disease after treatment during follow-up for 3months was more significant among patients treated by PRP. Intralesional PRP is a good and safe modality for treatment of OLP and intralesional TA. However, there were some side effects and recurrence of disease after follow-up for three months in patients treated by PRP more than those treated by TA.

Commonalities and Disparities between Endometriosis and Chronic Endometritis: Therapeutic Potential of Novel Antibiotic Treatment Strategy against Ectopic Endometrium.

Chronic endometritis (CE) is a local mucosal inflammatory disorder of the uterine lining, which is histopathologically recognized as the unusual infiltration of CD138(+) plasmacytes into the endometrial stromal compartment. Accumulating body of research documented that CE is associated with female infertility and several obstetric/neonatal complications. The major cause of CE is thought to be intrauterine infection represented by common bacteria (Escherichia coli, Enterococcus faecalis, Streptococcus, and Staphylococcus), Mycoplasma/Ureaplasma, and Mycobacterium. Additionally, local dysbiosis in the female reproductive tract may be involved in the onset and development of CE. Antibiotic treatments against these microorganisms are effective in the elimination of endometrial stromal plasmacytes in the affected patients. Meanwhile, endometriosis is a common female reproductive tract disease characterized by endometriotic tissues (ectopic endometrium) growing outside the uterus and potentially causes chronic pelvic symptoms (dysmenorrhea, dyspareunia, dyschezia, and dysuria), infertility, and ovarian cancers. Endometriosis involves endocrinological, genetic, and epigenetic factors in its etiology and pathogenesis. Recent studies focus on immunological, inflammatory, and infectious aspects of endometriosis and demonstrate several common characteristics between endometriosis and CE. This review aimed to better understand the immunological and microbial backgrounds underlying endometriosis and CE and look into the therapeutic potential of the novel antibiotic treatment strategy against endometriosis in light of endometrial infectious disease.

Diagnosis and Management of Allergic Rhinitis in Asthmatic Children.

Allergic rhinitis (AR) is a common upper airways inflammatory condition especially in paediatric population; its burden potentially impacts on quality of life, quality of sleep and daily performance, which can be difficult to perceive but not less relevant in the middle-long term. The present review aims to provide an updated overview on AR epidemiology, diagnosis and with a special focus on its connections with bronchial asthma. In fact, when considering asthmatic pediatric population, AR is probably the most important risk factor for asthma onset and the most impactful extra-bronchial determinant of asthma control. Under this perspective, allergen immunotherapy (AIT) should always be considered in the light of a precision medicine approach. In fact, AIT does represent a unique opportunity to specifically interfere with AR immunological background, improve both AR and bronchial asthma control and prevent allergic disease evolution. Verifying the patient's eligibility to that option should be considered as a priority for every physician managing children suffering from AR, especially when associated with bronchial asthma.

Pathogenesis, immunology, and immune‐targeted management of the multisystem inflammatory syndrome in children (MIS‐C) or pediatric inflammatory multisystem syndrome (PIMS): EAACI Position Paper

Multisystem inflammatory syndrome in children (MIS-C) is a rare, but severe complication of coronavirus disease 2019 (COVID-19). It develops approximately 4 weeks after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and involves hyperinflammation with multisystem injury, commonly progressing to shock. The exact pathomechanism of MIS-C is not known, but immunological dysregulation leading to cytokine storm plays a central role. In response to the emergence of MIS-C, the European Academy of Allergy and Clinical Immunology (EAACI) established a task force (TF) within the Immunology Section in May 2021. With the use of an online Delphi process, TF formulated clinical statements regarding immunological background of MIS-C, diagnosis, treatment, follow-up, and the role of COVID-19 vaccinations. MIS-C case definition is broad, and diagnosis is made based on clinical presentation. The immunological mechanism leading to MIS-C is unclear and depends on activating multiple pathways leading to hyperinflammation. Current management of MIS-C relies on supportive care in combination with immunosuppressive and/or immunomodulatory agents. The most frequently used agents are systemic steroids and intravenous immunoglobulin. Despite good overall short-term outcome, MIS-C patients should be followed-up at regular intervals after discharge, focusing on cardiac disease, organ damage, and inflammatory activity. COVID-19 vaccination is a safe and effective measure to prevent MIS-C. In anticipation of further research, we propose a convenient and clinically practical algorithm for managing MIS-C developed by the Immunology Section of the EAACI.

Induction of antigen-specific tolerance by hepatic AAV immunotherapy regardless of T cell epitope usage or mouse strain background

Invivo induction of antigen (Ag)-specific regulatory Tcells (Treg) is considered the holy grail of therapeutic strategies for restoring tolerance in autoimmunity. Unfortunately, in the autoimmune disease multiple sclerosis, an effective and durable therapy targeting the diverse repertoire of emerging Ags without compromising the patient's natural immunity has remained elusive. To address this deficiency, we have developed an Ag-specific adeno-associated virus (AAV) immunotherapy that will restore tolerance in a Treg-dependent manner. Using multiple strains of mice with different genetic and immunological backgrounds, we demonstrate that a liver directed AAV vector expressing a single transgene can prevent experimental autoimmune encephalomyelitis from developing and effectively mitigate pre-existing or established disease that was induced by one or more auto-reactive myelin oligodendrocyte glycoprotein-derived peptides. Overall, the results suggests that AAV can efficiently restore Ag-specific immune tolerance to an immunogenic protein that is neither restricted by the major histocompatibility complex haplotype, nor by the specific antigenic epitope(s) presented. These findings may pave the way for developing a comprehensive Ag-specific immunotherapy that does not require prior knowledge of the specific immunogenic epitopes and that may prove to be universally applicable to all MS patients, and adaptable for other autoimmune diseases.

Mucosa associated invariant T and natural killer cells in active and budesonide treated collagenous colitis patients.

Collagenous colitis (CC) is an inflammatory bowel disease, which usually responds to budesonide treatment. Our aim was to study the immunological background of the disease. Analyses of peripheral and mucosal MAIT (mucosa associated invariant T cells) and NK (natural killer) cells were performed with flow cytometry. Numbers of mucosal cells were calculated using immunohistochemistry. We studied the same patients with active untreated CC (au-CC) and again while in remission on budesonide treatment. Budesonide refractory patients and healthy controls were also included. The memory marker CD45R0 and activation marker CD154 and CD69 were used to further study the cells. Finally B cells, CD4+ and CD8+ T cells were also analysed. The percentages of circulating CD56dimCD16+ NK cells as well as MAIT cells (CD3+TCRVa7.2+CD161+) were decreased in au-CC compared to healthy controls. This difference was not seen in the mucosa; where we instead found increased numbers of mucosal CD4+ T cells and CD8+ T cells in au-CC. Mucosal immune cell numbers were not affected by budesonide treatment. In refractory CC we found increased mucosal numbers of MAIT cells, CD4+ and CD8+ T cells compared to au-CC. Patients with active collagenous colitis have lower percentages of circulating MAIT and NK cells. However, there was no change of these cells in the colonic mucosa. Most mucosal cell populations were increased in budesonide refractory as compared to au-CC patients, particularly the number of MAIT cells. This may indicate that T cell targeting therapy could be an alternative in budesonide refractory CC.

Expression of programmed cell death-1 on neuroblastoma cells in TH-MYCN transgenic mice.

Immunotherapy may improve the poor prognosis of high-risk neuroblastoma. Programmed cell death-1 (PD-1) is expressed in several cancers. The tyrosine hydroxylase MYCN (TH-MYCN) transgenic mouse model is widely used in neuroblastoma research, but detailed information on its immunological background is lacking. Therefore, we studied the immunological tumor microenvironment and tumor cell surface antigen expression in homozygote and hemizygote mice and effects of antibody therapy against PD-1. CD4, CD8, CD11b, and CD11c expression in immune cells from retroperitoneal lymph nodes and spleen was analyzed by flow cytometry. Tumor cell surface antigen expression was confirmed, and data from homozygote and hemizygote mice were compared. Effects of anti-PD-1 antibody were evaluated. CD4-, CD8-, CD11b-, and CD11c-positive cells were not significantly different in homozygote and hemizygote mice, and CD11b- and CD11c-positive cells were identified in the tumor microenvironment in both. Tumor cells expressed PD-1, and anti-PD-1 antibody had anti-tumor effects and significantly reduced the percentage of living tumor cells in cultures after 2h. The immunological background is similar in homozygote and hemizygote TH-MYCN transgenic mice, and both have PD-1-positive tumor cells. Anti-PD-1 antibody suppresses tumor growth. This mouse model may be a useful for studying immunotherapy of neuroblastoma.

The pathophysiological and immunological background of the monkeypox virus infection: An update.

In addition to the COVID-19 waves, the globe is facing global monkeypox (MPX) outbreak. MPX is an uncommon zoonotic infection characterized by symptoms similar to smallpox. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus that belongs to the genus Orthopoxvirus (OPXV). MPXV, which causes human disease, has been confined to Africa for many years, with only a few isolated cases in other areas. Outside of Africa, the continuing MPXV outbreak in multiple countries in 2022 is the greatest in recorded history. The current outbreak, with over 10 000confirmed cases in over 50countries between May and July 2022, demonstrates that MPXV may travel rapidly among humans and pose a danger to human health worldwide. The rapid spread of such outbreaks in recent times has elevated MPXto the status of a rising zoonotic disease with significant epidemic potential. While the MPXV is not as deadly or contagious as the variola virus that causes smallpox, it poses a threat because it could evolve into a more potent human pathogen. This review assesses the potential threat to the human population and provides a brief overview of what is currently known about this reemerging virus. By analyzing the biological effects of MPXV on human health, its shifting epidemiological footprint, and currently available therapeutic options, this review has presented the most recent insights into the biology of the virus. This study also clarifies the key potential causes that could be to blame for the present MPX outbreak and draw attention to major research questions and promising new avenues for combating the current MPXepidemic.

Changes in the urinary proteome before and after quadrivalent influenza vaccine and COVID-19 vaccination.

The proteome of urine samples from quadrivalent influenza vaccine cohort were analyzed with self-contrasted method. Significantly changed urine protein at 24 hours after vaccination was enriched in immune-related pathways, although each person’s specific pathways varied. We speculate that this may be because different people have different immunological backgrounds associated with influenza. Then, urine samples were collected from several uninfected SARS-CoV-2 young people before and after the first, second, and third doses of the COVID-19 vaccine. The differential proteins compared between after the second dose (24h) and before the second dose were enriched in pathways involving in multicellular organismal process, regulated exocytosis and immune-related pathways, indicating no first exposure to antigen. Surprisingly, the pathways enriched by the differential urinary protein before and after the first dose were similar to those before and after the second dose. It is inferred that although the volunteers were not infected with SARS-CoV-2, they might have been exposed to other coimmunogenic coronaviruses. Two to four hours after the third vaccination, the differentially expressed protein were also enriched in multicellular organismal process, regulated exocytosis and immune-related pathways, indicating that the immune response has been triggered in a short time after vaccination. Multicellular organismal process and regulated exocytosis after vaccination may be a new indicator to evaluate the immune effect of vaccines. Urinary proteome is a terrific window to monitor the changes in human immune function.