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Cytokine storm is an acute hyperinflammatory response that may be responsible for critical illness in many conditions including viral infections, cancer, sepsis, and multi-organ failure. The phenomenon has been implicated in critically ill patients infected with SARS-CoV-2, the novel coronavirus implicated in COVID-19. Critically ill COVID-19 patients experiencing cytokine storm are believed to have a worse prognosis and increased fatality rate. In SARS-CoV-2 infected patients, cytokine storm appears important to the pathogenesis of several severe manifestations of COVID-19: acute respiratory distress syndrome, thromboembolic diseases such as acute ischemic strokes caused by large vessel occlusion and myocardial infarction, encephalitis, acute kidney injury, and vasculitis (Kawasaki-like syndrome in children and renal vasculitis in adult). Understanding the pathogenesis of cytokine storm will help unravel not only risk factors for the condition but also therapeutic strategies to modulate the immune response and deliver improved outcomes in COVID-19 patients at high risk for severe disease. In this article, we present an overview of the cytokine storm and its implications in COVID-19 settings and identify potential pathways or biomarkers that could be targeted for therapy. Leveraging expert opinion, emerging evidence, and a case-based approach, this position paper provides critical insights on cytokine storm from both a prognostic and therapeutic standpoint.

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). Different factors contribute to residual anemia during eculizumab treatment: underlying bone marrow dysfunction, residual intravascular hemolysis and the emergence of C3-mediated extravascular hemolysis. These two latter pathogenic mechanisms are the target of novel strategies of anti-complement treatments, which can be split into terminal and proximal complement inhibitors. Many novel terminal complement inhibitors are now in clinical development: they all target C5 (as eculizumab), potentially paralleling the efficacy and safety profile of eculizumab. Possible advantages over eculizumab are long-lasting activity and subcutaneous self-administration. However, novel anti-C5 agents do not improve hematological response to eculizumab, even if some seem associated with a lower risk of breakthrough hemolysis caused by pharmacokinetic reasons (it remains unclear whether more effective inhibition of C5 is possible and clinically beneficial). Indeed, proximal inhibitors are designed to interfere with early phases of complement activation, eventually preventing C3-mediated extravascular hemolysis in addition to intravascular hemolysis. At the moment there are three strategies of proximal complement inhibition: anti-C3 agents, anti-factor D agents and anti-factor B agents. These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.

Acute lung injury (ALI) is an intractable disorder associated with macrophages. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers about macrophages in ALI over the past 10 years. We retrieved publications published from 2011 to 2020 and their recorded information from Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC). Bibliometrix package was used to analyze bibliometric indicators, and the VOSviewer was used to visualize the trend and hotspots of researches on macrophages in ALI. Altogether, 2,632 original articles were reviewed, and the results showed that the annual number of publications (Np) concerning the role of macrophages in ALI kept increasing over the past 10 years. China produced the most papers, the number of citations (Nc) and H-index of the USA ranked first. Shanghai Jiaotong University and INT IMMUNOPHARMACOL were the most prolific affiliation and journal, respectively. Papers published by Matute-Bello G in 2011 had the highest local citation score (LCS). Recently, the keywords “NLRP3” and “extracellular vesicles” appeared most frequently. Besides, researches on COVID-19–induced ALI related to macrophages seemed to be the hotspot recently. This bibliometric study revealed that publications related to macrophages in ALI tend to increase continuously. China was a big producer and the USA was an influential country in this field. Most studies were mainly centered on basic researches in the past decade, and pathways associated with the regulatory role of macrophages in inhibiting and attenuating ALI have become the focus of attention in more recent studies. What is more, our bibliometric analysis showed that macrophages play an important role in COVID-19–induced ALI and may be a target for the treatment of COVID-19.

IntroductionBesides recurrent infections, a proportion of patients with Common Variable Immunodeficiency Disorders (CVID) may suffer from immune dysregulation such as granulomatous-lymphocytic interstitial lung disease (GLILD). The optimal treatment of this complication is currently unknown. Experienced-based expert opinions have been produced, but a systematic review of published treatment studies is lacking.GoalsTo summarize and synthesize the published literature on the efficacy of treatments for GLILD in CVID.MethodsWe performed a systematic review using the PRISMA guidelines. Papers describing treatment and outcomes in CVID patients with radiographic and/or histologic evidence of GLILD were included. Treatment regimens and outcomes of treatment were summarized.Results6124 papers were identified and 42, reporting information about 233 patients in total, were included for review. These papers described case series or small, uncontrolled studies of monotherapy with glucocorticoids or other immunosuppressants, rituximab monotherapy or rituximab plus azathioprine, abatacept, or hematopoietic stem cell transplantation (HSCT). Treatment response rates varied widely. Cross-study comparisons were complicated because different treatment regimens, follow-up periods, and outcome measures were used. There was a trend towards more frequent GLILD relapses in patients treated with corticosteroid monotherapy when compared to rituximab-containing treatment regimens based on qualitative endpoints. HSCT is a promising alternative to pharmacological treatment of GLILD, because it has the potential to not only contain symptoms, but also to resolve the underlying pathology. However, mortality, especially among immunocompromised patients, is high.ConclusionsWe could not draw definitive conclusions regarding optimal pharmacological treatment for GLILD in CVID from the current literature since quantitative, well-controlled evidence was lacking. While HSCT might be considered a treatment option for GLILD in CVID, the risks related to the procedure are high. Our findings highlight the need for further research with uniform, objective and quantifiable endpoints. This should include international registries with standardized data collection including regular pulmonary function tests (with carbon monoxide-diffusion), uniform high-resolution chest CT radiographic scoring, and uniform treatment regimens, to facilitate comparison of treatment outcomes and ultimately randomized clinical trials.

Despite recent advances in using biologicals that target Th2 pathways, glucocorticoids form the mainstay of asthma treatment. Asthma morbidity and mortality remain high due to the wide variability of treatment responsiveness and complex clinical phenotypes driven by distinct underlying mechanisms. Emerging evidence suggests that inhalation of the toxic air pollutant, ozone, worsens asthma by impairing glucocorticoid responsiveness. This review discusses the role of oxidative stress in glucocorticoid resistance in asthma. The underlying mechanisms point to a central role of oxidative stress pathways. The primary data source for this review consisted of peer-reviewed publications on the impact of ozone on airway inflammation and glucocorticoid responsiveness indexed in PubMed. Our main search strategy focused on cross-referencing “asthma and glucocorticoid resistance” against “ozone, oxidative stress, alarmins, innate lymphoid, NK and γδ T cells, dendritic cells and alveolar type II epithelial cells, glucocorticoid receptor and transcription factors”. Recent work was placed in the context from articles in the last 10 years and older seminal research papers and comprehensive reviews. We excluded papers that did not focus on respiratory injury in the setting of oxidative stress. The pathways discussed here have however wide clinical implications to pathologies associated with inflammation and oxidative stress and in which glucocorticoid treatment is essential.

Polyphenols are essential antioxidants in our regular diet and their chemical structure has shown potential antibacterial effects. Important biological activities, including antioxidant, anticancer or antibacterial activities have been found in some of the polyphenols. In recent years, the benefits of polyphenols on human health have attracted more and more attention from the scientific community. Recent studies have shown that polyphenols such as anthocyanin, catechin, chlorogenic acid and resveratrol can inhibit pathogenic bacteria such as Escherichia coli and Salmonella to regulate the intestinal microflora. The imbalance of intestinal microflora and the destruction of the intestinal barrier function have been proved to have a potential relationship with the occurrence of chronic kidney diseases (CKD). These can trigger the immune system to cause inflammations, increase the production of uremic toxins, and further worsen the condition of CKD. Therefore, the maintenance of intestinal microflora and the intestinal tract in a stable and healthy state may be able to immunize and treat CKD. The use of common antibiotics may lead to drug resistance of pathogens, and the beneficial effect of polyphenols may become a natural substitute for antibiotics. This paper reviews the effects of different polyphenols, such as anthocyanin, catechin, chlorogenic acid, resveratrol, on regulating intestinal microorganisms, inhibiting pathogenic bacteria, and improving inflammations. In addition, this paper also reviews the effects of different polyphenols which have been studied in recent years to reduce intestinal injury, intestinal inflammatory response, and improve related functional parameters of intestinal inflammatory diseases. In conclusion, polyphenols would be a potential source to modulate the intestinal microbiota, improve inflammatory response, and reduce kidney damage as well as to immunize or treat CKD.

Salvage of endogenous immunoglobulin G (IgG) by the neonatal Fc receptor (FcRn) is implicated in many clinical areas, including therapeutic monoclonal antibody kinetics, patient monitoring in IgG multiple myeloma, and antibody-mediated transplant rejection. There is a clear clinical need for a fully parameterized model of FcRn-mediated recycling of endogenous IgG to allow for predictive modeling, with the potential for optimizing therapeutic regimens for better patient outcomes. In this paper we study a mechanism-based model incorporating nonlinear FcRn-IgG binding kinetics. The aim of this study is to determine whether parameter values can be estimated using the limited in vivo human data, available in the literature, from studies of the kinetics of radiolabeled IgG in humans. We derive mathematical descriptions of the experimental observations—timecourse data and fractional catabolic rate (FCR) data—based on the underlying physiological model. Structural identifiability analyses are performed to determine which, if any, of the parameters are unique with respect to the observations. Structurally identifiable parameters are then estimated from the data. It is found that parameter values estimated from timecourse data are not robust, suggesting that the model complexity is not supported by the available data. Based upon the structural identifiability analyses, a new expression for the FCR is derived. This expression is fitted to the FCR data to estimate unknown parameter values. Using these parameter estimates, the plasma IgG response is simulated under clinical conditions. Finally a suggestion is made for a reduced-order model based upon the newly derived expression for the FCR. The reduced-order model is used to predict the plasma IgG response, which is compared with the original four-compartment model, showing good agreement. This paper shows how techniques for compartmental model analysis—structural identifiability analysis, linearization, and reparameterization—can be used to ensure robust parameter identification.

This paper aims to present an overview of MICA and natural killer group 2 member D (NKG2D) genetic and functional interactions and their impact on kidney transplant outcome. Organ transplantation has gone from what can accurately be called a “clinical experiment” to a routine and reliable practice, which has proven to be clinically relevant, life-saving and cost-effective when compared with non-transplantation management strategies of both chronic and acute end-stage organ failures. The kidney is the most frequently transplanted organ in the world (transplant-observatory1). The two treatment options for end-stage renal disease (ESRD) are dialysis and/or transplantation. Compared with dialysis, transplantation is associated with significant improvements in quality of life and overall longevity. A strong relationship exists between allograft loss and human leukocyte antigens (HLA) antibodies (Abs). HLA Abs are not the only factor involved in graft loss, as multiple studies have shown that non-HLA antigens are also involved, even when a patient has a good HLA matche and receives standard immunosuppressive therapy. A deeper understanding of other biomarkers is therefore important, as it is likely to lead to better monitoring (and consequent success) of organ transplants. The objective is to fill the void left by extensive reviews that do not often dive this deep into the importance of MICA and NKG2D in allograft acceptance and their partnership in the immune response. There are few papers that explore the relationship between these two protagonists when it comes to kidney transplantation. This is especially true for the role of NKG2D in kidney transplantation. These reasons give a special importance to this review, which aims to be a helpful tool in the hands of researchers in this field.

Contains fulltext : 166590.pdf (Publisher’s version ) (Open Access) In order to combat chronic immune disorders (CIDs), it is an absolute necessity to understand the bigger picture, one that goes beyond insights at a one-disease, molecular, cellular, and static level. To unravel this bigger picture we advocate an integral, cross-disciplinary approach capable of embracing the complexity of the field. This paper discusses the current knowledge on common pathways in CIDs including general psychosocial and lifestyle factors associated with immune functioning. We demonstrate the lack of more in-depth psychosocial and lifestyle factors in current research cohorts and most importantly the need for an all-encompassing analysis of these factors. The second part of the paper discusses the challenges of understanding immune system dynamics and effectively integrating all key perspectives on immune functioning, including the patient's perspective itself. This paper suggests the use of techniques from complex systems science in describing and simulating healthy or deviating behavior of the immune system in its biopsychosocial surroundings. The patient's perspective data are suggested to be generated by using specific narrative techniques. We conclude that to gain more insight into the behavior of the whole system and to acquire new ways of combatting CIDs, we need to construct and apply new techniques in the field of computational and complexity science, to an even wider variety of dynamic data than used in today's systems medicine.

Basophil activation test (BAT) is an assay used to diagnose allergy by evaluating the expression of surface molecules in circulating and activated basophils with an in vitro flow cytometry (FC) approach. Separation of basophils from whole blood is virtually made by an electronic capture in FC. This process is called gating and uses a “phenotyping” protocol that targets membrane molecules typically or exclusively expressed by circulating basophils. Once “gated,” basophils are examined for their expression of molecules, such as CD63, CD203c, or CD193 (CCR3), usually up or downregulated by cellular activation from allergens or non-IgE-mediated stimuli. A recent article by Santos et al. reported that the CD123/HLA-DR protocol used to gate basophils in an FC approach could be fully improved by considering the introduction of CD203c as a gating additional molecule, as they reported a degree of correlation between basophil activation (as measured by the increased expression of CD203c) and decreased expression of CD123 without making a direct causal link between both the observations (1). They actually showed that, during cellular activation, the expression of membrane CD123, the alpha subunit of the interleukin-3 (IL-3) receptor, is downregulated, leading to a possible loss in the electronic capture of basophils and hence a false negative outcome of the activation test (1). Moreover, they suggested the introduction of CD203c marker, quite exclusively expressed by basophils, to improve BAT performance (1). In their paper, the authors hypothesized also that activated basophils should upregulate membrane expression of the class II MHC antigen HLA-DR, but their results confirmed that basophils do not express HLA-DR, even during allergic activation (1–4). The paper by Santos et al. contains interesting issues, which raised comments from this author. This evidence represents a novelty in the field, as it reports that a phenotyping marker, i.e., CD123, should be downregulated during basophil activation. In this regard, the evidence by Santos et al. would suggest that gating strategies using CCR3 (CD193), the eotaxin receptor, may be revised, as CCR3 is notoriously downregulated during basophil activation and may therefore behave as CD123, leading to considerations that would be very interesting to address in next future (1, 3, 5, 6). To the best of our knowledge, CD123 has never been considered an activation marker (7). Apparently, its association with a basophil activation marker, exclusively expressed by basophils, such as CD203c, should improve the ability to capture or gate these cells in FC (1, 7). The phenotyping protocol widely used to gate basophils includes both CD123 and HLA-DR (4). Santos et al. reported that while basophil HLA-DR remains unexpressed during any kind of activation, either IgE- or non-IgE-mediated, CD123 is downregulated on basophil membrane, then it led to a reduction in CD123-fluorescent cells captured as dots events in the FC analysis and to possible false negatives in the BAT evaluation (1). Previous reports of our group showed that CD123 is highly expressed (“bright”) on the membrane of basophils undergoing an in vitro BAT prior of any activation (3, 4). We also demonstrated, by evaluating the mean fluorescence (MFICD123) in the gate, that the behavior of CD123, in the protocol CD123bright/HLA-DRneg used to gate basophils, was unchanged even following different kinds of activation, i.e., CD123 did not significantly change its membrane expression following either an IgE- or a non-IgE-mediated basophil activation (3, 4); and furthermore, no evidence of direct inhibition of CD123 following basophil activation has been ever reported in the literature. My modest opinion is that the observed apparent reduction of CD123-FITC may be caused by effects related to the gating strategy involving CD203c. If we gate basophils through a SSC/CD203c approach and then evaluate the expression of CD123 and HLA-DR, we might be biased about the expression of CD123 by the fact that CD203c changes its fluorescence pattern upon activation. Yet, the opposite approach, i.e., gating with a CD123/HLA-DR and then with CD203c, was suggested with the purpose to improve basophil capture. A gating protocol adopting CD203c as a phenotyping marker, due to the upregulation of the latter upon activation, may lead to an overestimation of basophil count in the gate. The authors demonstrated that the introduction of CD203c in the CD123/HLA-DR phenotyping protocol leads to a reduction in the loss of basophils in the gate and ameliorated the ability to catch basophils expressing CD63, thus preventing possible bias in the diagnostic value of BAT (1). The authors showed in Figure 5b of their manuscript, an evidence that should recall perfectly a circumstance published by ours elsewhere [Figure 4, page 8/14 of Ref. (4)], showing the expression of CD63 and CD203c following an fMLP-induced activation, i.e., dot plot of Ref. (1) is quite perfectly akin dot plot of Ref. (4). The authors reported this evidence as particularly meaningful of their conclusions. They assessed that following fMLP activation, the reduction in the number of gated cells with a CD123/HLA-DR protocol was highly significant (p

Sarfati et al. recently published a thorough overview on the role exerted by basophils in the immune system and their relationship with T cells in chronic inflammation (1). In their paper, the authors fundamentally referred to the relationship with T cells, and basophil participation in innate and acquired immunity, through the complex network of immune cells and cytokines. Many further, though less appealing, mediators should be introduced, yet. The paper by Sarfati et al. contains interesting bullet points on the biology of basophils, which deserve further insights and raise also some concern about the use and meaning of these cells in immunology laboratory (2). Allergy tests usually consider basophils as independent leukocytes able to elicit or regulate a typical type I hypersensitivity reaction, most commonly reported as an allergic response. Therefore, in this perspective, basophils are investigated fundamentally by the membrane recycling and up- or downregulation of IgE-induced surface displaced molecules, which undergo a turn over mechanism due to the basophil-mediated immune response. Actually, these cells play a pivotal role in the immune system and even their use in allergy diagnosis should be reappraised (3, 4). This would mean that basophils need to be treated not only as isolated cells responding to allergens but also as innate T-cells, quite neglecting their close interaction with other immune cells such as T-cells, platelets or other leukocytes. Yet, basophils appear to interact with a wide group of immune cells, either from innate or acquired immunity, particularly in chronic inflammation. In this scenario, lipid-derived molecules might play a major role also for basophils. During allergy, leukocytes produce many mediators, some of which of recent interest, such as 15-hydroxyeicosatetraenoic acid (15-HETE) (5). This endogenous eicosanoid can interact with basophils, which possess receptors for 15-HETE (6) or bind to intracellular non G-coupled receptors such as PPAR-γ, which is expressed also in basophils (7). Aside from the overview described by the authors, this issue may be important during chronic allergic inflammation. Recent reports have shown that the activity of 15-lipooxygenase type 1 (15-LO-1) is fundamental in causing pathophysiology of asthma. During an inflammatory or physical injury, human airway epithelial cells increase their 15-LO-1 activity and the production of 15-HETE, besides the production of eoxin C4 (EXC4) or 14,15-leukotriene C4, from arachidonic acid (8). Basophils express cysteinyl leukotriene receptors (CysLTR) (9), CysLTR1 and 2 are upregulated in macrophages by IL-4 and IL-13 (10) and interact each other to regulate mitogenic signaling responses in mast cells (11). Cysteinyl leukotrienes (CysLTs) are important molecules produced by basophils, eosinophils, mast cells, and macrophages during innate immunity and in this sense represent important molecules to be focused when talking about basophils involvement in chronic inflammation (12). The authors questioned of how basophils are recruited to the site of inflammation and referred to CRTH2 (PGD2 receptor) and IL-3 receptor as possible target molecules for recruitment (1). At least for eosinophils, evidence suggested that CysLRRs are associated with the recruitment of these leukocytes in the site of allergic inflammation (13). To date, no information was reported about the possible involvement of these receptors in basophil diapedesis but this issue deserves major interest, due the role exerted in eosinophils. Basophils express LTC4, which is consequently transformed into LTD4 and the more stable LTE4 and in this sense they actively participate in asthma and control, through CysLTRs the induction of a Th2-mediated response to allergens (14). Actually, past data from cysteinyl leucotriene receptors antagonists confirm the role of these mediators in allergic asthma (15). This perspective may encourage researchers in evaluating CysLTRs markers on basophil membrane to improve cellular tests used for allergy diagnosis. During activation, basophils express a group of membrane molecules, which should provide clues about the role of these cells in the allergic inflammation, if selected as primary markers in a flow cytometry assay, such as the basophil activation test (BAT). While most common markers probing activated basophils are CD63 and CD203c, these molecules change their membrane expression directly linked to cell activation and independently from an IgE- or a non-IgE-mediated stimulus. Newly incoming markers might help researchers in differentiating the role of basophils in innate or acquired immunity. For example, the BM16 monoclonal antibody, which reacts with CD294, the prostaglandin D2 receptor, may give insights on the role of PGD2 in allergic inflammation, as PGD2 metabolites are well recognized markers of allergy, particularly for mast cells (16, 17). The search for new target molecules, either for allergy treatment or lab investigation, is a major goal for the development of novel approaches in diagnosis and therapy (18). In addition, the 2-oxoglutarate receptor 1 (OXGR1), a new cysteinyl receptor called receptor of the CysLTE or GPR99, is expressed in mast cells and its ligand LTE4 is able to recruit both eosinophils and basophils to the inflammatory site in asthma (19). Products from 5-lipooxygenase regulate basophil migration (5-oxo-ETE) and degranulation (LTB4) (20), then the role of these mediators in chronic inflammation involving basophils should be reappraised. CysLTs, particularly CysLT1, activate the recruitment of both alpha–beta and gamma–delta effector T cells to the inflamed tissue (21). During allergy, T cells increase their expression of CyLTRs (22), an evidence that would suggest the fundamental role exerted by Cys-leukotrienes in the relationship basophils/T cells, during inflammation. The conclusion, which the authors reached, describes a landscape where basophils play a strategic role at the cross-road of innate and acquired immunity, and in this sense, they reported a commonly accepted overview of the problem (23). Further insights about the function of lipid mediators in this complex basophil/T cell interplay might improve our knowledge and comprehension about the role of basophils in chronic inflammation.

The Editorial on the Research Topic Immunogenic Cell Death in Cancer: From Benchside Research to Bedside Reality Immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced antitumor immunity (1–3). ICD is distinguished by spatiotemporally defined emission of danger signals or damage-associated molecular patterns (DAMPs) that elevate the immunogenic potential of dying cells [Garg et al.; (4)]. The important role played by DAMPs in immunity, tissue remodeling, and inflammation is discussed in details by Venereau et al. (Marco E. Bianchi lab). Most potent ICD inducers, characterized so far, elicit danger signaling through oxidative-endoplasmic reticulum stress (5). Several ICD inducers have been characterized, e.g., some chemotherapies, some physicochemical therapies (e.g., radiotherapy or photodynamic therapy/PDT), and oncolytic viruses (2, 6). Here, radiotherapy is among the first recognized immunogenic therapies [on account of “abscopal-effect” (7)]. The immunogenic potential of radiotherapy and possibilities for its combination with immune checkpoint blockers is discussed by Derer et al. (Udo S. Gaipl lab). It is noteworthy that ICD can also be achieved by various “smart” combinatorial strategies – an important point for clinically applied non-ICD inducers, discussed in details by Bezu et al. (Guido Kroemer lab). Several lines of experimental evidence have established the validity of ICD. However, the overreliance on usage of prophylactic vaccination in transplantable (heterotopic) tumor models has attracted some criticism (8). While these criticisms are valid, the field is already moving toward tumors produced orthotopically (curative/therapeutic) or in genetically engineered mouse models (GEMM) (at least for few ICD inducers, e.g., hypericin-PDT, Newcastle disease virotherapy and anthracyclines) (9–12). Moreover, the clinical existence of ICD has been proven through retrospective analysis involving cancer patient’s survival/therapy-responsiveness data (13–17). These observations have encouraged the increased usage of ICD-associated DAMPs as predictive/prognostic biomarkers – a point discussed in detail by Fucikova et al. (Radek Spisek lab). The promising results generated by systemically administered ICD inducers have also paved way for application of ICD-based dendritic cell (DC) vaccines (12). This important development has been discussed from the preclinical/clinical vantage points of various solid tumors by Vandenberk et al. (Stefaan W. van Gool lab) and lymphoma by Zappasodi et al. (Massimo Di Nicola lab). In the latter case, it is clear that the field is moving toward chimeric antigen receptor (CAR)-T cell’s application, and it will be interesting to see its combination with ICD in near future. Nevertheless, the insurmountable complexity of cancer makes it inevitable that in certain contexts, ICD may fail. This failure may stem from various factors, e.g., tumor heterogeneity (8), MHC-level heterogeneity (12), pre-established niches enriched in immunosuppressive factors or immune-checkpoints (1), stem cell-based immune-evasion (12), low mutational load, inactivating mutations/polymorphisms in certain immune-receptors (1), general ablation of danger signaling (14), and other genetic or even epigenetic causes. Several of these pro-cancerous immune-evasive mechanisms and immunotherapeutic strategies required for overcoming them are discussed in detail by Kersten et al. (Karin E. de Visser lab). The strategies for targeting epigenetic processes to improve immunotherapy are further discussed by Wachowska et al. (Jakub Golab lab). We believe that the valuable contributions of key researchers/clinicians toward this research topic/special edition have largely fulfilled its primary aim, i.e., to foster a critical discussion on experimental and clinical relevance of ICD. In fact, to further summarize and organize the fields of ICD and DAMPs, we have produced a multi-author consensus paper within this research topic that attempts to classify DAMPs and ICD inducers with an eye on translational potential of ICD (Garg et al.). This classification paper brings together >50 authors from the fields of ICD and DAMPs, and tries to reach a comprehensive accord on various terminologies related to DAMPs/ICD, the historical background of these concepts, ICD classification system (Type I vs. Type II inducers), and the relevant preclinical/clinical criteria crucial for the field(s) (Garg et al.). We hope that this consensus paper will be a useful literature resource for various researchers/clinicians. These contributions, while summarizing the status quo, have also exposed a set of major questions and challenges that still need to be addressed.

Head and neck cancer (HNC) is the sixth most common malignancy worldwide; head and neck squamous cell carcinoma (HNSCC) account for the most cases of HNC. Past smoking and alcohol consumption are common risk factors of HNSCC; however, an increasing number of cases associated with human papillomavirus (HPV) infection have been reported in recent years. The treatment of HNSCC is integrated and multimodal including traditional surgery, radiotherapy, chemotherapy, and targeted therapy. Since pembrolizumab was approved in 2016, an increasing number of studies have focused on immunotherapy. However, not all of HNSCC patients have a better outcome on immunotherapy. Immunotherapy has been reported to be more effective in HPV-positive patients, but its molecular mechanism is still unclear. Some researchers have proposed that the high proportion of infiltrating immune cells in HPV-positive tumors and the difference in immune checkpoint expression level may be the reasons for their better response. As a result, a series of individualized immunotherapy trials have also been conducted in HPV-positive patients. This paper summarizes the current status of HNSCC immunotherapy, individualized immunotherapy in HPV-positive patients, and immune differences in HPV-positive tumors to provide new insights into HNSCC immunotherapy and try to identify patients who may benefit from immunotherapy.

Metabolic syndrome (MS) is a group of complex metabolic disorders syndrome, which refers to the pathological state of metabolism disorder of protein, fat, carbohydrate and other substances in human body. The kidney is an important organ of metabolism, and various metabolic disorders can lead to the abnormalities in the structure and function of the kidney. The recognition of pathogenesis and treatment measures of renal damage in MS is a very important part for the renal function preserve. Inflammatory response caused by various metabolic factors is a protective mechanism of the body, but persistent inflammation will become a harmful factor and aggravate kidney damage. Inflammasomes are sensors of the innate immune system that play crucial roles in initiating inflammation in response to acute infections and chronic diseases. They are multiprotein complex composed of cytoplasmic sensors (mainly NLR family members), apoptosis-associated speck-like protein (ASC or PYCARD) and pro-caspase-1. After receiving exogenous and endogenous stimuli, the sensors begin to assemble inflammasome and then promote the release of inflammatory cytokines IL-1β and IL-18, resulting in a special way of cell death named pyroptosis. In the kidney, NLRP3 inflammasome can be activated by a variety of pathways, which eventually leads to inflammatory infiltration, renal intrinsic cell damage and renal function decline. This paper reviews the function and specific regulatory mechanism of inflammasome in kidney damage caused by various metabolic disorders, which will provide a new therapeutic perspective and targets for kidney diseases.

The tumor immune microenvironment plays a vital role in the metastasis of colorectal cancer. As one of the most important immune cells, macrophages act as phagocytes, patrol the surroundings of tissues, and remove invading pathogens and cell debris to maintain tissue homeostasis. Significantly, macrophages have a characteristic of high plasticity and can be classified into different subtypes according to the different functions, which can undergo reciprocal phenotypic switching induced by different types of molecules and signaling pathways. Macrophages regulate the development and metastatic potential of colorectal cancer by changing the tumor immune microenvironment. In tumor tissues, the tumor-associated macrophages usually play a tumor-promoting role in the tumor immune microenvironment, and they are also associated with poor prognosis. This paper reviews the mechanisms and stimulating factors of macrophages in the process of colorectal cancer metastasis and intends to indicate that targeting macrophages may be a promising strategy in colorectal cancer treatment.

ObjectiveInjections of proteoglycan aggrecan (PGA) have been reported to induce axial spondyloarthritis (ax-SpA) in BALB/c mice. It is considered to be a model for radiographic ax-SpA. However, evaluation of the extent of axial disease by histopathological assessment of every intervertebral space is labor-intensive. The objective of our paper is to test the feasibility of Micro Computed Tomography (Micro-CT) in rapidly enumerating the number of intervertebral spaces affected in each mouse.MethodsArthritis was induced in BALB/c mice by intraperitoneal injections of PGA. Involvement of several spinal segments, and selected sacroiliac and hip joints were evaluated by histopathology. The involvement of all intervertebral spaces, sacroiliac and hip joints was evaluated by Micro-CT.ResultsBALB/c mice injected with PGA developed histopathology of SpA-like axial lesions, including spondylitis, sacroiliac joint arthritis and hip joint arthritis. Micro-CT allowed us to clearly enumerate the number of lesions in each mouse.ConclusionMicro-CT allows quantitative assessment of the extent of axial involvement in PGA-induced mouse spondylitis. This can be a useful tool in assessing therapeutic interventions.

There is little evidence around Camrelizumab combined with cytoreductive nephrectomy (CN) and radiotherapy (RT) as a treatment option for metastatic renal cell carcinoma (mRCC). The influence of CN on immune responses and the abscopal effect are not well understood. In this paper, we report a case of anti-programmed cell death-1 (PD-1) treated with combined RT once CN reduced the primary tumor burden (TB). This patient also encountered an increased response to targeted radiotherapy after immune resistance. We also observed a macrophage-to-lymphocyte ratio (MLR) peak, which may be correlated with subsequent pseudoprogression after thoracic radiotherapy. Consequently, even with the disease, this patient has remained stable. This peculiar instance suggests there is a need to investigate the underlying mechanisms of CN in promoting the abscopal effect during immunotherapy when combined with RT. It also suggests that there is a need for further investigation into the role of RT in overcoming immune resistance, and the value of MLR in predicting pseudoprogression. We hypothesize that a heavy tumor burden might suppress the abscopal effect, thereby ensuring that CN promotes it. However, radiotherapy may overcome immune resistance during oligoprogression.

Stroke is a multiphasic process, and the initial ischemic phase of neuronal damage is followed by secondary innate and adaptive responses that unfold over days after stroke, offer a longer time frame of intervention, and represent a novel therapeutic target. Therefore, revealing the distinct functions of immune cells in both brain and periphery is important for identification of immunotherapeutic targets for stroke to extend the treatment time window. In this paper an examination of the cellular dynamics of the immune response in the central nervous system (CNS) and periphery provoked by cerebral ischemia is provided. New data is presented for the number of immune cells in brain and spleen of mice during the 7 days following middle cerebral artery occlusion (MCAO). A novel analysis of the correlation among various cell types in the brain and spleen following stroke is presented. It is found that the infiltrated macrophages in the ischemic hemisphere positively correlate with neutrophils which implies their synergic effect in migrating into the brain after stroke onset. It is noted that during infiltration of adaptive immune cells, the number of neutrophils correlate positively with T cells, which suggests neutrophils contribute to T cell infiltration in the stroked brain. Furthermore, the correlation among neurological deficit and various immune cells suggests that microglia and splenic adaptive immune cells (T and B cells) are protective while infiltrating peripheral myeloid cells (macrophage and neutrophils) worsen stroke outcome. Comprehension of such immune responses post cerebral ischemia is crucial for differentiating the drivers of outcomes and also predicting the stroke outcome.

Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.

Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain’s health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers’ functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI.

BackgroundIncreased prevalence of depression has been observed among patients with multiple sclerosis (MS) and correlated with the elevated levels of proinflammatory cytokines and the overall deregulation of monoaminergic neurotransmitters that these patients exhibit. Antidepressants have proved effective not only in treating depression comorbid to MS, but also in alleviating numerous MS symptoms and even minimizing stress-related relapses. Therefore, these agents could prospectively prove beneficial as a complementary MS therapy.ObjectiveThis review aims at illustrating the underlying mechanisms involved in the beneficial clinical effects of antidepressants observed in MS patients.MethodsThrough a literature search we screened and comparatively assessed papers on the effects of antidepressant use both in vitro and in vivo MS models, taking into account a number of inclusion and exclusion criteria.ResultsIn vitro studies indicated that antidepressants promote neural and glial cell viability and differentiation, reduce proinflammatory cytokines and exert neuroprotective activity by eliminating axonal loss. In vivo studies confirmed that antidepressants delayed disease onset and alleviated symptoms in Experimental Autoimmune Encephalomyelitis (EAE), the most prevalent animal model of MS. Further, antidepressant agents suppressed inflammation and restrained demyelination by decreasing immune cell infiltration of the CNS.ConclusionAntidepressants were efficient in tackling numerous aspects of disease pathophysiology both in vitro and in vivo models. Given that several antidepressants have already proved effective in clinical trials on MS patients, the inclusion of such agents in the therapeutic arsenal of MS should be seriously considered, following an individualized approach to minimize the adverse events of antidepressants in MS patients.

Bispecific antibodies (BsAbs) are antibodies with two binding sites directed at two different antigens or two different epitopes on the same antigen. The clinical therapeutic effects of BsAbs are superior to those of monoclonal antibodies (MoAbs), with broad applications for tumor immunotherapy as well as for the treatment of other diseases. Recently, with progress in antibody or protein engineering and recombinant DNA technology, various platforms for generating different types of BsAbs based on novel strategies, for various uses, have been established. More than 30 mature commercial technology platforms have been used to create and develop BsAbs based on the heterologous recombination of heavy chains and matching of light chains. The detailed mechanisms of clinical/therapeutic action have been demonstrated with these different types of BsAbs. Three kinds of BsAbs have received market approval, and more than 110 types of BsAbs are at various stages of clinical trials. In this paper, we elaborate on the classic platforms, mechanisms, and applications of BsAbs. We hope that this review can stimulate new ideas for the development of BsAbs and improve current clinical strategies.

Gut immune cells have been increasingly appreciated as important players in the central nervous system (CNS) autoimmunity in animal models of multiple sclerosis (MS). Among the gut immune cells, innate lymphoid cell type 3 (ILC3) is of special interest in MS research, as they represent the innate cell counterpart of the major pathogenic cell population in MS, i.e. T helper (Th)17 cells. Importantly, these cells have been shown to stimulate regulatory T cells (Treg) and to counteract pathogenic Th17 cells in animal models of autoimmune diseases. Besides, they are also well known for their ability to stabilize the intestinal barrier and to shape the immune response to the gut microbiota. Thus, proper maintenance of the intestinal barrier and the establishment of the regulatory milieu in the gut performed by ILC3 may prevent activation of CNS antigen-specific Th17 cells by the molecular mimicry. Recent findings on the role of ILC3 in the gut-CNS axis and their relevance for MS pathogenesis will be discussed in this paper. Possibilities of ILC3 functional modulation for the benefit of MS patients will be addressed, as well.

19 Pág. Centro de Investigación en Sanidad Animal (CISA), Probiotics have been defined as live microorganisms that when administered in adequate amounts confer health benefits to the host. The use of probiotics in aquaculture is an attractive bio-friendly method to decrease the impact of infectious diseases, but is still not an extended practice. Although many studies have investigated the systemic and mucosal immunological effects of probiotics, not all of them have established whether they were actually capable of increasing resistance to different types of pathogens, being this the outmost desired goal. In this sense, in the current paper, we have summarized those experiments in which probiotics were shown to provide increased resistance against bacterial, viral or parasitic pathogens. Additionally, we have reviewed what is known for fish probiotics regarding the mechanisms through which they exert positive effects on pathogen resistance, including direct actions on the pathogen, as well as positive effects on the host., This work was supported by the European Research Council (ERC Consolidator Grant 2016 725061 TEMUBLYM), by the Spanish Ministry of Science, Innovation and Universities (project AGL2017-85494-C2-1-R) and by the Comunidad de Madrid (grant 2016-T1/BIO-1672).

Lupus nephritis (LN) is a common complication of systemic lupus erythematosus (SLE) and a major risk factor for morbidity and mortality. The abundant cell-free nucleic (DNA/RNA) in SLE patients, especially dsDNA, is a key substance in the pathogenesis of SLE and LN. The deposition of DNA/RNA-immune complexes (DNA/RNA-ICs) in the glomerulus causes a series of inflammatory reactions that lead to resident renal cell disturbance and eventually renal fibrosis. Cell-free DNA/RNA is the most effective inducer of type I interferons (IFN-I). Resident renal cells (rather than infiltrating immune cells) are the main source of IFN-I in the kidney. IFN-I in turn damages resident renal cells. Not only are resident renal cells victims, but also participants in this immunity war. However, the mechanism for generation of IFN-I in resident renal cells and the pathological mechanism of IFN-I promoting renal fibrosis have not been fully elucidated. This paper reviews the latest epidemiology of LN and its development process, discusses the mechanism for generation of IFN-I in resident renal cells and the role of IFN-I in the pathogenesis of LN, and may open a new perspective for the treatment of LN.

Methods for suppressing the host immune system over the long term and improving transplantation tolerance remain a primary issue in organ transplantation. Cell therapy is an emerging therapeutic strategy for immunomodulation after transplantation. Mesenchymal stem cells (MSCs) are adult multipotent stem cells with wide differentiation potential and immunosuppressive properties, which are mostly used in regenerative medicine and immunomodulation. In addition, emerging research suggests that MSC-derived exosomes have the same therapeutic effects as MSCs in many diseases, while avoiding many of the risks associated with cell transplantation. Their unique immunomodulatory properties are particularly important in the immune system-overactive graft environment. In this paper, we review the effects of MSC-derived exosomes in the immune regulation mechanism after organ transplantation and graft-versus-host disease (GvHD) from various perspectives, including immunosuppression, influencing factors, anti-inflammatory properties, mediation of tissue repair and regeneration, and the induction of immune tolerance. At present, the great potential of MSC-derived exosomes in immunotherapy has attracted a great deal of attention. Furthermore, we discuss the latest insights on MSC-derived exosomes in organ transplantation and GvHD, especially its commercial production concepts, which aim to provide new strategies for improving the prognosis of organ transplantation patients.

Since the beginning of the pandemic, few papers describe the placenta’s morphological and morphometrical features in SARS-CoV-2–positive pregnant women. Alterations, such as low placental weight, accelerated villous maturation, decidual vasculopathy, infarcts, thrombosis of fetal placental vessels, and chronic histiocytic intervillositis (CHI), have been described.ObjectiveTo analyze clinical data and the placental morphological and morphometric changes of pregnant women infected with SARS-CoV-2 (COVID-19 group) in comparison with the placentas of non-infected pregnant women, matched for maternal age and comorbidities, besides gestational age of delivery (Control group).MethodThe patients in the COVID-19 and the Control group were matched for maternal age, gestational age, and comorbidities. The morphological analysis of placentas was performed using Amsterdam Placental Workshop Group Consensus Statement. The quantitative morphometric evaluation included perimeter diameter and number of tertiary villi, number of sprouts and knots, evaluation of deposition of villous fibrin, and deposition of intra-villous collagen I and III by Sirius Red. Additionally, Hofbauer cells (HC) were counted within villi by immunohistochemistry with CD68 marker.ResultsCompared to controls, symptomatic women in the COVID-19 group were more likely to have at least one comorbidity, to evolve to preterm labor and infant death, and to have positive SARS-CoV-2 RNA testing in their concepts. Compared to controls, placentas in the COVID-19 group were more likely to show features of maternal and fetal vascular malperfusion. In the COVID-19 group, placentas of symptomatic women were more likely to show CHI. No significant results were found after morphometric analysis.ConclusionPregnant women with symptomatic SARS-CoV-2 infection, particularly with the severe course, are more likely to exhibit an adverse fetal outcome, with slightly more frequent histopathologic findings of maternal and fetal vascular malperfusion, and CHI. The morphometric changes found in the placentas of the COVID-19 group do not seem to be different from those observed in the Control group, as far as maternal age, gestational age, and comorbidities are paired. Only the deposition of villous fibrin could be more accentuated in the COVID-19 group (p = 0.08 borderline). The number of HC/villous evaluated with CD68 immunohistochemistry did not show a difference between both groups.

Sepsis is associated with a dysregulated inflammatory response to infection. Despite the activation of inflammation, an immune suppression is often observed, predisposing patients to secondary infections. Therapies directed at restoration of immunity may be considered but should be guided by the immune status of the patients. In this paper, we described the use of a high-dimensional flow cytometry (HDCyto) panel to assess the immunophenotype of patients with sepsis. We then isolated peripheral blood mononuclear cells (PBMCs) from patients with septic shock and mimicked a secondary infection by stimulating PBMCs for 4 h in vitro with lipopolysaccharide (LPS) with or without prior exposure to either IFN-γ, or LAG-3Ig. We evaluated the response by means of flow cytometry and high-resolution clustering cum differential analysis and compared the results to PBMCs from healthy donors. We observed a heterogeneous immune response in septic patients and identified two major subgroups: one characterized by hypo-responsiveness (Hypo) and another one by hyper-responsiveness (Hyper). Hypo and Hyper groups showed significant differences in the production of cytokines/chemokine and surface human leukocyte antigen-DR (HLA-DR) expression in response to LPS stimulation, which were observed across all cell types. When pre-treated with either interferon gamma (IFN-γ) or lymphocyte-activation gene 3 (LAG)-3 recombinant fusion protein (LAG-3Ig) prior to LPS stimulation, cells from the Hypo group were shown to be more responsive to both immunostimulants than cells from the Hyper group. Our results demonstrate the importance of patient stratification based on their immune status prior to any immune therapies. Once sufficiently scaled, this approach may be useful for prescribing the right immune therapy for the right patient at the right time, the key to the success of any therapy.

Immersion vaccination relies on the response of fish mucosa-associated lymphoid tissues, the Crucian carp (Carassius auratus) and Grouper (Epinephelus coioides) were researched in this paper to examine local mucosal immune responses and associated humoral system responses following immersion vaccination. We administered 1.5 × 107 CFU/ml formalin-inactivated Vibrio harveyi cells and measured mucus and serum antibody titers as well as IgM, MHC II mRNA levels in immune organs. The mucosal antibody response preceded the serum response indicating a role for local mucosal immunity in immersion vaccination. IgM and MHC II mRNA levels were relatively greater for the spleen and head kidney indicating the importance and central position of systemic immunity. Expression levels were also high for the gills while skin levels were the lowest. IgM and MHC II mRNA levels were altered over time following vaccination and the hindgut, liver and spleen were similar indicating a close relationship, so the absolute value of r is used to analyze the correlation among different organs immunized. It can be inferred the existence of an internal immune molecular mechanism for Immune synergy hindgut-liver-spleen, from the peak time (14th day), the relative ratio of genes expression in the same tissues between the immunized grouper and the control group (26 times), and Pearson correlation coefficient (0.8r|V. harveyi indicated that the relative protection rates for the crucian carp and Grouper was basically the same at 44.4% and 47.4%, respectively. It is believe that crucian carp may be used as a substitute for the valuable grouper in immunity experiment, just from aspect of the relative percent survival (RPS) and how it changes with time. But they were not consistent about the IgM mRNA expression between that of crucian carp and grouper after immersion the Vibrio vaccine.

Serum amyloid A (SAA) is an acute phase protein with a significant importance for patients with inflammatory rheumatic diseases (IRD). The central role of SAA in pathogenesis of IRD has been confirmed by recent discoveries, including its involvement in the activation of the inflammasome cascade and recruitment of interleukin 17 producing T helper cells. Clinical utility of SAA in IRD was originally evaluated nearly half a century ago. From the first findings, it was clear that SAA could be used for evaluating disease severity and monitoring disease activity in patients with rheumatoid arthritis and secondary amyloidosis. However, cost-effective and more easily applicable markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), overwhelmed its use in clinical practice. In the light of emerging evidences, SAA has been discerned as a more sensitive biomarker in a wide spectrum of IRD, especially in case of subclinical inflammation. Furthermore, a growing number of studies are confirming the advantages of SAA over many other biomarkers in predicting and monitoring response to biological immunotherapy in IRD patients. Arising scientific discoveries regarding the role of SAA, as well as delineating SAA and its isoforms as the most sensitive biomarkers in various IRD by recently developing proteomic techniques are encouraging the revival of its clinical use. Finally, the most recent findings have shown that SAA is a biomarker of severe Coronavirus disease 2019 (COVID-19). The aim of this review is to discuss the SAA-involving immune system network with emphasis on mechanisms relevant for IRD, as well as usefulness of SAA as a biomarker in various IRD. Therefore, over a hundred original papers were collected through an extensive PubMed and Scopus databases search. These recently arising insights will hopefully lead to a better management of IRD patients and might even inspire the development of new therapeutic strategies with SAA as a target.

Trillions of symbiotic microbial cells colonize our body, of which the larger part is present in the human gut. These microbes play an essential role in our health and a shift in the microbiome is linked to several diseases. Recent studies also suggest a link between changes in gut microbiota and neurological disorders. Gut microbiota can communicate with the brain via several routes, together called the microbiome–gut–brain axis: the neuronal route, the endocrine route, the metabolic route and the immunological route. Helicobacter is a genus of Gram-negative bacteria colonizing the stomach, intestine and liver. Several papers show the role of H. pylori in the development and progression of neurological disorders, while hardly anything is known about other Helicobacter species and the brain. We recently reported a high prevalence of H. suis in patients with Parkinson’s disease and showed an effect of a gastric H. suis infection on the mouse brain homeostasis. Here, we discuss the potential role of H. suis in neurological disorders and how it may affect the brain via the microbiome–gut–brain axis.

Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.

Until recently, the treatment landscape for hepatocellular cancer (HCC) was dominated by tyrosine kinase inhibitors (TKIs) which offered an overall survival (OS) benefit when used both in the first-and second-line setting compared to best supportive care. However, the treatment landscape has changed with the introduction of immune checkpoint inhibitors (ICIs) for the treatment of HCC with significant improvement in OS and progression free survival reported with combination atezolizumab and bevacizumab compared to sorafenib in the first-line setting. Nonetheless, the response to ICIs is 20–30% and invariably patients will progress. What remains unclear is which therapeutics should be used following ICI exposure. Extrapolating from the evidence base in renal cell carcinoma, subsequent therapy with TKIs offers both a response and survival benefit and are recommended by European guidelines. However, there are a number of novel therapies emerging that target mechanisms of ICI resistance that hold promise both in combination with ICI or as subsequent therapy. This paper will discuss the evidence for ICIs in HCC, the position of second-line therapies following ICIs and research strategies moving forward.

Beauveria bassiana is one of the most widespread insect pathogens and can be used in the biological control of agricultural, forestry and medical pests. The mechanisms by which B. bassiana leads to mortality in different host insects are also different. For house flies, B. bassiana has strong virulence, but its microecological mechanism is not clear. In this paper, the virulence of three strains of B. bassiana (TB, CB and BB) isolated from different hosts to house flies was studied. The results showed that the three strains of B. bassiana had strong pathogenicity to house fly adults. Specifically, TB was the strongest, CB was the second strongest, and BB was the weakest, with maximum lethal effects on house fly populations 5, 6, and 7 days after infection, respectively. Further study showed that the intestinal flora of house flies was disordered 3, 4, and 5 days after B. bassiana TB, CB and BB strain infection, respectively. Intestinal flora dysbacteriosis may be an important reason for the death of house flies caused by B. bassiana. After infection, the negative interaction ratio of bacteria in the house fly intestine decreased, and the stronger the virulence was, the lower the negative interaction ratio was. The time from B. bassiana infection to intestinal flora dysbacteriosis was not fixed. We named this period the “spring stage”. The stronger the virulence of the B. bassiana strain was, the shorter the “spring stage” was. Therefore, the “spring stage” can be used as a virulence marker for evaluating the pathogenicity of different B. bassiana strains.

To improve pathogenetic studies in cancer development and reliable preclinical testing of anti-cancer treatments, three-dimensional (3D) cultures, including spheroids, have been widely recognized as more physiologically relevant in vitro models of in vivo tumor behavior. Currently, the generation of uniformly sized spheroids is still challenging: different 3D cell culture methods produce heterogeneous populations in dimensions and morphology, that may strongly influence readouts reliability correlated to tumor growth rate or antitumor natural killer (NK) cell-mediated cytotoxicity. In this context, an increasing consensus claims the integration of microfluidic technologies within 3D cell culture, as the physical characterization of tumor spheroids is unavoidably demanded to standardize protocols and assays for in vitro testing. In this paper, we employed a flow-based method specifically conceived to measure weight, size and focused onto mass density values of tumor spheroids. These measurements are combined with confocal and digital imaging of such samples. We tested the spheroids of four colorectal cancer (CRC) cell lines that exhibit statistically relevant differences in their physical characteristics, even though starting from the same cell seeding density. These variations are seemingly cell line-dependent and associated with the number of growing cells and the degree of spheroid compaction as well, supported by different adenosine-triphosphate contents. We also showed that this technology can estimate the NK cell killing efficacy by measuring the weight loss and diameter shrinkage of tumor spheroids, alongside with the commonly used cell viability in vitro test. As the activity of NK cells relies on their infiltration rate, the in vitro sensitivity of CRC spheroids proved to be exposure time- and cell line-dependent with direct correlation to the cell viability reduction. All these functional aspects can be measured by the system and are documented by digital image analysis. In conclusion, this flow-based method potentially paves the way towards standardization of 3D cell cultures and its early adoption in cancer research to test antitumor immune response and set up new immunotherapy strategies.

Prenatal Diagnosis (PND) forms an important part of primary preventive management for families having a child affected with primary immunodeficiency. Although individually sparse, collectively this group of genetic disorders represents a significant burden of disease. This paper discusses the prenatal services available for affected families at various centers across the country and the challenges and ethical considerations associated with genetic counseling. Mutation detection in the index case and analysis of chorionic villous sampling or amniocentesis remain the preferred procedures for PND and phenotypic analysis of cordocentesis sample is reserved for families with well-characterized index case seeking PND in the latter part of the second trimester of pregnancy. A total of 112 families were provided PND services in the last decade and the presence of an affected fetus was confirmed in 32 families. Post-test genetic counseling enabled the affected families to make an informed decision about the current pregnancy.

Vaccine development utilizing various platforms is one of the strategies that has been proposed to address the coronavirus disease 2019 (COVID-19) pandemic. Adjuvants are critical components of both subunit and certain inactivated vaccines because they induce specific immune responses that are more robust and long-lasting. A review of the history of coronavirus vaccine development demonstrates that only a few adjuvants, including aluminum salts, emulsions, and TLR agonists, have been formulated for the severe acute respiratory syndrome-associated coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and currently the SARS-CoV-2 vaccines in experimental and pre-clinical studies. However, there is still a lack of evidence regarding the effects of the adjuvants tested in coronavirus vaccines. This paper presents an overview of adjuvants that have been formulated in reported coronavirus vaccine studies, which should assist with the design and selection of adjuvants with optimal efficacy and safety profiles for COVID-19 vaccines.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease including the cardiovascular system. Atherosclerosis is the most common cardiovascular complication of SLE and a significant risk factor for morbidity and mortality. Vascular damage/protection mechanism in SLE patients is out of balance, caused by the cascade reaction among oxidative stress, proinflammatory cytokines, Neutrophil Extracellular Traps, activation of B cells and autoantibodies and abnormal T cells. As a precursor cell repairing vascular endothelium, endothelial progenitor cells (EPCs) belong to the protective mechanism and show the reduced number and impaired function in SLE. However, the pathological mechanism of EPCs dysfunction in SLE remains ill-defined. This paper reviews the latest SLE epidemiology and pathogenesis, discusses the changes in the number and function of EPCs in SLE, expounds the role of EPCs in SLE atherosclerosis, and provides new guidance and theoretical basis for exploring novel targets for SLE treatment.

Neoangiogenesis is a recognized hallmark of cancer, granting tumor cells to dispose of metabolic substrates through a newly created vascular supply. Neoangiogenesis was also confirmed in melanoma, where vascular proliferation is associated with increased aggressiveness and poorer prognosis. Furthermore, melanoma cells show the so-called vascular mimicry, consisting in the assumption of endothelial-like features inducing the expression of pro-angiogenic receptors and ligands, which take part in the interplay with extracellular matrix (ECM) components and are potentiated by the ECM remodeling and the barrier molecule junction alterations that characterize the metastatic phase. Although neoangiogenesis was biologically proven and clinically associated with worse outcomes in melanoma patients, in the past anti-angiogenic therapies were employed with poor improvement of the already unsatisfactory results associated with chemotherapic agents. Among the novel therapies of melanoma, immunotherapy has led to previously unexpected outcomes of treatment, yet there is a still strong need for potentiating the results, possibly by new regimens of combination therapies. Molecular models in many cancer types showed mutual influences between immune responses and vascular normalization. Recently, clinical trials are investigating the efficacy of the association between anti-angiogenetic agents and immune-checkpoint inhibitors to treat advanced stage melanoma. This paper reviews the biological bases of angiogenesis in melanoma and summarizes the currently available clinical data on the use of anti-angiogenetic compounds in melanoma.

With the wide applications of magnetic fields (MFs) in medicine, researchers from different disciplines have gained interest in understanding the effect of various types of MFs on living cells and organisms. In this paper, we mainly focus on the immunological and physical aspects of the immune responses and their mechanisms under different types of MFs. Immune cells were slightly affected by low-frequency alternating MFs but were strongly influenced by moderate-intensity MFs and high-gradient MFs (HGMFs). Larger immune cells, such as macrophages, were more sensitive to HGMFs, which biased the cell polarization into the anti-inflammatory M2 phenotype. Subject to the gradient forces of varying directions and strength, the elongated M2 macrophage also remodeled the cytoskeleton with actin polymerization and changed the membrane receptors and ion channel gating. These alterations were very similar to changes caused by the small GTPase RhoA interference in macrophage. Regulation of iron metabolism may also contribute to the MF effects in macrophages. High MFs were found to regulate the iron content in monocyte-/macrophage-derived osteoclasts by affecting the expression of iron-regulation genes. On the other hand, paramagnetic nanoparticles (NPs) combined with external MFs play an important role in T-cell immunity. Paramagnetic NP-coated T-cells can cluster their T-cell receptors (TCRs) by using an external MF, thus increasing the cell–cell contact and communication followed by enhanced tumor killing capacity. The external MF can also guide the adoptively transferred magnetic NP-coated T-cells to their target sites in vivo, thus dramatically increasing the efficiency of cell therapy. Additionally, iron oxide NPs for ferroptosis-based cancer therapy and other MF-related therapeutic applications with obstacles were also addressed. Furthermore, for a profound understanding of the effect of MFs on immune cells, multidisciplinary research involving both experimental research and theoretical modeling is essential.

The host immune system has multiple innate immune receptors that can identify, distinguish and react to viral infections. In innate immune response, the host recognizes pathogen-associated molecular patterns (PAMP) in nucleic acids or viral proteins through pathogen recognition receptors (PRRs), especially toll-like receptors (TLRs) and induces immune cells or infected cells to produce type I Interferons (IFN-I) and pro-inflammatory cytokines, thus when the virus invades the host, innate immunity is the earliest immune mechanism. Besides, cytokine-mediated cell communication is necessary for the proper regulation of immune responses. Therefore, the appropriate activation of innate immunity is necessary for the normal life activities of cells. The suppressor of the cytokine signaling proteins (SOCS) family is one of the main regulators of the innate immune response induced by microbial pathogens. They mainly participate in the negative feedback regulation of cytokine signal transduction through Janus kinase signal transducer and transcriptional activator (JAK/STAT) and other signal pathways. Taken together, this paper reviews the SOCS proteins structures and the function of each domain, as well as the latest knowledge of the role of SOCS proteins in innate immune caused by viral infections and the mechanisms by which SOCS proteins assist viruses to escape host innate immunity. Finally, we discuss potential values of these proteins in future targeted therapies.

The inflammatory response to and the subsequent development of Adult Respiratory Distress Syndrome (ARDS) is considered to underpin COVID-19 pathogenesis. With a developing world catastrophe, we need to examine our known therapeutic stocks, to assess suitability for prevention and/or treatment of this pro-inflammatory virus. Analyzing commonly available and inexpensive immunomodulatory and anti-inflammatory medications to assess their possible effectiveness in improving the host response to COVID-19, this paper recommends the following: (1) optimize current health—cease (reduce) smoking, ensure adequate hypertension and diabetes control, continue exercising; (2) start on an HMG CoA reductase inhibitor “statin” for its immunomodulatory and anti-inflammatory properties, which may reduce the mortality associated with ARDS; and (3) consider using Diclofenac (or other COX-2 inhibition medications) for its anti-inflammatory and virus toxicity properties. For purposes of effectiveness, this needs to be in the early course of the disease (post infection and/or symptom presentation) and given in a high dose. The downsides to these recommended interventions are considered manageable at this stage of the pandemic.

Immunodeficiency disorders and autoimmune diseases are common, but a lack of effective targeted drugs and the side-effects of existing drugs have stimulated interest in finding therapeutic alternatives. Naturally derived substances are a recognized source of novel drugs, and tick saliva is increasingly recognized as a rich source of bioactive molecules with specific functions. Ticks use their saliva to overcome the innate and adaptive host immune systems. Their saliva is a rich cocktail of molecules including proteins, peptides, lipid derivatives, and recently discovered non-coding RNAs that inhibit or modulate vertebrate immune reactions. A number of tick saliva and/or salivary gland molecules have been characterized and shown to be promising candidates for drug development for vertebrate immune diseases. However, further validation of these molecules at the molecular, cellular, and organism levels is now required to progress lead candidates to clinical testing. In this paper, we review the data on the immuno-pharmacological aspects of tick salivary compounds characterized in vitro and/or in vivo and present recent findings on non-coding RNAs that might be exploitable as immunomodulatory therapies.

Primary Sjogren’s syndrome (pSS) is an autoimmune disorder in which lymphocytic infiltration leads to lacrimal and salivary glands dysfunction, which results in symptoms of dryness (xerophthalmia and xerostomia). Extraglandular features are common and may affect several organs. Renal involvement has long been known as one of the systemic complications of pSS. The most classical lesion frequent SS-associated nephropathies are tubulointerstitial nephritis (TIN) and less frequently membranoproliferative glomerulonephritis (MPGN) related to cryoglobulinemia. Renal biopsy is some cases, mandatory, in the diagnosis of renal involvement in these patients. Patients may present with proximal renal tubular acidosis, distal renal tubular acidosis and chronic kidney disease. Response to treatment is usually favourable. However, occasionally severe and rarely lethal outcomes have been described. Recently, several case series and cross-sectional studies have been published which investigated the factors associated with renal involvement in pSS and the most accurate screening tests for early detection. The presence of xerophthalmia, anti-SSA and rheumatoid factor positivity, low C3 levels and other features have all shown either positive or inverse associations with the development of renal complications. Serum creatinine, alpha-1-microglobulin, cystatin-C have been evaluated as early detection biomarkers with variable accuracy. More advanced techniques may be necessary to confirm proximal and distal renal tubular acidosis, along with nephrogenic diabetes insipidus. The aim of the current paper is to summarize and critically examine these findings in order to provide updated guidance on serum biomarkers and further testing for kidney involvement in pSS.

The most prominent pathological features of multiple sclerosis (MS) are demyelination and neurodegeneration. The exact pathogenesis of MS is unknown, but it is generally regarded as a T cell-mediated autoimmune disease. Increasing evidence, however, suggests that other components of the immune system, particularly B cells and antibodies, contribute to the cumulative CNS damage and worsening disability that characterize the disease course in many patients. We have previously described strongly elevated T cell reactivity to an extracellular domain of the most abundant CNS myelin protein, myelin proteolipid protein (PLP) in people with MS. The current paper addresses the question of whether this region of PLP is also a target of autoantibodies in MS. Here we show that serum levels of isotype-switched anti-PLP181−230 specific antibodies are significantly elevated in patients with MS compared to healthy individuals and patients with other neurological diseases. These anti-PLP181−230 antibodies can also live-label PLP-transfected cells, confirming that they can recognize native PLP expressed at the cell surface. Importantly, the antibodies are only elevated in patients who carry HLA molecules that allow strong T cell responses to PLP. In that subgroup of patients, there is a positive correlation between the levels of anti-PLP181−230 antibodies and the severity of MS. These results demonstrate that anti-PLP antibodies have potentially important roles to play in the pathogenesis of MS.

To date the pathophysiology of COVID-19 remains unclear: this represents a factor determining the current lack of effective treatments. In this paper, we hypothesized a complex host response to SARS-CoV-2, with the Contact System (CS) playing a pivotal role in innate immune response. CS is linked with different proteolytic defense systems operating in human vasculature: the Kallikrein–Kinin (KKS), the Coagulation/Fibrinolysis and the Renin–Angiotensin (RAS) Systems. We investigated the role of the mediators involved. CS consists of Factor XII (FXII) and plasma prekallikrein (complexed to high-molecular-weight kininogen-HK). Autoactivation of FXII by contact with SARS-CoV-2 could lead to activation of intrinsic coagulation, with fibrin formation (microthrombosis), and fibrinolysis, resulting in increased D-dimer levels. Activation of kallikrein by activated FXII leads to production of bradykinin (BK) from HK. BK binds to B2-receptors, mediating vascular permeability, vasodilation and edema. B1-receptors, binding the metabolite [des-Arg9]-BK (DABK), are up-regulated during infections and mediate lung inflammatory responses. BK could play a relevant role in COVID-19 as already described for other viral models. Angiotensin-Converting-Enzyme (ACE) 2 displays lung protective effects: it inactivates DABK and converts Angiotensin II (Ang II) into Angiotensin-(1-7) and Angiotensin I into Angiotensin-(1-9). SARS-CoV-2 binds to ACE2 for cell entry, downregulating it: an impaired DABK inactivation could lead to an enhanced activity of B1-receptors, and the accumulation of Ang II, through a negative feedback loop, may result in decreased ACE activity, with consequent increase of BK. Therapies targeting the CS, the KKS and action of BK could be effective for the treatment of COVID-19.

Surface antigen one (Sao) protein is a bacterial surface protein identified in the important zoonotic pathogen Streptococcus suis serotype 2 (S. suis 2) during an extensive search for functional proteins. The Sao protein is anchored to the bacterial cell wall by the LPVTG motif and is widely distributed in many S. suis serotypes. In this paper, we present the immunodominant epitope peptide of the Sao protein that is recognized by BALB/c antibodies against the Sao protein: 355SEKQMPSVVNENAVTPEKQMTNKENDNIET384 (location Sao355−384). To determine the core epitope recognized by antibodies, we prepared truncation peptide libraries. Analyses of the immunoreactivity of truncation peptides with anti-Sao355−384 serum revealed that the most immunoreactive sequence was 355SEKQMPSVVNENAVTPEK372 (location Sao355−372). Moreover, we observed that this core epitope also showed good specificity based on the ratio of reactivity with serum from S. suis–positive patients compared to serum from S. suis–negative patients. Our results point to the potential of using the Sao355−372 peptide in diagnostic assays to determine S. suis infection in humans.

In recent years, neutrophil extracellular traps at the forefront of neutrophil biology have proven to help capture and kill pathogens involved in the inflammatory process. There is growing evidence that persistent neutrophil extracellular traps drive the pathogenesis of autoimmune diseases. In this paper, we summarize the potential of neutrophil extracellular traps to drive the pathogenesis of rheumatoid arthritis and experimental animal models. We also describe the diagnosis and treatment of rheumatoid arthritis in association with neutrophil extracellular traps.

Schistosomiasis japonica is an ancient parasitic disease that has severely impacted human health causing a substantial disease burden not only to the Chinese people but also residents of other countries such as the Philippines, Indonesia and, before the 1970s, Japan. Since the founding of the new People’s Republic of China (P. R. China), effective control strategies have been implemented with the result that the prevalence of schistosomiasis japonica has decreased markedly in the past 70 years. Historically, the Dongting Lake region in Hunan province is recognised as one of the most highly endemic for schistosomiasis in the P.R. China. The area is characterized by vast marshlands outside the lake embankments and, until recently, the presence of large numbers of domestic animals such as bovines, goats and sheep that can act as reservoir hosts for Schistosoma japonicum. Considerable social, economic and environmental changes have expanded the Oncomelania hupensis hupensis intermediate snail host areas in the Dongting lake region increasing the potential for both the emergence of new hot spots for schistosomiasis transmission, and for its re-emergence in areas where infection is currently under control. In this paper, we review the history, the current endemic status of schistosomiasis and the control strategies in operation in the Dongting Lake region. We also explore epidemiological factors contributing to S. japonicum transmission and highlight key research findings from studies undertaken on schistosomiasis mainly in Hunan but also other endemic Chinese provinces over the past 10 years. We also consider the implications of these research findings on current and future approaches that can lead to the sustainable integrated control and final elimination of schistosomiasis from the P. R. China and other countries in the region where this unyielding disease persists.

Case-based, interactive sessions for small groups (in a large medical school class of 150 students) reinforce basic immunology concepts by including clinical scenarios that stimulate student learning and consolidate critical concepts. Careful design of cases (designing backwards from the key concepts) leads students through successively more complicated and linked group-work questions. This paper details why cases are effective learning tools, how to design an effective case, how to ask appropriate questions and how to help students apply basic immunology concepts to a case. Each group work session is facilitated and followed by a question and answer presentation by faculty, where student groups are directly asked to answer the questions and also challenged with “bonus questions” not presented with the original case. This allows students to “put together” immunology information into a “story” that they can tell and prevents student frustration by summarizing the results at the end of each case. Case design is carefully discussed including clinical relevancy and accuracy, how to write questions that do not give away the answers, how to emphasize mechanistic questions that allow students to “clinically explain as a physician” the immunological basis for the answers. Additionally, students better understand the role of immunity in both normal and disease states. A case-based approach promotes student learning by re-emphasizing basic concepts in the context of the case and promotes better students understanding of critical immunological concepts. Keywords: Immunology education, case-based learning, medical school education, team-based learning, key concepts, active learning, integrated curriculum.