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Summary: Food allergy is related to increasing risk of the development of allergic asthma, but the precise interplay between sensitization to different allergens in different compartments of the body is not fully understood. The aim of this study was to develop a novel humanized murine model of mixed food and respiratory allergy that recapitulates the human anaphylactic response and to more clearly understand the impact of food allergies on asthma. Immunodeficient mice transferred with peripheral blood mononuclear cells (PBMCs) from donors with peanut and house dust mite (HDM) allergy were exposed and challenged to peanut. Between peanut exposure and challenge, mice were intranasally treated to HDM. Allergic parameters were analyzed. Allergen‐specific immunoglobulin (Ig)E in sera could only be measured in mice treated with peripheral blood mononuclear cells (PBMCs) plus allergen. A preceding peanut exposure increased IgE levels, histamine release, bronchial hyper‐responsiveness and lung inflammation. Recruitment of inflammatory cells to the airways was aggravated associated with an enhanced T helper type 2 (Th2)/Th17 cytokine secretion when the two allergies were present. A preceding peanut exposure amplifies allergic asthma in this humanized model, which may contribute to the understanding of underlying immunological mechanism of polysensitization occurring in allergic individuals and evaluation of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Summary: Many cancer types are intrinsically associated with specific types of amyloidosis, in which amyloid is accumulated locally inside tumors or systemically. Usually, this condition relates to the hyperproduction of specific amylogenic proteins. Recently, we found that the accumulation of amyloid beta (Aβ) peptide immunofluorescence is linked to glioma cells in mouse tumors. Here we report that amyloid‐specific histochemical dyes reveal amyloid accumulation in all human glioma samples. Application of two different antibodies against Aβ peptide (a polyclonal antibody against human Aβ1–42 and a monoclonal pan‐specific mAb‐2 antibody against Aβ) showed that the amyloid in glioma samples contains Aβ. Amyloid was linked to glioma cells expressing glial‐specific fibrillary acidic protein (GFAP) and to glioma blood vessels. Astrocytes close to the glioma site and to affected vessels also accumulated Aβ. We discuss whether amyloid is produced by glioma cells or is the result of systemic production of Aβ in response to glioma development due to an innate immunity reaction. We conclude that amyloid build‐up in glioma tumors is a part of the tumor environment, and may be used as a target for developing a novel class of anti‐tumor drugs and as an antigen for glioma visualization. [ABSTRACT FROM AUTHOR]

Summary: Primary pneumococcal peritonitis is a rare infection that has been described in women but has not been previously linked with immunodeficiency. The complement system plays a central role in immune defence against Streptococcus pneumoniae and, in order to evade complement attack, pneumococci have evolved a large number of mechanisms that limit complement‐mediated opsonization and subsequent phagocytosis. We investigated an apparently immunocompetent woman with primary pneumococcal peritonitis and identified a family with deficiency for complement factor I. Primary pneumococcal peritonitis should be considered a possible primary immunodeficiency presentation. [ABSTRACT FROM AUTHOR]

Summary: A group of European FOCIS Centers of Excellence adapted panels of the Human Immunophenotyping Consortium (HIPC) for whole blood analysis. Using four core panels [T/regulatory T cell/B/natural killer (T/Treg/B/NK) and myeloid cells] the main leukocyte populations were analyzed in a clinical–diagnostic setting in a harmonized manner across different platforms. As a first step, the consortium presents here the absolute and relative frequencies of the leukocyte subpopulations in the peripheral blood of more than 300 healthy volunteers across six different European centers. [ABSTRACT FROM AUTHOR]

Summary: Since the emergence of COVID‐19, caused by the SARS‐CoV‐2 virus at the end of 2019, there has been an explosion of vaccine development. By 24 September 2020, a staggering number of vaccines (more than 200) had started preclinical development, of which 43 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socializing. Importantly, to effectively control the COVID‐19 pandemic, production needs to be scaled‐up from a small number of preclinical doses to enough filled vials to immunize the world's population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS‐CoV‐2 and the potential for vaccine‐induced immunopathology. We describe the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising preclinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began we are at a point where preclinical and early clinical data are being generated for the vaccines; an overview of this important area will help our understanding of the next phases. [ABSTRACT FROM AUTHOR]

Summary: Background: The impact of countries' bacillus Calmette–Guérin (BCG) vaccination policies on the course of coronavirus disease (COVID‐19) outbreak is a curiosity. In this study, the relationship between BCG vaccination status and severity of COVID‐19 pneumonia and the factors affecting disease severity were investigated. Methods: A retrospective cross‐sectional study was conducted between March and June 2020 in patients diagnosed with COVID‐19 pneumonia, confirmed by severe acute respiratory syndrome coronavirus‐2 polymerase chain reaction positivity in a nasopharyngeal sample and pulmonary infiltrates in computed chest tomography, in a state hospital in Istanbul, Turkey. Socio‐demographic features, body mass index, smoking status, concomitant diseases, income rates and BCG vaccination status of subjects were analyzed. Result: The study population comprised 123 adults with COVID‐19 pneumonia [mean age = 49·7 years, standard deviation = 13·3 years; 82 (66·7%) male]. While the rate of cases vaccinated with BCG is lower (68·5 versus 88·2%, P = 0·026), mean age (54·0 ± 11·5 years versus 38·3 ± 10·7 years; P < 0·001), diabetes (32·6 versus 5·9%, P = 0·002) and low income (84·3 versus 52·9%, P < 0·001) are higher in patients with severe disease compared to those with mild disease. According to multivariate analysis increasing age [odds ratio (OR) = 1·119; 95% confidence interval (CI) = 1·062–1·178, P < 0·001] and low income (OR = 3·209; 95% CI = 1·008–10·222, P = 0·049) are associated with severe disease in COVID‐19 pneumonia. Conclusion: This study reveals that BCG vaccination is not associated with disease severity in COVID‐19 pneumonia. Age and low income are the main determinants of severe COVID‐19 pneumonia. [ABSTRACT FROM AUTHOR]

Summary: Innate immune sensing of viral molecular patterns is essential for development of antiviral responses. Like many viruses, SARS‐CoV‐2 has evolved strategies to circumvent innate immune detection, including low cytosine–phosphate–guanosine (CpG) levels in the genome, glycosylation to shield essential elements including the receptor‐binding domain, RNA shielding and generation of viral proteins that actively impede anti‐viral interferon responses. Together these strategies allow widespread infection and increased viral load. Despite the efforts of immune subversion, SARS‐CoV‐2 infection activates innate immune pathways inducing a robust type I/III interferon response, production of proinflammatory cytokines and recruitment of neutrophils and myeloid cells. This may induce hyperinflammation or, alternatively, effectively recruit adaptive immune responses that help clear the infection and prevent reinfection. The dysregulation of the renin–angiotensin system due to down‐regulation of angiotensin‐converting enzyme 2, the receptor for SARS‐CoV‐2, together with the activation of type I/III interferon response, and inflammasome response converge to promote free radical production and oxidative stress. This exacerbates tissue damage in the respiratory system, but also leads to widespread activation of coagulation pathways leading to thrombosis. Here, we review the current knowledge of the role of the innate immune response following SARS‐CoV‐2 infection, much of which is based on the knowledge from SARS‐CoV and other coronaviruses. Understanding how the virus subverts the initial immune response and how an aberrant innate immune response contributes to the respiratory and vascular damage in COVID‐19 may help to explain factors that contribute to the variety of clinical manifestations and outcome of SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Summary: While donor‐specific human leukocyte antigen (HLA) antibodies are a frequent cause for chronic antibody‐mediated rejection in organ transplantation, this is not the case for antibodies targeting blood group antigens, as ABO‐incompatible (ABO‐I) organ transplantation has been associated with a favorable graft outcome. Here, we explored the role of CD4 T cell‐mediated alloresponses against endothelial HLA‐D‐related (DR) in the presence of anti‐HLA class I or anti‐A/B antibodies. CD4 T cells, notably CD45RA‐memory CD4 T cells, undergo extensive proliferation in response to endothelial HLA‐DR. The CD4 T cell proliferative response was enhanced in the presence of anti‐HLA class I, but attenuated in the presence of anti‐A/B antibodies. Microarray analysis and molecular profiling demonstrated that the expression of CD274 programmed cell death ligand 1 (PD‐L1) increased in response to anti‐A/B ligation‐mediated extracellular signal‐regulated kinase (ERK) inactivation in endothelial cells that were detected even in the presence of interferon‐γ stimulation. Anti‐PD‐1 antibody enhanced CD4 T cell proliferation, and blocked the suppressive effect of the anti‐A/B antibodies. Educated CD25+CD127− regulatory T cells (edu.Tregs) were more effective at preventing CD4 T cell alloresponses to endothelial cells compared with naive Treg; anti‐A/B antibodies were not involved in the Treg‐mediated events. Finally, amplified expression of transcript encoding PD‐L1 was observed in biopsy samples from ABO‐I renal transplants when compared with those from ABO‐identical/compatible transplants. Taken together, our findings identified a possible factor that might prevent graft rejection and thus contribute to a favorable outcome in ABO‐I renal transplantation. [ABSTRACT FROM AUTHOR]

Summary: Peroxiredoxins (PRXs) are intracellular anti‐oxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5 and PRX6) in the cerebrospinal fluid (CSF) and serum of 16 patients with MS, 16 patients with NMOSD and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1‐6) in the central nervous system (CNS) were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (P < 0·05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood–brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD. [ABSTRACT FROM AUTHOR]

Innate and adaptive immune responses in the central nervous system (CNS) play critical roles in the pathogenesis of neurological diseases. In the first of a two‐part special issue, leading researchers discuss how imaging modalities are used to monitor immune responses in several neurodegenerative diseases and glioblastoma and brain metastases. While comparative studies in humans between imaging and pathology are biased towards the end stage of disease, animal models can inform regarding how immune responses change with disease progression and as a result of treatment regimens. Magnetic resonance imaging (MRI) and positron emission tomography (PET) are frequently used to image disease progression, and the articles indicate how one or more of these modalities have been applied to specific neuroimmune diseases. In addition, advanced microscopical imaging using two‐dimensional photon microscopy and in vitro live cell imaging have also been applied to animal models. In this special issue (Parts 1 and 2), as well as the imaging modalities mentioned, several articles discuss biomarkers of disease and microscopical studies that have enabled characterization of immune responses. Future developments of imaging modalities should enable tracking of specific subsets of immune cells during disease allowing longitudinal monitoring of immune responses. These new approaches will be critical to more effectively monitor and thus target specific cell subsets for therapeutic interventions which may be applicable to a range of neurological diseases. [ABSTRACT FROM AUTHOR]

Summary: Tumor necrosis factor (TNF)‐α is largely regarded as a proinflammatory cytokine, but several recent researches have demonstrated that TNF‐α could possess immunoregulatory roles with potential to suppress anti‐tumor immunity. Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and HBV‐specific CD8 T cells could exert anti‐tumor roles in HCC patients. Here, we found that HBV‐specific CD8 T cells, both in the peripheral blood and in the tumor microenvironment, were more enriched with TNF‐α‐expressing cells than interferon (IFN)‐γ‐expressing cells. Compared to IFN‐γ‐expressing HBV‐specific CD8 T cells, TNF‐α‐expressing HBV‐specific CD8 T cells presented lower expression of inhibitory checkpoint molecules, including programmed cell death (PD)‐1, T cell immunoglobulin mucin‐3 (TIM‐3) and cytotoxic T lymphocyte antigen (CTLA)‐4. HBV‐specific CD8 T cells could mediate the lysis of autologous primary tumor cells, and the inhibition of TNF‐α could further elevate their cytotoxic capacity. Subsequently, we demonstrated that TNF‐α inhibition in HBV‐specific CD8 T cells could significantly increase granzyme B (GZMB) and perforin 1 (PRF1) expression while having no effect towards granzyme A (GZMA) expression. The addition of exogenous TNF‐α at low levels had no consistent effect on the expression of GZMA, GZMB and PRF1, but at higher levels, exogenous TNF‐α significantly reduced GZMA, GZMB and PRF1 expression. Overall, these results suggested that TNF‐α‐expressing cells probably presented a deleterious role in HCC but were enriched in HBV‐specific CD8 T cells. [ABSTRACT FROM AUTHOR]

Summary: Children diagnosed with a combination of type 1 diabetes (T1D) and celiac disease (CD) show a dysregulated T helper type 1 (Th1)/Th17 response. Besides the cellular involvement, several soluble immune markers are involved in the autoimmune process of both T1D and CD. Only few studies have examined the peripheral pattern of different cytokines, chemokines and acute‐phase proteins (APP) in children with combined T1D and CD. To our knowledge, no studies have evaluated the serum levels of adipocytokines and matrix metalloproteinases (MMPs) in this context. The purpose of the present study was to acquire more knowledge and to gain deeper understanding regarding the peripheral immunoregulatory milieu in children with both T1D and CD. The study included children diagnosed with both T1D and CD (n = 18), children with T1D (n = 27) or CD (n = 16) and reference children (n = 42). Sera were collected and analysis of 28 immune markers (cytokines, chemokines, APPs, adipocytokines and MMPs) was performed using the Luminex technique. The major findings showed that children with a double diagnosis had lower serum levels of interleukin (IL)‐22, monocyte chemoattractant protein (MIP)‐1α, monocyte chemoattractant protein (MCP)‐1, procalcitonin, fibrinogen, visfatin and matrix metalloproteinase (MMP)‐2. These results indicate a suppressed immune profile in children with combined T1D and CD, including Th17 cytokines, chemokines, APPs, adipocytokines and MMPs. We conclude that, besides cytokines and chemokines, other immune markers, e.g. APPs, adipocytokines and MMPs, are of importance for further investigations to elucidate the heterogeneous immune processes present in patients diagnosed with T1D in combination with CD. [ABSTRACT FROM AUTHOR]

Summary: Systemic sclerosis (SSc) is a T helper type 2 (Th2)‐associated autoimmune disease characterized by vasculopathy and fibrosis. Efficacy of B cell depletion therapy underscores antibody‐independent functions of B cells in SSc. A recent study showed that the Th2 cytokine interleukin (IL)‐4 induces granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐producing effector B cells (GM‐Beffs) in humans. In this study, we sought to elucidate the generation mechanism of GM‐Beffs and also determine a role of this subset in SSc. Among Th‐associated cytokines, IL‐4 most significantly facilitated the generation of GM‐Beffs within memory B cells in healthy controls (HCs). In addition, the profibrotic cytokine transforming growth factor (TGF)‐β further potentiated IL‐4‐ and IL‐13‐induced GM‐Beffs. Of note, tofacitinib, a Janus kinase (JAK) inhibitor, inhibited the expression of GM‐CSF mRNA and protein in memory B cells induced by IL‐4, but not by TGF‐β. GM‐Beffs were enriched within CD20+CD30+CD38−/low cells, a distinct population from plasmablasts, suggesting that GM‐Beffs exert antibody‐independent functions. GM‐Beffs were also enriched in a CD30+ fraction of freshly isolated B cells. GM‐Beffs generated under Th2 conditions facilitated the differentiation from CD14+ monocytes to DC‐SIGN+CD1a+CD14−CD86+ cells, which significantly promoted the proliferation of naive T cells. CD30+ GM‐Beffs were more pronounced in patients with SSc than in HCs. A subpopulation of SSc patients with the diffuse type and concomitant interstitial lung disease exhibited high numbers of GM‐Beffs. Together, these findings suggest that human GM‐Beffs are enriched in a CD30+ B cell subset and play a role in the pathogenesis of SSc. [ABSTRACT FROM AUTHOR]

Summary: Modern era advancements in medical care, with improved treatment of infections, can result in delayed diagnosis of congenital immunodeficiencies. In this study we present a retrospective cohort of 16 patients diagnosed with Chronic Granulomatous Disease (CGD) at adulthood. Some of the patients had a milder clinical phenotype, but others had a classic phenotype with severe infectious and inflammatory complications reflecting a profoundly impaired neutrophil function. It is therefore of great importance to investigate the individual journey of each patient through different misdiagnoses and the threads which led to the correct diagnosis. Currently the recommended definitive treatment for CGD is hematopoietic stem cell transplantation (HSCT). Although survival of our patients to adulthood might argue against the need for early HSCT during infancy, we claim that the opposite is correct, as most of them grew to be severely ill and diagnosed at a stage when HSCT is debatable with potentially an unfavorable outcome. This cohort stresses the need to increase awareness of this severe congenital immunodeficiency among clinicians of different specialties who might be treating undiagnosed adult patients with CGD. [ABSTRACT FROM AUTHOR]

Summary: Cladribine (CdA), an oral prodrug approved for the treatment of relapsing multiple sclerosis, selectively depletes lymphocytes. CdA passes the blood–brain barrier, suggesting a potential effect on central nervous system (CNS) resident cells. We examined if CdA modifies the phenotype and function of naive and activated primary mouse microglia, when applied in the concentrations 0·1–1 μM that putatively overlap human cerebrospinal fluid (CSF) concentrations. Primary microglia cultures without stimulation or in the presence of proinflammatory lipopolysaccharide (LPS) or anti‐inflammatory interleukin (IL)‐4 were treated with different concentrations of CdA for 24 h. Viability was assessed by MTT [3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide] assay. Phagocytotic ability and morphology were examined by flow cytometry and random migration using IncuCyte Zoom and TrackMate. Change in gene expression was examined by quantitative polymerase chain reaction (qPCR) and protein secretion by Meso Scale Discovery. We found that LPS and IL‐4 up‐regulated deoxycytidine kinase (DCK) expression. Only activated microglia were affected by CdA, and this was unrelated to viability. CdA 0·1–1 μM significantly reduced granularity, phagocytotic ability and random migration of activated microglia. CdA 10 μM increased the IL‐4‐induced gene expression of arginase 1 (Arg1) and LPS‐induced expression of IL‐1β, tumor necrosis factor (TNF), inducible nitric oxide synthase (iNOS) and Arg1, but protein secretion remained unaffected. CdA 10 μM potentiated the increased expression of anti‐inflammatory TNF receptor 2 (TNF‐R2) but not TNF‐R1 induced by LPS. This suggests that microglia acquire a less activated phenotype when treated with 0·1–1 μM CdA that putatively overlaps human CSF concentrations. This may be related to the up‐regulated gene expression of DCK upon activation, and suggests a potential alternative mechanism of CdA with direct effect on CNS resident cells. [ABSTRACT FROM AUTHOR]

Summary: Uveitis is a serious intra‐ocular inflammatory disease that can lead to visual impairment even blindness worldwide. Notch signaling can regulate the differentiation of naive CD4+ T cells, influencing the development of uveitis. DNA methylation is closely related to the autoimmune diseases. In this study, we measured the Notch1 DNA methylation level, determined the Notch1 and related DNA methylases mRNA expression and evaluated the ratio of T helper type 17 regulatory T cell (Th17/Treg) in peripheral blood mononuclear cells (PBMCs) from uveitis patients and normal control subjects; we also tested the levels of relevant inflammatory cytokines in serum from the participants. Results indicated that compared with those in normal control individuals, the expression of ten–eleven translocation 2 (TET2) and Notch1 mRNA is elevated in uveitis patients, whereas the methylation level in Notch1 DNA promotor region [−842 ~ −646 base pairs (bp)] is down‐regulated, and is unrelated to anatomical location. Moreover, the Th17/Treg ratio is up‐regulated in PBMCs from uveitis patients, accompanied by the elevated levels of proinflammatory cytokines [e.g. interleukin (IL)‐2, IL‐6, IL‐17 and interferon (IFN)‐γ] in serum from uveitis patients. These findings suggest that the over‐expression of TET2 DNA demethylase may lead to hypomethylation of Notch1, activate the Notch1 signaling, induce naive CD4+ T cells to differentiate theTh17 subset and thus disturb the balance of the Th17/Treg ratio in uveitis patients. Overall, hypomethylation of Notch1 DNA is closely associated with the occurrence of uveitis. Our study preliminarily reveals the underlying mechanism for the occurrence of uveitis related to the hypomethylation of Notch1 DNA, providing a novel therapeutic strategy against uveitis in clinical practice. [ABSTRACT FROM AUTHOR]

Summary: In multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), myeloid cells comprise a major part of the inflammatory infiltrate in the central nervous system (CNS). We previously described that motile sperm domain‐containing protein 2 (MOSPD2) is expressed on human myeloid cells and regulates monocyte migration in vitro. The role of MOSPD2 in EAE pathogenesis was studied by generating MOSPD2 knock‐out (KO) mice and monoclonal antibodies directed against MOSPD2. We found that EAE development in MOSPD2 KO mice was significantly suppressed. While frequency representation of leukocyte subsets in lymphoid tissues was comparable, the ratio of inflammatory monocytes in the blood was markedly reduced in MOSPD2 KO mice. In addition, T cells from MOSPD2 KO mice displayed reduced secretion of proinflammatory cytokines and increased production of interleukin (IL)‐4. Prophylactic and post‐onset treatment using monoclonal antibodies (mAbs) generated against MOSPD2 abrogated development and reduced EAE severity. These results suggest that MOSPD2 is key in regulating migration of inflammatory monocytes, and that anti‐MOSPD2 mAbs constitute a potential therapy for the treatment of CNS inflammatory diseases. [ABSTRACT FROM AUTHOR]

Summary: Major histocompatibility complex class I (MHC‐I)‐dependent inhibitory receptors on natural killer (NK) cells have been found to contribute to NK cell dysfunction in hepatocellular carcinoma (HCC). However, the roles of MHC‐I‐independent inhibitory receptors on NK cells in HCC remain poorly defined. In this study, we analyzed the expression of the MHC‐I‐independent inhibitory receptors sialic acid‐binding immunoglobulin‐like lectin (Siglec)‐7 and Siglec‐9 on NK cells by analyzing the peripheral blood of 35 HCC patients and 63 healthy donors. We observed that HCC patients had lower frequencies and total numbers of NK cells in the peripheral blood. Importantly, both the expression levels of Siglec‐7 on NK cells and the frequencies of Siglec‐7+ NK cells were significantly reduced in HCC patients, which was accompanied by a decrease in activating receptor and an increase in inhibitory receptor expression on NK cells. Moreover, Siglec‐7+ NK cells expressed higher levels of activating receptors and displayed stronger effector functions, compared with Siglec‐7− NK cells. Our findings demonstrate for the first time that reduced Siglec‐7 expression predicts NK cell dysfunction in HCC patients, suggesting that Siglec‐7 may be a potential marker of functional NK cell subset in HCC patients. [ABSTRACT FROM AUTHOR]

Summary: Dendritic cells (DCs) are sentinels of the immune system that bridge innate and adaptive immunity. By capturing antigens in peripheral tissue, processing and presenting them with concurrent expression of co‐stimulatory molecules and cytokine secretion they control and modulate immune reactions. Through pattern recognition receptors, DCs sense molecules that are associated with infection or tissue damage, frequently resulting in the formation of inflammasomes upon intracellular stimulation. The inherited autoinflammatory familial Mediterranean fever (FMF) is associated with deregulated activity of the pyrin inflammasome leading to acute inflammatory episodes. However, differentiation and function of DCs in this disease are as yet unclear. Therefore, we first determined DC subpopulation frequency in peripheral blood of a cohort of FMF patients. Joint evaluation without classification according to specific patient characteristics, such as mutational status, did not disclose significant differences compared to healthy controls. For the further examination of phenotype and function, we used immature and mature monocyte‐derived DCs (imMo‐DCs, mMo‐DCs) that were generated in vitro from FMF patients. Immunophenotypical analysis of imMo‐DCs revealed a significantly elevated expression of CD83, CD86 and human leukocyte antigen D‐related (HLA‐DR) as well as a significant down‐regulation of CD206, CD209 and glycoprotein NMB (GPNMB) in our FMF patient group. Furthermore, FMF imMo‐DCs presented a significantly higher capacity to migrate and to stimulate the proliferation of unmatched allogeneic T cells. Finally, the transition towards a more mature, and therefore activated, phenotype was additionally reinforced by the fact that peripheral blood DC populations in FMF patients exhibited significantly increased expression of the co‐stimulatory molecule CD86. [ABSTRACT FROM AUTHOR]

Summary: Toll‐like receptors (TLRs) are evolutionarily conserved receptors essential for the host defence against pathogens. Both immune and non‐immune cells can express TLRs, although at different levels. Systemic sclerosis (SSc) is a chronic disease in which autoimmunity, dysregulated profibrotic mediator release and activation of fibroblasts lead to dysregulated collagen deposition and fibrosis. There is now increasing knowledge that the innate immune system and, in particular, TLRs take a part in SSc pathogenesis. The list of endogenous ligands that can stimulate TLRs in SSc is growing: these ligands represent specific danger‐associated molecular patterns (DAMPs), involved either in the initiation or the perpetuation of inflammation, and in the release of factors that sustain the fibrotic process or directly stimulate the cells that produce collagen and the endothelial cells. This review reports evidences concerning TLR signalling involvement in SSc. We report the new DAMPs, as well as the TLR‐linked pathways involved in disease, with emphasis on type I interferon signature in SSc, the role of plasmacytoid dendritic cells (pDCs) and platelets. The dissection of the contribution of all these pathways to disease, and their correlation with the disease status, as well as their values as prognostic tools, can help to plan timely intervention and design new drugs for more appropriate therapeutic strategies. [ABSTRACT FROM AUTHOR]

Summary: Capping protein regulator and myosin 1 linker 2 (CARMIL2) deficiency is characterized by impaired T cell activation, which is attributed to defective CD28‐mediated co‐signaling. Herein, we aimed to analyze the effect of exogenous interleukin (IL)‐2 on in‐vitro T cell activation and proliferation in a family with CARMIL2 deficiency. This study included four children (one male and three females; aged 2·5–10 years at presentation). The patients presented with inflammatory bowel disease and recurrent viral infections. Genetic analysis revealed a novel homozygous 25‐base pairs deletion in CARMIL2. Immunoblotting demonstrated the absence of CARMIL2 protein in all four patients and confirmed the diagnosis of CARMIL2 deficiency. T cells were activated in‐vitro with the addition of IL‐2 in different concentrations. CD25 and interferon (IFN)‐γ levels were measured after 48 h and 5 days of activation. CD25 surface expression on activated CD8+ and CD4+ T cells was significantly diminished in all patients compared to healthy controls. Additionally, CD8+ T cells from all patients demonstrated significantly reduced IFN‐γ production. When cells derived from CARMIL2‐deficient patients were treated with IL‐2, CD25 and IFN‐γ production increased in a dose‐dependent manner. T cell proliferation, as measured by Cell Trace Violet, was impaired in one patient and it was also rescued with IL‐2. In conclusion, we found that IL‐2 rescued T cell activation and proliferation in CARMIL2‐deficient patients. Thus, IL‐2 should be further studied as a potential therapeutic modality for these patients. [ABSTRACT FROM AUTHOR]

Summary: Autoimmune diabetes mellitus is a rare but significant side effect of treatment with immune checkpoint inhibitors. Immune checkpoint inhibitor‐induced diabetes mellitus (CPI‐DM) is characterized by acute onset of dramatic hyperglycemia with severe insulin deficiency and occurrence following exposure to programmed cell death‐1/programmed cell death ligand‐1 (PD‐1/PD‐L1) inhibitors rather than cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4) inhibitors. As a growing number of patients undergo immunotherapy, further understanding of the characteristics of CPI‐DM patients is needed for improved prognostic and diagnostic application in order to reduce overall morbidity for this already at‐risk population. Additionally, understanding of the features and mechanisms of CPI‐DM may contribute to understanding mechanisms of spontaneous type I diabetes mellitus (T1DM). Here, we summarize the clinical features of CPI‐DM and interrogate the genetic and cellular mechanisms that may contribute to the disease, as well as the clinical challenges for predicting and treating these patients as increasing cancer immunotherapies reach clinical utility. [ABSTRACT FROM AUTHOR]

Summary: Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non‐small‐cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)‐4 and programmed cell death 1 (PD‐1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self‐tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune‐related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field. [ABSTRACT FROM AUTHOR]

Summary: The immune response is governed by a highly complex set of interactions among cells and mediators. T cells may be rendered dysfunctional by the presence of high levels of antigen in the absence of co‐stimulation while myeloid cells may be programmed towards an immunosuppressive state that promotes cancer growth and metastasis while deterring tumor immunity. In addition, inhibitory programs driven by immune checkpoint regulators dampen anti‐tumor immunity. The ideal cancer immunotherapy treatment will improve both cross‐priming in the tumor microenvironment and relieve suppression by the inhibitory checkpoints. Recently, blockade of programmed cell death 1 (PD‐1) and cytotoxic T lymphocyte antigen 4 (CTLA‐4) has elicited impressive results, but not in all patients, so additional targets are under investigation. V‐set immunoglobulin domain suppressor of T cell activation (VISTA) is a novel immunoregulatory receptor that is broadly expressed on cells of the myeloid and lymphoid lineages, and is frequently implicated as a poor prognostic indicator in multiple cancers. Importantly, antibody targeting of VISTA uniquely engages both innate and adaptive immunity. This, combined with the expression of VISTA and its non‐redundant activities compared to other immune checkpoint regulators, qualifies VISTA to be a promising target for improving cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Summary: Immune tolerance is one of the leading causes of chemotherapy resistance in carcinoma cases. Studies have shown that programmed cell death ligand‐1 (PD‐L1), an inhibitory molecule expressed by cancer cells, plays a significant role in immune tolerance through the induction of T cell dysfunction. The results of our RNA sequencing in previous studies revealed that microRNA‐145 (miR‐145), which is known to be down‐regulated by cisplatin in cisplatin‐resistant ovarian cancer cells, also represses gene PD‐L1 expression. However, the mechanism by which miR‐145 contributes to regulate PD‐L1 expression in cisplatin resistance of ovarian cancer is yet to be fully understood. Here, we show that cisplatin‐mediated miR‐145 down‐regulation increased PD‐L1 expression via targeting the c‐Myc transcription factor, thereby inducing T cell apoptosis in vitro. We also report that expression of miR‐145 is negatively correlated with PD‐L1 expression in human ovarian cancer tissues, malignant grades and the recurrent risks of ovarian cancer after chemotherapy. In summary, our findings suggest that the miR‐145/c‐Myc/PD‐L1 axis contributes to cisplatin resistance in ovarian cancer and support that miR‐145 might act as an adjuvant therapeutic target in chemotherapy of ovarian cancer. [ABSTRACT FROM AUTHOR]

Summary: Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40–80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)‐induced KD vasculitis mouse model. LCWE‐injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE‐injected mice developed cardiac ganglion inflammation, that may affect the impulse‐conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE‐injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)‐1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1−/− mice and in wild‐type mice treated with anakinra. Thus, similar to clinical KD, the LCWE‐induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL‐1 signaling. These data support the acceleration of anti‐IL‐1 therapy trials to benefit KD patients. [ABSTRACT FROM AUTHOR]

Summary: Systemic lupus erythematosus is a chronic inflammatory disease which involves multiple organs. Self‐specific B and T cells play a main role in the pathogenesis of lupus and have been defined as a logical target for selective therapy. The protein annexin A1 (ANX A1) is a modulator of the immune system involving many cell types. An abnormal expression of ANX A1 was found on activated B and T cells during autoimmunity, suggesting its importance as a potential therapeutic target. We hypothesize that it may be possible to down‐regulate the activity of autoreactive T and B cells from lupus patients in a humanized immunodeficient mouse model by treating them with an antibody against ANX A1. When cultured in the presence of anti‐ANX A1, peripheral blood mononuclear cells (PBMC) from lupus patients showed a decreased number of immunoglobulin (Ig)G anti‐dsDNA antibody‐secreting plasma cells, decreased T cell proliferation and expression of activation markers and increased B and T cell apoptosis. We employed a humanized model of SLE by transferring PBMCs from lupus patients to immunodeficient non‐obese diabetic‐severe combined immunodeficient (NOD‐SCID) mice. The humanized animals presented autoantibodies, proteinuria and immunoglobulin deposition in the renal glomeruli. Treatment of these NOD‐SCID mice with an anti‐ANX A1 antibody prevented appearance of anti‐DNA antibodies and proteinuria, while the phosphate‐buffered saline (PBS)‐injected animals had high levels after the transfer. The treatment reduced the levels of autoantibodies to several autoantigens, lupus‐associated cytokines and disease symptoms. [ABSTRACT FROM AUTHOR]

Summary: Different vaccine strains included in the live attenuated influenza vaccine (LAIV) have variable efficacy. The reasons for this are not clear and may include differences in immunogenicity. We report a Phase IV open‐label study on the immunogenicity of a single dose of quadrivalent LAIV (Fluenz™ Tetra) in children during the 2015/16 season, to investigate the antibody responses to different strains. Eligible children were enrolled to receive LAIV; nasal samples were collected before and approximately 4 weeks after immunization. There was a significant increase in nasal immunoglobulin (Ig)A to the H3N2, B/Victoria lineage (B/Brisbane) and B/Yamagata lineage (B/Phuket) components, but not to the H1N1 component. The fold change in nasal IgA response was inversely proportional to the baseline nasal IgA titre for H1N1, H3N2 and B/Brisbane. We investigated possible associations that may explain baseline nasal IgA, including age and prior vaccination status, but found different patterns for different antigens, suggesting that the response is multi‐factorial. Overall, we observed differences in immune responses to different viral strains included in the vaccine; the reasons for this require further investigation. [ABSTRACT FROM AUTHOR]

Summary: Tertiary lymphoid structure (TLS) provides a local and critical microenvironment for both cellular and humoral immunity and supports effective antigen presentation and lymphocyte activation. However, the gene expression profile and prognostic significance of TLS in oral cancer remain largely unrevealed. In this study, we found the presence of both intratumoral and peritumoral TLSs in a series of 65 patients with oral cancer treated by surgical resection, with positive detection rates of 33.8 and 75.4%, respectively. The presence of intratumoral TLSs, but not peritumoral TLSs, was significantly associated with decreased P53 and Ki67 scores (P = 0·027 and 0·047, respectively). The survival analyses revealed that oral cancer patients with higher grades of TLSs was associated with improved disease‐free survival (DFS) and overall survival (OS) (P = 0·037 and 0·031, respectively). Gene expression profiling analysis of the cytokines and chemokines responsible for lymph‐node neogenesis identified a three‐up‐regulated‐gene set, i.e. IL7, LTB and CXCL13, which was shown to be correlated with human oral cancer‐associated TLSs. This study provides a framework for better understanding of oral cancer‐associated TLSs and for delineating future innovative prognostic biomarkers and immune therapeutic strategies for oral cancer. [ABSTRACT FROM AUTHOR]

Summary: There have been many studies on the mechanisms of internalization of DNA–anti‐DNA immune complexes by cells, including the one used for rheumatoid factor‐expressing mouse B cells. In parallel, studies on the role of intracellular DNA sensors in the pathogenesis of systemic lupus erythematosus (SLE) have been conducted, including the one using a mouse model lacking one of the sensors. These and other data have established a framework for understanding the pathogenic role of anti‐DNA antibodies, but studies on normal cells are limited. Here, we used the monoclonal anti‐dsDNA antibody 2C10, 2‐kbp dsDNA and healthy human peripheral blood mononuclear cells (PBMCs) to test whether and how 2C10 and/or DNA cause pathology in normal cells. We found that on culture with PBMCs, 2C10 preferentially entered monocytes and that DNA enhanced this internalization. In contrast, DNA alone was not significantly internalized by monocytes, but 2C10 facilitated its internalization. This was suppressed by cytochalasin D, but not by methyl‐β‐cyclodextrin, chloroquine or an Fc blocker, suggesting the involvement of macropinocytosis in this process. Internalization of 2C10 and DNA together resulted in production of interferon (IFN)‐α, IFN‐γ, tumor necrosis factor (TNF)‐α, monocyte chemoattractant protein‐1 (MCP‐1), interleukin (IL)‐1β, IL‐6, IL‐10 and IL‐33 by PBMCs. Cytokine production was suppressed by chloroquine and shikonin, but not by RU.521, suggesting dependence on activation of the Toll‐like receptor (TLR)‐9 and absent in melanoma 2 (AIM‐2) pathways. These results established a simple model to demonstrate that anti‐DNA antibodies can cause dysregulation of cytokine network mimicking systemic lupus erythematosus in culture of normal PBMCs, and emphasize again the importance of maintaining anti‐DNA antibodies at low levels by treatment. [ABSTRACT FROM AUTHOR]

Summary: Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)‐related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti‐phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still‐unknown pathways. [ABSTRACT FROM AUTHOR]

Summary: The human body is populated by a large number of microorganisms and exist in symbiosis with these immensely diverse communities, which are suggested to influence health and disease. The microbiota plays an essential role in the maturation and function of the immune system. The prevalence of atopic diseases has increased drastically over the past decades, and the co‐occurrence of multiple allergic diseases and allergic sensitization starting in early life has gained a great deal of attention. Immune responses in different organs affected by allergic diseases (e.g. skin, intestine and lung) may be linked to microbial changes in peripheral tissues. In the current review, we provide an overview of the current understanding of microbial interactions in allergic diseases and their potential role in the atopic march. [ABSTRACT FROM AUTHOR]

Summary: Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN‐stimulating pathways, but also from decreased activation of type I IFN‐inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR‐induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR‐mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR‐induced interleukin (IL)‐1β production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR‐mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL‐1β. This dysregulation may contribute to the development of nephritis in SLE patients. [ABSTRACT FROM AUTHOR]

Summary: Psoriasis is a common, inflammatory immune‐mediated skin disease mainly presenting with plaques whose pathogenesis is based on the central role of the interleukin (IL)‐23/IL‐17 axis. However, the mechanisms acting in papular lesions of early‐phase psoriasis are not fully understood. The aim of this study was to assess the involvement of autoinflammation, a state of sterile inflammation mainly driven by IL‐1 over‐production that has been recently hypothesized to act in the early phase of disease. Lesional skin of 10 patients with recent onset, untreated psoriasis has been investigated for expression of IL‐1β, IL‐17, IL‐23 and other cytokines involved in the disease in comparison with normal skin of 10 healthy controls using a protein array method. Immunohistochemical phenotyping of inflammatory infiltrate and co‐localization experiments with immunofluorescence confocal microscopy were conducted. IL‐1β was significantly more expressed in psoriasis than in normal skin (P < 0·0001). The chemokine IL‐8 was also over‐expressed in psoriasis (P = 0·03) while IL‐12, IL‐17, IL‐23, tumour necrosis factor‐α and interferon‐γ were only slightly more expressed in psoriasis than in normal skin, without reaching statistical significance. The inflammatory infiltrate consisted mainly of neutrophils with a relevant number of macrophages and dendritic cells and only scattered, predominantly T helper 1 lymphocytes. IL‐1β co‐localized mainly with CD66b, a neutrophil marker, suggesting that neutrophils were the major source of this cytokine. IL‐1β over‐expression in combination with low expression of cytokines that are predominant in late‐phase plaque psoriasis may support the role of autoinflammation in early‐phase disease, possibly paving the way to randomized trials with IL‐1 antagonists. [ABSTRACT FROM AUTHOR]

Summary: Vaccination against meningococcal serogroup B is recommended for patients with a complement deficiency; however, although immunogenicity in this patient group has been shown, efficacy has not yet been established. In this study, we collected serum from children with a complement deficiency in the alternative pathway or in late terminal pathway before and after vaccination with multi‐component meningococcal serogroup B (MenB)‐4C. MenB‐4C is a multi‐component, protein‐based vaccine against MenB consisting of factor H‐binding protein, Neisserial heparin‐binding protein, Neisserial adhesion A and outer membrane vesicles containing Porin A. We assessed the vaccine immunogenicity and vaccine‐mediated protection by a whole cell enzyme‐linked immunosorbent assay with Neisseria meningitidis serogroup B strains H44/76, 5/99 and NZ98/254, which shows that vaccination induced antibody titers against meningococcus. We show that the classical serum bactericidal activity assay with exogenous serum indicates the presence of vaccine‐induced antibodies and capacity to activate complement‐mediated pathogen lysis. However, in children with a late terminal pathway deficiency, no complement‐mediated pathogen lysis was observed when autologous serum was applied in the serum bactericidal activity assay, demonstrating a lack of serum bactericidal activity in children with complement deficiencies. However, MenB‐4C vaccination still induced effective complement‐dependent opsonophagocytic killing against N. meningitidis serogroup B in reconstituted whole blood with autologous serum from children with an alternative pathway or late terminal pathway deficiency. These findings support the recommendation to vaccinate all complement‐deficient children against MenB. [ABSTRACT FROM AUTHOR]

Summary: Pneumonia is a common and severe infectious lung disease. Host genetics, together with underlying medical and lifestyle conditions, determine pneumonia susceptibility. We performed a secondary analysis of the results of two genome‐wide studies for pneumonia in 23andMe participants (40 600 cases/90 039 controls) (Tian et al., 2017) and UK Biobank (BB) participants (12 614 cases/324 585 controls) (via the Global Biobank Engine) and used the GTEx database to correlate the results with expression quantitative trait loci (eQTLs) data in lung and whole blood. In the 23andMe pneumonia single nucleotide polymorphism (SNP) set, 177 genotyped SNPs in the human leukocyte antigen (HLA) region satisfied the genome‐wide significance level, P ≤ 5·0E‐08. Several target genes (e.g. C4A, VARS2, SFTA2, HLA‐C, HLA‐DQA2) were unidirectionally regulated by many HLA eSNPs associated with a higher risk of pneumonia. In lung, C4A transcript was up‐regulated by 291 pneumonia risk alleles spanning the half the HLA region. Among SNPs correlated with the expression levels of SFTA2 and VARS2, approximately 75% overlapped: all risk alleles were associated with VARS2 up‐regulation and SFTA2 down‐regulation. To find shared gene loci between pneumonia and pulmonary function (PF), we used data from the Global Biobank Engine and literature on genome‐wide association studies (GWAS) of PF in general populations. Numerous gene loci overlapped between pneumonia and PF: 28·8% in the BB data set and 49·2% in the 23andMe data set. Enrichment analysis within the database of Genotypes and Phenotypes (dbGaP) and National Human Genome Research Institute‐European Bioinformatics Institute (NHGRI‐EBI) Catalog of pneumonia and pneumonia/PF gene sets identified significant overlap between these gene sets and genes related to inflammatory, developmental, neuropsychiatric and cardiovascular and obesity‐related traits. [ABSTRACT FROM AUTHOR]

Summary: Many options now exist for constructing oral vaccines which, in experimental systems, have shown themselves to be able to generate highly effective immunity against infectious diseases. Their suitability for implementation in clinical practice, however, for prevention of outbreaks, particularly in low‐ and middle‐income countries (LMIC), is not always guaranteed, because of factors such as cost, logistics and cultural and environmental conditions. This brief overview provides a summary of the various approaches which can be adopted, and evaluates them from a pharmaceutical point, taking into account potential regulatory issues, expense, manufacturing complexity, etc., all of which can determine whether a vaccine approach will be successful in the late stages of development. Attention is also drawn to problems arising from inadequate diet, which impacts upon success in stimulating effective immunity, and identifies the use of lipid‐based carriers as a way to counteract the problem of nutritional deficiencies in vaccination campaigns. [ABSTRACT FROM AUTHOR]

Summary: Global incidence of dengue has drastically increased in the last few years. Despite the global morbidity and mortality associated with dengue infection, mechanisms of immune control and viral pathogenesis are poorly explored. Pancytopenias, along with increased oxidative stress, are salient clinical findings in severe dengue patients. Previously, we demonstrated significant differences of circulating immune complexes (CICs) among severe and non‐severe dengue patients. Accordingly, here we sought to determine the contributory role of affinity‐purified antibody‐bound CICs in dengue severity. To characterize intracellular oxidative stress induced by antibody‐bound CICs, 5‐(and‐6)‐chloromethyl‐2′‐7′‐dichlorodihydrofluorescein diacetate (DCFDA) was measured by flow cytometry. At the same time, CICs sensitized healthy red blood cells (RBC) and patients' RBC morphology was determined by scanning electron microscopy and flow cytometry analysis. Erythrophagocytosis and ferritin levels were further determined in severe and non‐severe dengue patients. Our results showed that the severe patients had high titres of immunoglobulin (Ig)M‐bound CICs (P < 0·0001) in their sera, increased intracellular oxidative stress (P < 0·0001), high ferritin levels (P < 0·0001), altered morphology of RBC and finally enhanced erythrophagocytosis. This study shows for the first time that RBC morphology is altered in severe dengue patients. Taken together, this study suggests that the enhanced IgM‐bound CICs could contribute to the increased oxidative stress and act directly on RBC destruction of severe dengue patients, and is an important pathophysiological determinant. Hence, IgM‐bound CICs can serve as an important laboratory parameter to monitor dengue infection progression. [ABSTRACT FROM AUTHOR]

Summary: Various reports of disease‐related lung pathologies in common variable immunodeficiency disorder (CVID) patients have been published, with differing histological and high‐resolution computed tomography (HRCT) findings. Data were extracted from the validated Oxford Primary Immune Deficiencies  Database (PID) database (1986–2016) on adult, sporadic CVID patients with suspected interstitial lung disease (ILD). Histology of lung biopsies was studied in relation to length of follow‐up, clinical outcomes, HRCT findings and chest symptoms, to look for evidence for different pathological processes. Twenty‐nine CVID patients with lung histology and/or radiological evidence of ILD were followed. After exclusions, lung biopsies from 16 patients were reanalysed for ILD. There were no well‐formed granulomata, even though 10 patients had systemic, biopsy‐proven granulomata in other organs. Lymphocytic infiltration without recognizable histological pattern was the most common finding, usually with another feature. On immunochemistry (n = 5), lymphocytic infiltration was due to T cells (CD4 or CD8). Only one patient showed B cell follicles with germinal centres. Interstitial inflammation was common; only four of 11 such biopsies also showed interstitial fibrosis. Outcomes were variable and not related to histology, suggesting possible different pathologies. The frequent nodules on HRCT were not correlated with histology, as there were no well‐formed granulomata. Five patients were asymptomatic, so it is essential for all patients to undergo HRCT, and to biopsy if abnormal HRCT findings are seen. Internationally standardized pathology and immunochemical data are needed for longitudinal studies to determine the precise pathologies and prognoses in this severe complication of CVIDs, so that appropriate therapies may be found. [ABSTRACT FROM AUTHOR]

Summary: Primary Sjögren's syndrome (pSS) is a chronic inflammatory, autoimmune and systemic disorder commonly associated with dry eyes and a dry mouth. Recently, the hypothetical link between epithelial–mesenchymal transition (EMT)‐dependent salivary gland (SG) fibrosis and chronic inflammatory conditions has been suggested. In this study, we present data demonstrating a negative correlation of the epithelial marker E‐cadherin expression and a positive correlation of mesenchymal vimentin and collagen type I expression with increasing degrees of tissue inflammation in pSS SG specimens. In addition, as it is not clear whether dysregulated cytokines in pSS, interleukin (IL)‐17 and IL‐22 may also contribute to the EMT‐dependent fibrosis process, the effect of IL‐17 and IL‐22 treatment on EMT‐dependent SG fibrosis was evaluated in primary human salivary gland epithelial cells (SGEC) isolated from healthy subjects. Here we present data demonstrating that IL‐17 and IL‐22 can induce SGEC to undergo a morphological and phenotypical transition to a mesenchymal phenotype. In support of this, vimentin and collagen type I were up‐regulated while a decreased expression of E‐cadherin occurs after interleukin treatment, and co‐operation between IL‐17 and Il‐22 was required to induce the EMT. [ABSTRACT FROM AUTHOR]

Summary: Cytokine storm syndromes are a clinically heterogeneous group of conditions resulting from a maladaptive host response to an inflammatory trigger. These syndromes lead to rapid progression of immune‐mediated damage to healthy tissues resulting in life‐threatening multi‐system organ failure. Prompt recognition of disease and medical intervention to limit damage to healthy tissues is essential to prevent cytokine storm morbidity and mortality. However, the diagnosis of cytokine storm syndromes is challenging, given the clinical heterogeneity in disease presentations. Therefore, expeditious and readily available tests to diagnose disease and differentiate between the various types of cytokine storm syndromes are of clinical utility. The recently published work of Shimizu and colleagues brings us closer to making this a reality. [ABSTRACT FROM AUTHOR]

The most profound of primary immunodeficiencies, severe combined immunodeficiency (SCID), presents in infancy. Infants appear healthy at birth, but they are unable to clear pathogens, particularly viruses, and present with recurrent infection, progressive pnueumonitis and failure to thrive due to enteric viral infection, often associated with persistent vaccine‐strain rotavirus. The administration of live vaccines is contraindicated in these infants, but most who are eligible receive bacillus Calmette–Guérin vaccination and the live rotavirus vaccine before the diagnosis of SCID is made, making treatment more complicated. Newborn infants with SCID can be screened using the newborn bloodspot to measure T lymphocyte receptor excision circles (TRECs), episomal DNA formed during T lymphocyte receptor development and very low or absent in SCID. Introduction of this programme in the United Kingdom will require the neonatal BCG vaccination programme to be altered, with vaccination at 28 days, once the SCID screening result is known. Although SCID newborn screening has been successfully introduced in other countries, the change in neonatal BCG vaccination requires the introduction of newborn screening to be carefully introduced. An evaluation of impact of screening on SCID diagnosis, treatment and outcomes, together with an evaluation of the technology used to detect TRECs, and the impact of screening and changes to the BCG programme on families will commence in six screening regions in England in September 2021 for 2 years – should the evaluation prove positive, it is likely that screening for this fatal disease will be introduced across the United Kingdom. [ABSTRACT FROM AUTHOR]

Summary: Type 1 diabetes (T1D) results from autoimmune destruction of insulin‐producing beta cells in pancreatic islets. Various immune cell populations are involved in disease development and natural course. However, to our knowledge, so far there are no comprehensive comparative investigations of all main immune cell populations and their most important subsets at the onset of disease. Therefore, in the current study, we analyzed 51 peripheral blood immune cell populations in 22 young T1D patients and in 25 age‐matched controls using a comprehensive polychromatic flow cytometry panel developed for whole blood by the COST Action no. BM0907 ENTIRE (European Network for Translational Immunology Research and Education: From Immunomonitoring to Personalized Immunotherapy) consortium. We found that in T1D patients, frequencies and absolute counts of natural killer (NK) cells, dendritic cells (DC) and T cells, as well as their respective subsets, were significantly altered compared to controls. Further, we observed that changes in several cell populations (e.g. CD14+CD16+ non‐classical monocytes, plasmablasts) were dependent on the age of the patient. In addition to age‐related changes, we also found that alterations in immune cell patterns were associated with parameters such as the presence of ketoacidosis and C‐peptide serum levels. Our study provides a foundation for future studies investigating different cell lineages and their role in T1D and illustrates the value of polychromatic flow cytometry for evaluating all main peripheral immune cells and their subsets in whole blood samples. [ABSTRACT FROM AUTHOR]

Summary: Hepatic stellate cells (HSCs) have a central role in liver inflammation and fibrosis by producing inflammatory and fibrotic mediators. Their activation is regulated through direct cell–cell interactions, but also through systemic and local effects of soluble factors such as cytokines. The effects of the proinflammatory cytokines interleukin (IL)‐17 and tumor necrosis factor (TNF)‐α and cell interactions with hepatocytes on HSC activation were assessed. Human HSC and HepaRG cells were exposed to IL‐17 and/or TNF‐α. IL‐17 and TNF‐α contribution from immune cells was determined in a co‐culture model with phytohemagglutinin (PHA)‐activated peripheral blood mononuclear cells (PBMC), HSC and/or hepatocytes. IL‐17 enhanced TNF‐α effects on the induction of IL‐6, IL‐1β, and the chemokine IL‐8, chemokine (C‐C motif) ligand 20 (CCL20) and monocyte chemoattractant protein‐1 (MCP‐1) expression/secretion in isolated HSC cultures. HSC–hepatocyte interactions did not enhance IL‐6, IL‐8 and CCL20 production compared to hepatocyte alone. However, HSC–hepatocyte interactions increased C‐reactive protein expression. IL‐17 and/or TNF‐α had no direct profibrotic effects on collagen 1 α1, tissue inhibitor of matrix metalloproteinase (TIMP) and matrix metalloproteinase (MMP) 2 gene expression, whereas mRNA levels of MMP3, an enzyme involved in matrix destruction, were up‐regulated in HSCs. The use of specific inhibitors of IL‐17 and TNF‐α indicated their contribution to the strong increase of IL‐6 and IL‐8 production induced by PBMC, HSC and/or hepatocyte interactions. As chronic liver inflammation leads to liver fibrosis, IL‐17 and/or TNF‐α neutralization can be of interest to control liver inflammation and therefore its effects on fibrosis. [ABSTRACT FROM AUTHOR]

Summary: Despite improvements in treatment, coronary artery disease is still responsible for one‐third of all deaths globally, due predominantly to myocardial infarction (MI) and stroke. There is an important potential in developing new strategies for treatment of patients with these conditions. Inflammation, and in particular the actions of the complement system, has emerged as part of the pathogenesis in reperfusion injury in patients with MI. To further qualify this, we examined the association between the plasma levels of lectin pathway proteins and myocardial end‐points, left ventricular ejection fraction (LVEF) and infarct size in a cohort of patients with ST‐elevation myocardial infarction (STEMI). A blood sample was drawn the day after percutaneous coronary intervention from 73 patients with STEMI. The primary end‐points, LVEF and infarct size, were measured with magnetic resonance imaging 6–9 days after the infarct. Complement pattern‐recognition molecules of the lectin pathway (mannan‐binding lectin, H‐ficolin, L‐ficolin and M‐ficolin) were analysed along with soluble membrane attack complex (sMAC) and C‐reactive protein (CRP) in plasma with immunofluorometric assays <50%. CRP correlated negatively with LVEF, regression coefficient = –0·17 (P = 0·01). None of the lectin pathway proteins correlated to LVEF or infarct size, nor did soluble membrane attack complex (sMAC). There were no differences in plasma levels of these complement proteins when comparing patients with ejection fraction <50% to patients with ejection fraction <50%. Pattern‐recognition molecules of the lectin pathway and sMAC do not predict short‐term cardiac outcomes after MI. [ABSTRACT FROM AUTHOR]

Summary: Increased peripheral levels of cytokines and central microglial activation have been reported in patients with psychiatric disorders. The degree of both innate and adaptive immune activation is also associated with worse clinical outcomes and poor treatment response in these patients. Understanding the possible causes and mechanisms leading to this immune activation is therefore an important and necessary step for the development of novel and more effective treatment strategies for these patients. In this work, we review the evidence of literature pointing to childhood trauma as one of the main causes behind the increased immune activation in patients with psychiatric disorders. We then discuss the potential mechanisms linking the experience of early life adversity (ELA) to innate immune activation. Specifically, we focus on the innervation of the bone marrow from sympathetic nervous system (SNS) as a new and emerging mechanism that has the potential to bridge the observed increases in both central and peripheral inflammatory markers in patients exposed to ELA. Experimental studies in laboratory rodents suggest that SNS activation following early life stress exposure causes a shift in the profile of innate immune cells, with an increase in proinflammatory monocytes. In turn, these cells traffic to the brain and influence neural circuitry, which manifests as increased anxiety and other relevant behavioural phenotypes. To date, however, very few studies have been conducted to explore this candidate mechanism in humans. Future research is also needed to clarify whether these pathways could be partially reversible to improve prevention and treatment strategies in the future. [ABSTRACT FROM AUTHOR]

Summary: Anti‐phospholipid syndrome (APS) is characterized by recurrent pathological pregnancy, arterial or venous thrombosis in the presence of anti‐phospholipid antibody (aPL). Complement activation is recognized as an intermediate link leading to placental thrombosis and placental inflammation in APS model mice. Decay accelerating factor (DAF, CD55), MAC‐inhibitory protein (MAC‐IP, CD59) and membrane co‐factor protein (MCP, CD46) are important complement inhibitory proteins (CIPs) highly expressed in normal placenta to curb excessive complement activation and its mediated injuries. Anti‐β2 glycoprotein I (anti‐β2GPI) antibody is an important aPL. We found that placental DAF and CD46 decreased in β2GPI passively immunized APS model mice, accompanied by C3 deposition, neutrophil infiltration and increased proinflammatory cytokine levels detected in its placenta. Progesterone supplement can up‐regulate DAF but not CD46 expression, curb C3 activation and decrease proinflammatory cytokines levels to reduce fetal loss frequency. Progesterone receptor antagonist (mifepristone) or knock‐down DAF with specific siRNA, above the protective effects of progesterone, were significantly weakened. Another sex hormone, oestrogen, has no significant effect on placental DAF and C3 contents and fetal loss frequency in the APS mice model. This may be an important mechanism by which progesterone induces maternal–fetal immune tolerance. At the same time, it may provide evidence for the use of progesterone in APS abortion patients. [ABSTRACT FROM AUTHOR]

Summary: Type 1 diabetes mellitus is an autoimmune metabolic disorder characterized by chronic hyperglycemia, the presence of autoreactive T and B cells and autoantibodies against self‐antigens. A membrane‐bound enzyme on the pancreatic beta‐cells, glutamic acid decarboxylase 65 (GAD65), is one of the main autoantigens in type 1 diabetes. Autoantibodies against GAD65 are potentially involved in beta‐cell destruction and decline of pancreatic functions. The human complement receptor type 1 (CD35) on B and T lymphocytes has a suppressive activity on these cells. We hypothesized that it may be possible to eliminate GAD65‐specific B cells from type 1 diabetes patients by using chimeric molecules, containing an anti‐CD35 antibody, coupled to peptides resembling GAD65 B/T epitopes. These molecules are expected to selectively bind the anti‐GAD65 specific B cells by the co‐cross‐linking of the immunoglobulin receptor and CD35 and to deliver a suppressive signal. Two synthetic peptides derived from GAD65 protein (GAD65 epitopes) and anti‐CD35 monoclonal antibody were used for the construction of two chimeras. The immunomodulatory activity of the engineered antibodies was tested in vitro using peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients. A reduction in the number of anti‐GAD65 IgG antibody‐secreting plasma cells and increased percentage of apoptotic B lymphocytes was observed after treatment of these PBMCs with the engineered antibodies. The constructed chimeric molecules are able to selectively modulate the activity of GAD65‐specific B lymphocytes and the production of anti‐GAD65 IgG autoantibodies by co‐cross‐linking of the inhibitory CD35 and the B cell antigen receptor (BCR). This treatment presents a possible way to alter the autoimmune nature of these cells. [ABSTRACT FROM AUTHOR]