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Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper, we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH)(3)) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on pre-existing immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is presensitized to the antigen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilized in AIT redirect the Th2 immune response towards Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current three-to-five-year regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need.

Melanocytes are static, minimally proliferative cells. This leaves them vulnerable in vitiligo. Yet upon malignant transformation, they form vicious tumors. This profound switch in physiology is accompanied by genetic change and is driven by environmental factors. If UV exposure in younger years supports malignant transformation and melanoma formation, it can likewise impart mutations on melanocytes that reduce their viability, to initiate vitiligo. A wide variety of microbes can influence these diametrically opposed outcomes before either disease takes hold. These microbes are vehicles of change that we are only beginning to study. Once a genetic modification occurs, there is a wide variety of immune cells ready to respond. Though it does not act alone, the T cell is among the most decisive responders in this process. The same biochemical process that offered the skin protection by producing melanin can become an Achilles heel for the cell when the T cells target melanosomal enzymes or, on occasion, neoantigens. T cells are precise, determined, and consequential when they strike. Here, we probe the relationship between the microbiome and its metabolites, epithelial integrity, and the activation of T cells that target benign and malignant melanocytes in vitiligo and melanoma.

Th2 immunity and allergic immune surveillance play critical roles in host responses to pathogens, parasites and allergens. Numerous studies have reported significant links between Th2 responses and cancer, including insights into the functions of IgE antibodies and associated effector cells in both antitumour immune surveillance and therapy. The interdisciplinary field of AllergoOncology was given Task Force status by the European Academy of Allergy and Clinical Immunology in 2014. Affiliated expert groups focus on the interface between allergic responses and cancer, applied to immune surveillance, immunomodulation and the functions of IgE-mediated immune responses against cancer, to derive novel insights into more effective treatments. Coincident with rapid expansion in clinical application of cancer immunotherapies, here we review the current state-of-the-art and future translational opportunities, as well as challenges in this relatively new field. Recent developments include improved understanding of Th2 antibodies, intratumoral innate allergy effector cells and mediators, IgE-mediated tumour antigen cross-presentation by dendritic cells, as well as immunotherapeutic strategies such as vaccines and recombinant antibodies, and finally, the management of allergy in daily clinical oncology. Shedding light on the crosstalk between allergic response and cancer is paving the way for new avenues of treatment.

Summary Chronic Immune Thrombocytopenia (cITP)isan acquired immune-mediated disease associated with a T-helper cell type 1 (Th1) immune polarization, whose genetic risk factors, however, are largely unknown. We investigated polymorphisms in promoter regions of genes that code molecules involved in proinflammatory immune response [IL1B )31T/C, IL1RN variable number tandem repeats (VNTR), IL2 )330T/G, and TNF )307G/A] as well as in genes that code Toll like receptors (TLR) (TLR2 Arg753Gln, TLR4 Asp299Gly and TLR5 Arg 392stop ) in 122 patients with cITP and 541 blood donors. The frequencies of the IL1RN polymorphic allele 2 (P =0 AE001) and of the IL2 )330 polymorphic allele G (P =0 AE004) were significantly higher in cITP patients than in blood donors. In logistic analysis adjusting for age and gender, the polymorphisms remained independently associated with cITP. Enhanced serum concentrations of interleukin (IL)-1a and IL-1b were observed in cITP (P

This paper was prepared by the Research, Science, and Therapy Committee of the American Academy of Periodontology to provide the dental profession an overview of current and potential methods to modulate the host response in the treatment of periodontal diseases. Specifically, it discusses components of periodontal disease pathogenesis (i.e., immune and inflammatory responses, excessive production of matrix metalloproteinases and arachidonic acid metabolites, and regulation of bone metabolism) and their modulation. J Periodontol 2002;73:460-470.

Summary Haemato‐oncological patients are at risk in case of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection. Currently, vaccination is the best‐evaluated preventive strategy. In the present study, we aimed to assess serological response, predictive markers, and safety of BNT162b2 in haemato‐oncological patients. A total of 259 haemato‐oncological patients were vaccinated with two 30 µg doses of BNT162b2 administered 21 days apart. Serological response was assessed by ELECSYS® Anti‐SARS‐CoV‐2‐S immunoassay before vaccination, and at 3 and 7 weeks after the first dose (T1, T2). Safety assessment was performed. At T2 spike protein receptor binding domain (S/RBD) antibodies were detected in 71·4% of haematological and in 94·5% of oncological patients (P

Herpes simplex virus (HSV) 1 and 2 are viruses that infect individuals worldwide and for which there is no cure or vaccine available. The protective response against herpes is mostly mediated by CD8 T lymphocytes that respond to the immunodominant SSIEFARL epitope. However, there are some obstacles concerning the use of free SSIEFARL for vaccine or immunotherapy. The aim of this study was to evaluate the feasibility of nanoencapsulation of SSIEFARL and its immunostimulatory properties. Nano/SSIEFARL was produced by interfacial polymerization in methylmetacrylate, and the physico‐chemical properties, morphology and immunobiological parameters were evaluated. To evaluate the ex vivo capacity of Nano/SSIEFARL, we used splenocytes from HSV‐1‐infected mice to enhance the frequency of SSIEFARL‐specific CD8 T lymphocytes. The results indicate that Nano/SSIEFARL has a spherical shape, an average diameter of 352 ± 22 nm, the PDI was 0.361 ± 0.009 and is negatively charged (−26.30 ± 35). The stability at 4°C was 28 days. Also, Nano/SSIEFARL is not toxic for cells at low concentrations in vitro and it is taken up by JAWS II dendritic cells. No histopathological changes were observed in kidneys, liver and lymph nodes of animals treated with Nano/SSIEFARL. Nan/SSIEFARL increased the production of IL‐1β, TNF‐α and IL‐12 by the dendritic cells. Finally, Nano/SSIEFARL expanded the frequency of SSIEFARL‐specific CD8+T lymphocytes at the same rate as free SSIEFARL. In conclusion all data together indicate that SSIEFARL is suitable for nanoencapsulation, and the system produced presents some immunoadjuvant properties that can be used to improve the immune response against herpes.

Summary Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), including patients with chronic myeloid leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS‐CoV‐2 BNT162b2 (Pfizer‐BioNTech) vaccine have been raised. In the present study, we evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. Seroconversion and cellular immune response before and after vaccination were assessed. By day 21 after vaccination, anti‐Spike immunoglobulin G was detected in 14/16 (87·5%) of the patients with CML and all developed a neutralising antibody response [serum dilution that inhibits 50% infection (ID50) >50], including medium (ID50 of 200–500) or high (ID50 of 501–2000) neutralising antibodies titres in nine of the 16 (56·25%) patients. T‐cell response was seen in 14/15 (93·3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response nine of 15, polyfunctional CD8+ T‐cell response nine of 15). These data demonstrate the immunogenicity of a single dose of SARS‐CoV‐2 BNT162b2 vaccine in most patients with CML, with both neutralising antibodies and polyfunctional T‐cell responses seen in contrast to patients with solid tumour or lymphoid haematological malignancies.

The ability of two surgeons to assess accurately nutritional depletion and immune state in surgical patients by clinical examination has been studied. The clinical status of all the surgical patients (198) in a large teaching hospital was assessed by two surgeons without knowledge of the results of objective testing. One of the surgeons had had a formal training in nutritional assessment techniques, the other had not. Each was asked to make two clinical assessments, one of nutritional depletion the other of immune competence. On the same day each patient also had an objective assessment of nutritional depletion (relative weight index) and immune competence (delayed hypersensitivity skin testing to four antigens). While the two surgeons identified more than 80% of the patients objectively assessed as being not depleted, they could pick only 40% of the patients who were depleted. Similarly, they identified 60% of the patients who reacted normally to the skin tests but they picked only 31% of the patients with impaired reactivity. The surgeon with nutritional training performed better than the untrained surgeon. This study suggests that malnourished patients cannot be adequately identified by clinical examination

The immune system is subject to an array of identified autoregulatory processes, but immunoregulation may also have a further basis in a network of immune-neuroendocrine interactions. Two antigens each produced an increase of more than 100% in electrical activity of individual neurones in the ventromedial but not in the anterior nucleus of the rat hypothalamus. Animals that failed to respond to antigen manifested no increase in the firing rate. These findings constitute the first evidence for a flow of information from the activated immune system to the hypothalamus, suggesting that the brain is involved in the immune response.

Summary Panobinostat is a pan‐deacetylase inhibitor that modulates the expression of oncogenic and immune‐mediating genes involved in tumour cell growth and survival. We evaluated panobinostat‐induced post‐transplant responses and identified correlative biomarkers in patients with multiple myeloma who had failed to achieve a complete response after autologous transplantation. Patients received panobinostat 45 mg administered three‐times weekly (TIW) on alternate weeks of 28‐day cycles commencing 8–12 weeks post‐transplant. Twelve of 25 patients (48%) improved their depth of response after a median (range) of 4·3 (1·9–9·7) months of panobinostat. In responders, T‐lymphocyte histone acetylation increased after both three cycles (P

Cancer stemness and immune evasion are closely associated, and play critical roles in tumor development and resistance to immunotherapy. However, little is known about the underlying molecular mechanisms that coordinate this association. Here, it is reported that elevated circular RNA FAT1 (circFAT1) in squamous cell carcinoma (SCC) unifies and regulates the positive association between cancer stemness and immune evasion by promoting STAT3 activation. circFAT1 knockdown (KD) reduces tumorsphere formation of SCC cells in vitro and tumor growth in vivo. Bioinformatic analysis reveals that circFAT1 KD impairs the cancer stemness signature and activates tumor cell‐intrinsic immunity. Mechanistically, circFAT1 binding to STAT3 in the cytoplasm prevents STAT3 dephosphorylation by SHP1 and promotes STAT3 activation, resulting in inhibition of STAT1‐mediated transcription. Moreover, circFAT1 KD significantly enhances PD1 blockade immunotherapy by promoting CD8+ cell infiltration into tumor microenvironment. Taken together, the results demonstrate that circFAT1 is an important regulator of cancer stemness and antitumor immunity., Cancer stemness and immune evasion are tightly associated with tumor development and immunotherapy resistance. This study shows that circFAT1 controls cancer stemness and immune evasion by regulating STAT3 activation. CircFAT1 binds to STAT3 and prevents STAT3 dephosphorylation by SHP1, resulting in the promotion of STAT3 activation. Knockdown of circFAT1 impairs cancer stemness and enhances PD1 blockade immunotherapy.

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The models that can accurately resemble human-relevant responses to viral infection are lacking. Here, we create a biomimetic human disease model on chip that allows to recapitulate lung injury and immune responses induced by SARS-CoV-2 in vitro at organ level. This human alveolar chip reproduced the key features of alveolar-capillary barrier by co-culture of human alveolar epithelium, microvascular endothelium and circulating immune cells under fluidic flow in normal and disease. Upon SARS-CoV-2 infection, the epithelium exhibited higher susceptibility to virus than endothelium. Transcriptional analyses showed activated innate immune responses in epithelium and cytokine-dependent pathways in endothelium at 3 days post-infection, revealing the distinctive responses in different cell types. Notably, viral infection caused the immune cell recruitment, endothelium detachment, and increased inflammatory cytokines release, suggesting the crucial role of immune cells involving in alveolar barrier injury and exacerbated inflammation. Treatment with remdesivir could inhibit viral replication and alleviate barrier disruption on chip. This organ chip model can closely mirror human-relevant responses to SARS-CoV-2 infection, which is difficult to be achieved by in vitro models, providing a unique platform for COVID-19 research and drug development. This article is protected by copyright. All rights reserved.

The epidemiological burden of COVID-19 is a healthcare challenge throughout the world, not only in terms of testing the limits of medical capacities, but also as an enigma considering preventive strategies and methods. The upper respiratory tract mucosa is the first line of defense, as a physical barrier, as well as through multiple innate and adaptive immune mechanisms which are crucial for efficient antiviral responses. Identifying methods able to reduce or prevent colonization, viral adhesion, and promote virus shedding on mucous membranes or have the ability to inactivate pathogens and thus reduce virus dose and/or increase immune response would be essential in the management of COVID-19 outbreak and help in flattening the curve. We review the effects of propolis, an old remedy with proven antiviral properties, as a possible low-cost inhibitor of SARS-CoV-2 in the oropharyngeal niche, prophylaxis, or adjuvant therapy.

Immunotherapy aiming to harness the exquisite power of the immune system has emerged as a crucial part of clinical cancer management. However, only a subset of cancer patients responds to current immunotherapy because of low immunogenicity of the tumor cells and immunosuppressive tumor microenvironment. Herein, host–guest prodrug nanovectors are reported for active tumor targeting and combating immune tolerance in tumors. The prodrug nanovectors are designed by integrating hyaluronic acid (HA) and reduction‐labile heterodimer of Pheophorbide A (PPa) and NLG919 into the supramolecular nanocomplexes, where PPa and NLG919 act as a photosensitizer and potent inhibitor of indoleamine 2,3‐dioxygenase 1 (IDO‐1), respectively. Meanwhile, HA is employed to achieve active tumor targeting by recognizing CD44 overexpressed on the surface of tumor cell membranes. Near infrared (NIR) laser irradiation triggers the release of reactive oxygen species to provoke antitumor immunogenicity and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Meanwhile, the immunosuppressive tumor microenvironment (ITM) is reversed by NLG919‐mediated IDO‐1 inhibition. Combination of photodynamic immunotherapy and IDO‐1 blockade efficiently eradicates CT26 colorectal tumors in the immunocompetent mice. The host–guest nanoplatform capable of eliciting effective antitumor immunity by inactivating inhibitory immune response can be applied to other immune modulators for improved cancer immunotherapy., Host–guest prodrug nanovectors integrating hyaluronic acid, and heterodimer of NLG919 and Pheophorbide A are reported for photodynamic immunotherapy of cancer. The combination of prodrug nanovector with near infrared laser irradiation triggers the generation of reactive oxygen species for eliciting antitumor immunogenicity and intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Meanwhile, NLG919 activates the CTLs by relieving the immunosuppressive tumor microenvironment.

Summary Pathogens secrete effector proteins to interfere with plant innate immunity, in which Ca2+/calmodulin (CaM) signalling plays key roles. Thus far, few effectors have been identified that directly interact with CaM for defence suppression. Here, we report that SFI5, an RXLR effector from Phytophthora infestans, suppresses microbe‐associated molecular pattern (MAMP)‐triggered immunity (MTI) by interacting with host CaMs.We predicted the CaM‐binding site in SFI5 using in silico analysis. The interaction between SFI5 and CaM was tested by both in vitro and in vivo assays. MTI suppression by SFI5 and truncated variants were performed in a tomato protoplast system.We found that both the predicted CaM‐binding site and the full‐length SFI5 protein interact with CaM in the presence of Ca2+. MTI responses, such as FRK1 upregulation, reactive oxygen species accumulation, and mitogen‐activated protein kinase activation were suppressed by truncated SFI5 proteins containing the C‐terminal CaM‐binding site but not by those without it. The plasma membrane localization of SFI5 and its ability to enhance infection were also perturbed by loss of the CaM‐binding site.We conclude that CaM‐binding is required for localization and activity of SFI5. We propose that SFI5 suppresses plant immunity by interfering with immune signalling components after activation by CaMs.

The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives (ImQ) to generate Toll‐like receptor (TLR) 7/8 specific prodrugs are presented. In vivo activity of ImQs to induce inflammation was confirmed in zebrafish larvae. After covalent ligation to fully biodegradable polyphosphazenes (ImQ‐polymer), the macromolecular prodrugs were designed to undergo intracellular pH‐sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8 (danger signal). We showed ImQ dissociation from prodrugs at a pH 5 pointing towards endosomal prodrug degradability. ImQ‐polymers strongly activated ovalbumin‐specific T cells in murine splenocytes as shown by increased proliferation and expression of the IL‐2 receptor (CD25) on CD8+ T cells accompanied by strong IFN‐γ release. ImQ prodrugs presented here are suggested to form the basis of novel nanovaccines, for example, for intravenous or intratumoral cancer immunotherapeutic applications to trigger physiological antitumor immune responses.

Summary Plant–pathogen interactions are complex associations driven by the interplay of host and microbe-encoded factors. With secreted pathogen proteins (effectors) and immune signalling components found in the plant nucleus, this compartment is a battleground where susceptibility is specified. We hypothesized that, by defining changes in the nuclear proteome during infection, we can pinpoint vital components required for immunity or susceptibility. We tested this hypothesis by documenting dynamic changes in the tomato (Solanum lycopersicum) nuclear proteome during infection by the oomycete pathogen Phytophthora capsici. We enriched nuclei from infected and noninfected tissues and quantitatively assessed changes in the nuclear proteome. We then tested the role of candidate regulators in immunity through functional assays. We demonstrated that the host nuclear proteome dynamically changes during P. capsici infection. We observed that known nuclear immunity factors were differentially expressed and, based on this observation, selected a set of candidate regulators that we successfully implicated in immunity to P. capsici. Our work exemplifies a powerful strategy to gain rapid insight into important nuclear processes that underpin complex crop traits such as resistance. We have identified a large set of candidate nuclear factors that may underpin immunity to pathogens in crops.

Cancer is an age‐associated disease, potentially related to the altered immune system of elderly individuals. However, cancer has gradually decreased incidence in the eldest globally such as the most common lung cancer, the mechanisms of which remain to be elucidated. In this study, it was found that the number of lung‐resident γδT cells was significantly increased with altered gene expression in aged mice (20–24 months) versus young mice (10–16 weeks). Aged lung Vγ4+ and Vγ6+ γδT cells predominantly produced interleukin‐17A (IL‐17A), resulting in increased levels in the serum and lungs. Moreover, the aged mice exhibited smaller tumors and reduced numbers of tumor foci in the lungs after challenge with intravenous injection of B16/F10 melanoma cells compared with the young mice. Aged lung Vγ4+ and Vγ6+ γδT cells were highly cytotoxic to B16/F10 melanoma cells with higher expression levels of CD103. The markedly longer survival of the challenged aged mice was dependent on γδT17 cells, since neutralization of IL‐17A or depletion of indicated γδT cells significantly shortened the survival time. Consistently, supplementation of IL‐17A significantly enhanced the survival time of young mice with lung melanoma. Furthermore, the anti‐tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota, as demonstrated through co‐housing of the aged and young mice. Intrinsically altered lung γδT17 cells underlying age‐dependent changes control lung melanoma, which will help to better understand the lung cancer progression in the elderly and the potential use of γδT17 cells in anti‐tumor immunotherapy., In the aged mice (20–24 months), the number of lung‐resident γδT cells was significantly increased with altered gene expression compared with the young mice (10–16 weeks). Aged lung γδT cells predominantly produced interleukin‐17A (IL‐17A), which played a critical role in resistance to the development of lung melanoma in the aged. Furthermore, the anti‐tumor activity of aged lung γδT17 cells was not affected by alterations in the load and composition of commensal microbiota.

Age‐related reductions in vaccine‐induced B cells in aging indicate that germinal centers (GCs), the anatomical site where the development of humoral responses takes place, may lose efficacy with age. We have investigated the baseline follicular and GC composition in nonhuman primates (NHPs) with respect to their age. There was a marked reduction in follicular area in old animals. We found significantly lower normalized numbers of follicular PD1hi CD4 T (Tfh) and proliferating (Ki67hi) GC B cells with aging, a profile associated with significantly higher numbers of potential follicular suppressor FoxP3hiLag3hi CD4 T cells. Furthermore, a positive correlation was found between Tfh and follicular CD8 T cells (fCD8) only in young animals. Despite the increased levels of circulating preinflammatory factors in aging, young animals had higher numbers of monocytes and granulocytes in the follicles, a profile negatively associated with numbers of Tfh cells. Multiple regression analysis showed an altered association between GC B cells and other GC immune cell populations in old animals suggesting a differential mechanistic regulation of GC activity in aging. Our data demonstrate defective baseline GC composition in old NHPs and provide an immunological base for further understanding the adaptive humoral responses with respect to aging., Steady‐state germinal center immune reactivity is compromised in aged NHPs. This loss of reactivity is characterized by changes in many GC associated cell populations including Tfh, B cells, and follicular Tregs.

Background Fasciola hepatica causes economically important disease in livestock worldwide. The relevance of this parasitic infection extends beyond its direct consequences due to its immunoregulatory properties. Objectives Given the importance of the T helper 1 (Th1) immune response in controlling infections with Mycobacterium avium subspecies paratuberculosis (MAP) in cattle, we aimed to establish the immunological consequences that co-infection with F. hepatica might have on the course of Johne's disease (JD). Methods This study compared the in vitro response of bovine immune cells to infection with MAP or exposure to MAP antigens following F. hepatica infection or stimulation with F. hepatica products. Results We found a decreased proliferation of peripheral blood mononuclear cells (PBMCs) after infection with F. hepatica. This reduction was inversely correlated with fluke burden. Pre-stimulation with F. hepatica molecules produced a significant reduction of ileocaecal lymph node leucocyte proliferation in response to MAP antigens. Additionally,F. hepatica products reduced expression of the CD14 receptor by macrophages and increased levels of apoptosis and bacterial (MAP) uptake. Conclusions Overall, F. hepatica infection had little impact on the in vitro response of immune cells to MAP, whereas in vitro co-stimulation with F. hepatica molecules had a measurable effect. Whether this is likely to affect JD progression during in vivo chronic conditions remains unclear.

© 2018 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd. Objectives: A growing evidence base implicates human cytomegalovirus (HCMV) as a risk factor for TB disease. We investigated total IgG and mycobacteria-specific antibodies in a cross-sectional study nested within a rural Ugandan General Population Cohort (GPC), in relation to HIV infection and the magnitude of HCMV IgG response. Methods: Sera from 2189 individuals (including 27 sputum-positive TB cases) were analysed for antibodies against mycobacteria (Ag85A, PPD, LAM, ESAT6/CFP10) and HCMV, tetanus toxoid (TT) and total IgG. Results: Anti-mycobacterial antibodies increased with age until approximately 20 years, when they plateaued. Higher HCMV exposure (measured by IgG) was associated with lower levels of some anti-mycobacterial antibodies, but no increase in total IgG. HIV infection was associated with a decrease in all anti-mycobacterial antibodies measured and with an increase in total IgG. Conclusions: The increase in anti-mycobacterial antibodies with age suggests increasing exposure to non-tuberculous mycobacteria (NTM), and to M.tb itself. HIV infection is associated with decreased levels of all mycobacterial antibodies studied here, and high levels of HCMV IgG are associated with decreased levels of some mycobacterial antibodies. These findings point towards the importance of humoral immune responses in HIV/TB co-infection and highlight a possible role of HCMV as a risk factor for TB disease.

Immunogenic cell death (ICD) is distinguished by the release of tumor‐associated antigens (TAAs) and danger‐associated molecular patterns (DAMPs). This cell death has been studied in the field of cancer immunotherapy due to the ability of ICD to induce antitumor immunity. Herein, endoplasmic reticulum (ER) stress‐mediated ICD inducing fluorinated mitochondria‐disrupting helical polypeptides (MDHPs) are reported. The fluorination of the polypeptide provides a high helical structure and potent anticancer ability. This helical polypeptide destabilizes the mitochondrial outer membrane, leading to the overproduction of intracellular reactive oxygen species (ROS) and apoptosis. In addition, this oxidative stress triggers ER stress‐mediated ICD. The in vivo results show that cotreatment of fluorinated MDHP and antiprogrammed death‐ligand 1 antibodies (αPD‐L1) significantly regresses tumor growth and prevents metastasis to the lungs by activating the cytotoxic T cell response and alleviating the immunosuppressive tumor microenvironment. These results indicate that fluorinated MDHP synergizes with the immune checkpoint blockade therapy to eliminate established tumors and to elicit antitumor immune responses., Endoplasmic reticulum (ER) stress‐mediated immunogenic cell death (ICD) inducing fluorinated mitochondria‐disrupting helical polypeptides (MDHPs) are developed. Intracellular oxidative stress by mitochondrial outer membrane destabilization triggers ER stress‐mediated ICD. In addition, combination regimen of fluorinated MDHP and immune checkpoint inhibitor significantly regresses tumor growth and prevents metastasis to the lungs by activating the cytotoxic T cell response.

Chronic kidney disease (CKD) is associated with accelerated atherosclerosis progression and high incidence of cardiovascular events, hinting that atherosclerotic plaques in CKD may be vulnerable. However, its cause and mechanism remain obscure. Here, it is shown that apolipoprotein E‐deficient (ApoE−/−) mouse with CKD (CKD/ApoE−/− mouse) is a useful model for investigating the pathogenesis of plaque vulnerability, and premature senescence and phenotypic switching of vascular smooth muscle cells (VSMCs) contributes to CKD‐associated plaque vulnerability. Subsequently, VSMC phenotypes in patients with CKD and CKD/ApoE−/− mice are comprehensively investigated. Using multi‐omics analysis and targeted and VSMC‐specific gene knockout mice, VSMCs are identified as both type‐I‐interferon (IFN‐I)‐responsive and IFN‐I‐productive cells. Mechanistically, mitochondrial damage resulting from CKD‐induced oxidative stress primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway to trigger IFN‐I response in VSMCs. Enhanced IFN‐I response then induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner, resulting in the loss of fibrous cap VSMCs and fibrous cap thinning. Conversely, blocking IFN‐I response remarkably attenuates CKD‐associated plaque vulnerability. These findings reveal that IFN‐I response in VSMCs through immune sensing of mitochondrial damage is essential for the pathogenesis of CKD‐associated plaque vulnerability. Mitigating IFN‐I response may hold promise for the treatment of CKD‐associated cardiovascular diseases., Oxidative stress‐induced mitochondrial damage under chronic kidney disease (CKD) milieu primes the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway in vascular smooth muscle cells (VSMCs) to trigger type‐I‐interferon response, which induces VSMC premature senescence and phenotypic switching in an autocrine/paracrine manner and finally results in plaque vulnerability.

Metal phosphorous trichalcogenides (MPX3) are novel 2D nanomaterials that have recently been exploited as efficient photothermal–chemodynamic agents for cancer therapy. As a representative MPX3, FePSe3 has the potential to be developed as magnetic resonance imaging (MRI) and photoacoustic imaging (PAI) agents due to the composition of Fe and the previously revealed PA signal. Here, a FePSe3‐based theranostic agent, FePSe3@APP@CCM, loaded with anti‐PD‐1 peptide (APP) as the inner component and CT26 cancer cell membrane (CCM) as the outer shell is reported, which acts as a multifunctional agent for MR and PA imaging and photothermal and immunotherapy against cancer. FePSe3@APP@CCM induces highly efficient tumor ablation and suppresses tumor growth by photothermal therapy under near‐infrared laser excitation, which further activates immune responses. Moreover, APP blocks the PD‐1/PD‐L1 pathway to activate cytotoxic T cells, causing strong anticancer immunity. The combined therapy significantly prolongs the lifespan of experimental mice. The multimodal imaging and synergistic therapeutic effects of PTT and its triggered immune responses and APP‐related immunotherapy are clearly demonstrated by in vitro and in vivo experiments. This work demonstrates the potential of MPX3‐based biomaterials as novel theranostic agents., In this work, it is shown that the novel biomimetic nanosystem FePSe3@APP@CCM can be used for magnetic resonance/photoacoustic imaging‐guided synergistic anticancer photothermal therapy (PTT) and immunotherapy. The nanosheets (NSs) are decorated with cancer cell membranes and show immune escape and homologous targeting abilities. Under near‐infrared laser irradiation, these NSs provide direct PTT and multiple immunotherapies.

Background and Objectives Allogeneic hematopoietic stem cell transplantation (HSCT) is a routine clinical procedure performed to treat patients with haematological malignancies, primary immune deficiencies or metabolic disorders. Infections during lymphopenia after allogeneic HSCT are associated with high mortality and morbidity. Typical infectious agents are Epstein–Barr virus, cytomegalovirus, herpes simplex virus, varicella-zoster virus and fungi. The study aim was to evaluate whether measurement of the responses of antigen-specific T-cells, recognizing infectious pathogens would correlate to protective functions in the stem cell recipient post-transplant. Materials and Methods Twenty-one grafts were analysed by flow cytometry and cells were stimulated in vitro with relevant infectious antigens, followed by evaluation of T-cell proliferation and cytokine production. Results were compared to the recipients’ clinical records 1-year post-transplantation. Results We show that an extensive repertoire of transferred antigen-specific T-cells from allogeneic donor grafts against infectious agents, involved in post-transplant infections, are linked to an absence of infectious complications for the recipient up-to 1-year post-transplant. The protective effect was associated with antigen-specific T-cell proliferation and IL-1β secretion. Conclusion Our results suggest that assaying T-cell function before HSCT could determine individual risks for infectious complications and thus aid in clinical decision-making regarding prophylactic and pre-emptive anti-infective therapy.

Immunotherapy has shown tremendous promise for improving cancer treatment. Unfortunately, antigen‐presenting cells (APCs) in cancer patients cannot effectively recognize and process tumor antigens to activate host immune responses. In this study, an approach is developed to improve cancer immunotherapy that utilizes endogenous antigen‐carrying nanoparticles (EAC‐NPs), which encompasses a set of antigens isolated from solid tumors and adjuvants. The EAC‐NPs specifically target APCs and subsequently result in enhanced T cell responses and improved antitumor efficacy. Mechanistic studies reveal that the EAC‐NPs enhance and prolong the presence of immune compounds in APCs, which ensure persistent antigen loading and stimulation, induce a rapid proliferation of CD4+ and CD8+ T cells, and significantly increase the ratios of intratumoral CD4+ T/Treg and CD8+ T/Treg. The work using nanotechnology provides a promising strategy in improving antitumor immunity by enhancing the immunogenicity and presentation of tumor self‐antigens for cancer immunotherapy., Endogenous antigen‐carrying nanoparticles are phagocytosed by antigen‐presenting cells (APCs) triggering antigen and Toll‐like receptor signaling. Then the APCs induce highly efficient differentiation of T cells toward helper T (CD4+) cells and cytotoxic T lymphocytes (CD8+) to finally generate potent antitumor immune responses. A promising strategy is established for cancer immunotherapy by enhancing the immunogenicity and presentation of tumor self‐antigens.

The continued threat of emerging, highly lethal infectious pathogens such as Middle East respiratory syndrome coronavirus (MERS‐CoV) calls for the development of novel vaccine technology that offers safe and effective prophylactic measures. Here, a novel nanoparticle vaccine is developed to deliver subunit viral antigens and STING agonists in a virus‐like fashion. STING agonists are first encapsulated into capsid‐like hollow polymeric nanoparticles, which show multiple favorable attributes, including a pH‐responsive release profile, prominent local immune activation, and reduced systemic reactogenicity. Upon subsequent antigen conjugation, the nanoparticles carry morphological semblance to native virions and facilitate codelivery of antigens and STING agonists to draining lymph nodes and immune cells for immune potentiation. Nanoparticle vaccine effectiveness is supported by the elicitation of potent neutralization antibody and antigen‐specific T cell responses in mice immunized with a MERS‐CoV nanoparticle vaccine candidate. Using a MERS‐CoV‐permissive transgenic mouse model, it is shown that mice immunized with this nanoparticle‐based MERS‐CoV vaccine are protected against a lethal challenge of MERS‐CoV without triggering undesirable eosinophilic immunopathology. Together, the biocompatible hollow nanoparticle described herein provides an excellent strategy for delivering both subunit vaccine candidates and novel adjuvants, enabling accelerated development of effective and safe vaccines against emerging viral pathogens., To improve vaccination efforts against Middle East respiratory syndrome coronavirus (MERS‐CoV), a virus‐mimicking vaccine is herein prepared with a capsid‐like hollow polymeric nanoparticle loaded with STING agonists and coated in MERS‐CoV antigens. The viromimetic nanoparticle facilitates safe and effective vaccination against the lethal virus and offers a versatile platform for combatting emerging infectious threats.

Mammary gland regression following weaning (involution) is associated with extensive cell death and the acquisition of an inflammatory signature. Characterising the interplay between mammary epithelial cells, the re-emerging stroma, and immune cells has implications for the understanding of the pathogenesis of pregnancy associated breast cancer. Stat3 has a role in orchestrating cell death and involution, and we sought to determine whether expression of Stat3 by the mammary epithelium influences also the innate immune environment and inflammatory cell influx in the gland. We examined mice in which Stat3 is conditionally deleted only in the mammary epithelium. Distinct sets of genes associated with the acute phase response and innate immunity are markedly up-regulated during first phase involution in a Stat3-dependent manner. During second phase involution, chitinase 3-like 1, which has been associated with wound healing and chronic inflammatory conditions, is dramatically up-regulated by Stat3. Also at this time, the number of mammary macrophages and mast cells increases per unit area, and this increase is impaired in the absence of epithelial Stat3. Furthermore, expression of arginase-1 and Ym1, markers of alternatively activated macrophages, is significantly decreased in the absence of Stat3, whilst iNOS, a marker associated with classically activated macrophages, shows significantly increased expression in the Stat3 deleted glands. Thus, Stat3 is a key transcriptional regulator of genes associated with innate immunity and wound healing and influences mammary macrophage and mast cell numbers. The presence of epithelial Stat3 appears to polarize the macrophages and epithelial cells towards an alternatively activated phenotype, since in the absence of Stat3, the gland retains a phenotype associated with classically activated macrophages. These findings have relevance to the study of pregnancy associated breast cancer and the role of Stat3 signalling in recruitment of alternatively activated tumour-associated macrophages in breast cancer. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The idiotypic network can be experimentally altered to induce protective immune responses against microbial pathogens. Both internal image and noninternal image anti‐idiotypic (anti‐Id) antibodies have been shown to trigger antigen (Ag)‐specific immune responses. Therefore, mechanisms of anti‐Id vaccination appear to go beyond structural mimicry of Ag, but remain undefined. Using the neurotropic murine coronavirus animal model, we have previously shown that a polyclonal noninternal image anti‐Id (Ab2) could vaccinate BALB/c mice. To characterize its mode of action, we have examined the immune modulating capability of this Ab2 in vivo in strains of mice with different H‐2 haplotypes. Even though only internal image anti‐Id are expected to induce non‐genetically restricted immunity, this noninternal image Ab2 induced protective immunity in four of eight genetically different strains of mice susceptible to coronavirus infection. These were BALB/c (H‐2d), DBA/1 (H‐2d), DBA/1 (H‐2q), and SWR (H‐2q) mice. Protection was generally correlated with the induction of specific antiviral Ab (Ab3) that showed biological properties, such as virus neutralization in vitro, similar to the initial Ab1. To evaluate the genetic implication of the H‐2 haplotypes in protection, congenic mice were also tested. Vaccination profiles suggest that cooperation between background gene(s) of the BALB/c mouse with H‐2d and H‐2q loci is necessary for an optimal protective immune response, although the main genetic element(s) regulating the antiviral response to Ab2 inoculation appeared to be located outside the major histocompatibility complex. These results are consistent with the ability of Ab2 to induce protective antiviral antibodies in genetically different animals by biological mimicry.

Faecal samples from suckling (n=205) and weaned piglets (n=82) with diarrhoea from 24 farms in Southern Germany were examined for shedding of important metazoic parasitic, viral and bacterial pathogens using culture, microscopic and electronmicroscopic methods. Escherichia coli isolates were tested further for the enterotoxin genes est‐Ia and elt‐I by colony blot hybridization. Isospora suis was diagnosed in 26.9 % and Cryptosporidium parvum in 1.4 % of the piglets investigated. The proportion of coronavirus‐positive animals was 13.4 % and 4 % were positive for rotavirus. It was found that 17.6 % of the animals were infected with enterotoxigenic E. coli (ETEC; 10.1 % ETEC‐ST‐Ia and 8.6 % ETEC‐LT‐I, respectively). The occurrence of the pathogens was significantly associated with the age of the animals examined (P

The antibody response to rabbit gamma-globulin (RGG) of high-responder, but not of low-responder Biozzi mice decreased with age. Injection with aggregate-freed RGG reduced the response of high-responder but not of low-responder mice to subsequent injections with aggregated RGG. This reduction in the antibody response, formed by high-responder mice, decreased with increasing age; aggregate-freed RGG appeared to sensitize 6-month-old low-responder mice to a subsequent injection with aggregated RGG. When animals, not pretreated with aggregate-freed RGG, were immunized with RGG and lipopolysaccharide (LPS), the immune response was greatly enhanced. The response of both pretreated low and high responders was substantially smaller than that of corresponding animals which were not given aggregate-freed RGG, prior to immunization. LPS revealed an inhibitory effect on low-responder mice of aggregate-freed RGG, which was not detected upon immunization with heat-aggregated RGG alone. The involvement of nonspecific suppressor cells and of B cell tolerance in low-responder mice is discussed.

With a view to specifically suppressing the IgE isotype, rats of high (BN) and low (PVG.RT1u) IgE-responding phenotypes were immunized with a highly purified rat IgE myeloma (IR2) in an attempt to induce an anto-anti-IgE response. Rat IgE antibodies against epsilon determinants were detected in the serum of IR2-immunized animals using a solid-phase (plate) radioimmunoassay. The auto-anti-IgE antibodies detected were found to bind to IR2, to a second rat IgE myeloma (IR162) and to mouse monoclonal IgE but not rat IgG. The specificity of the anti-epsilon binding was shown by inhibition studies. The raising of an auto-anti-IgE response in PVG.RT1u rats severely depleted the serum level of circulating IgE for at least 8 weeks. In BN rats, immunization with IR2 caused marked fluctuations in serum IgE levels. The rats in both strains remained healthy throughout the experiment. The rate and route of IgE break down was not altered in anti-IgE-producing rats. The relevance of the present model in understanding and possibly controlling allergic disorders is considered.

The lymphoid cell composition of milky spots was analyzed in unprimed mice before and after i.p. immunization with sheep red blood cells. Milky spots contained surface immunoglobulin-positive B lymphocytes, and T cells of the helper and cytotoxic phenotype. After secondary antigen challenge (a) the number of lymphocytes increased up to 40-fold, (b) B and T cells were found to segregate into distinct areas in situ, and (c) lymphocytes were found to associate with I-A-negative stromal cells in vivo. These findings qualify milky spots as a peripheral lymphoid organ exhibiting a remarkable change in number and composition of lymphocytes in response to a local antigen stimulus.

In the F1 hybrid of autoimmune New Zealand Black (NZB) and phenotypically normal New Zealand White (NZW) mice, there occurs a severe systemic lupus erythematosus (SLE)-like autoimmune disease more fulminant than that found in the parental NZB mice. To determine the role of the H-2 complex in the pathogenesis of autoimmune disease of the (NZB X NZW)F1 hybrid, we developed H-2-congenic NZB (NZB.H-2z) and NZW (NZW.H-2d) strains, and compared the degree of autoimmune features between congenic H-2d/H-2d and H-2z/H-2z homozygous F1 hybrids and the original H-2d/H-2z heterozygous (NZB X NZW)F1 hybrid. We found that autoimmune features such as productions of IgG class anti-DNA antibodies and retroviral gp70 immune complexes and the development of renal disease were to a great extent reduced in both H-2 homozygous F1 hybrids, as compared with the H-2 heterozygous (NZB X NZW)F1 hybrid. It would thus appear that the heterozygosity of H-2d haplotype derived from NZB and H-2z from NZW is essential for the autoimmune disease characteristic of the (NZB X NZW)F1 hybrid.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a new member of the coronavirus family that can cause coronavirus disease 2019 (COVID‐19). COVID‐9 has become a global pandemic with severe health issues around the world. Identifying the accurate immunopathogenesis of the COVID‐19 and the immune response against SARS‐CoV‐2 is necessary for the development of therapeutic approaches and rational drug design. This paper aims to overview the updated clinical data on the immunopathogenesis of the COVID‐19 and review the innate and adaptive immune response to SARS‐CoV‐2. Also, challenges of the immune response to SARS‐CoV‐2 leading to dysfunctional immune response and their contribution to the progression of the disease have been discussed. To achieve a more efficient immune response, multiple methods could be applied, including regulation of the immune response, augmentation of the immune system against the virus, inhibition of the dysfunctional immune checkpoints, and inhibition of the viral replication/infection. Based on the immune response against SARS‐CoV‐2 and its dysfunction, we introduce potential immunotherapies as well as reviewing recruiting/completed clinical trials of COVID‐19., Understanding the immunology of coronavirus disease 2019 (COVID‐19) is necessary for rational drug and vaccine design against it. In this paper, we have reviewed the updated data on immunobiology and immunotherapeutic‐based approaches for COVID‐19.

If there was any doubt of the primary role that plant secondary metabolites play in host-parasite co-evolution, the "From the Cover" paper by Tan et al. (2019) featured in this issue of Molecular Ecology will lay these doubts to rest. The group's previous work on monarch butterflies (Danaus plexippus) infected with the protozoan pathogen Ophryocystis elektroscirrha (OE) demonstrated higher survival and lower spore load on high cardenolide-producing milkweed (Asclepias curassavica) (Figure 1a) compared with low cardenolide-producing milkweed (A. incarnata) (de Roode, Pedersen, Hunter, & Altizer, 2008) (Figure 1b). The mechanism of this protective effect is not directly clear, but a leading hypothesis is that the cardenolides confer protection through toxicity to the parasite. However, the role of the caterpillar immune system in managing this parasite is largely unknown. Novel insights into the influence of toxic plant metabolites on caterpillar immunity are explored in Tan et al. (2019). Using transcriptomics to probe this model system, the authors found that herbivore immune genes were down-regulated and detoxification genes were up-regulated when larvae were reared on the milkweed species with high cardenolide concentrations (A. curassavica). Surprisingly, immune genes were not significantly up- or down-regulated in response to protozoan infection alone. This tantalizing result suggests that sequestered plant metabolites, not immunity, is reining in protozoan infections in these larvae, and promoting survival. As the authors point out, the strategy to invest in sequestration may come at a cost, which is to the detriment of the immune response (Smilanich, Dyer, Chambers, & Bowers, 2009). However, the cost becomes worth the investment when chemical sequestration takes on an antipathogen role. The novelty of the Tan et al. (2019) paper is that they show the investment in sequestration leading to a possible divestment in immunity.

New paradigms emerge when existing ones fail to address known factors adequately or are invalidated by new evidence. In this paper, we explore some long-held tenets in the pathogenesis of periodontitis and, in light of emerging data and concepts, challenge their validity. For decades periodontitis has been considered to be caused by specific bacteria or groups of bacteria and, accordingly, treatment protocols have been based largely on anti-infective therapies. However, close inspection of the available data leads one to question whether overgrowth of bacteria is the cause or the result of periodontitis. Over the same decades considerable evidence was presented which indicated that it is more likely to be the host response to the bacteria that leads to the tissue changes noted in gingivitis and periodontitis. Thus, it seems that it is the host inflammatory and immune responses, and not specific bacteria or their ‘putative’ virulence factors, which determine whether periodontitis develops and progresses. In this review, we highlight aspects of the pathogenesis of periodontitis that we suggest should be re-evaluated in light of the current evidence and discuss emerging treatment paradigms. No longer should the tissue changes noted in this classic chronic inflammatory condition be considered to be solely of microbial origin. In this review, we explore the evidence for a role of bacteria in the initiation, progression and treatment of periodontitis. The title of this review is a rewording of a recent paper entitled ‘Periodontitis: a polymicrobial disruption of host homeostasis’ (21). We present this title in the context of unlearning learned concepts in periodontics and the need for a significant re-evaluation of our understanding of the pathogenesis of periodontitis.

Insect immunity is exclusively innate, lacking the antibody-based adaptive immunity of vertebrates. Innate immunity is a naturally occurring, non-specific system that does not require previous infectious experience. In this paper, I describe insect immunity and review the roles of prostaglandins and other eicosanoids as crucial signals that mediate insect immune reactions to challenge. Despite physical barriers (the integument) and robust epithelial immune functions in salivary glands, tracheal systems and midgut, many microbes and parasitoids invade insect haemocoels. Once invaders are detected within the body, insects unleash potent immune effectors, traditionally assorted into cellular (haemocytic) and humoral immunity. Humoral immunity refers to induced expression of genes encoding antimicrobial peptides and the enzymes lysozyme and prophenoloxidase. These proteins appear in haemolymph of infected insects 6–12 h post-infection. Haemocytic immunity is characterized by direct interactions between invaders and circulating haemocytes. These reactions begin immediately when an infection is detected and, in the case of bacterial infections, are the predominant responses, responsible for clearing the vast majority of infecting bacterial cells within the first 2 h after infection. As a measure of cellular immunity, a recent field study shows that virtually all insects become infected and many fully recover from the infections. Insect immune functions are of such biological significance that they may limit the effectiveness of some biological control programmes. I highlight the efficacy of insect immunity and the importance of eicosanoids as immune signals by reviewing two cases in which microbes have evolved the ability to suppress host insect immunity by inhibiting eicosanoid biosynthesis. I complete the paper with a description of a major research goal in the Biological Control of Insects Research Laboratory, now focused on developing molecular tools to cripple pest insect immunity at the field level.

Myeloid-derived suppressor cells (MDSC) are important to the tumour microenvironment as they actively suppress the immune system and promote tumour progression and metastasis. These cells block T-cell activation in the tumour microenvironment, preventing anti-tumour immune activity. The ability of a treatment to alter the suppressive function of these cells and promote an immune response is essential to enhancing overall therapeutic efficacy. Interleukin-12 (IL-12) has the potential not only to promote anti-tumour immune responses but also to block the activity of cells capable of immune suppression. This paper identifies a novel role for IL-12 as a modulator of MDSC activity, with implications for IL-12 as a therapeutic agent. Treatment with IL-12 was found to alter the suppressive function of MDSC by fundamentally altering the cells. Interleukin-12-treated MDSC exhibited up-regulation of surface markers indicative of mature cells as well as decreases in nitric oxide synthase and interferon-γ mRNA both in vitro and in vivo. Treatment with IL-12 was also found to have significant therapeutic benefit by decreasing the percentage of MDSC in the tumour microenvironment and increasing the percentage of active CD8(+) T cells. Treatment with IL-12 resulted in an increase in overall survival accompanied by a reduction in metastasis. The findings in this paper identify IL-12 as a modulator of immune suppression with significant potential as a therapeutic agent for metastatic breast cancer.

Surface nanotopograpy has been recognized as an important regulator of cellular responses including those of immune cells, the latter being of particular importance for implantable materials since these can determine biomaterial fate. In this paper, evidence is provided that the scale of surface nanotopography modulates the conformation of attached serum proteins,which in turn controls immune cell adhesion and activation. Model surfaces of tailored nanotopography of heights of 16, 38, and 68 nm are created by covalent immobilization of gold nanoparticles to an oxazoline-rich plasma polymer film. This strategy not only produces surfaces of tailored nanofeature density but allows control of the outermost surface chemistry.Circular dichroism spectroscopy and Mac-1 positive THP-1 monocytes studies demonstrate distinct protein unfolding patterns, which upregulate or down regulate the expression of proinflammatory cytokines and cells attachment. The findings presented in this paper shed light on the missing relationship between surface nanotopography, protein unfolding, and the immune response. On the other hand, this work demonstrates the possibility to use specifically tailored surface nanotoporaphy scales to modulate and achieve desired immune responses. Refereed/Peer-reviewed

This paper is intended to serve as a traditional Tibetan medical response to advancements in basic longevity research, with particular attention to current models of caloric restriction. This is a complicated task, as Tibetan medicine traditionally approaches dietary modification from a radically different perspective, and relies upon a complex model of health and balance in the treatment and prevention of disease. This paper offers a brief overview of the traditional Tibetan medicine (TTM) model and suggests potential areas for collaborative research on dietary modification.

The digestive tract works through a complex network of integrative functions. At the level of the gut, this integration occurs between the immune, neuromotor and enteroendocrine systems, coordinating the physical and chemical elements of the intestinal barrier in order to facilitate digestion whilst protecting the gut from unwanted components of the luminal contents. Gastrointestinal function is controlled and coordinated by the central nervous system to ensure effective motility, secretion, absorption and mucosal immunity. It follows that perturbations in this complex network could lead to gut dysfunction and symptom generation. Recently, attention has been focused on the emerging hypothesis that gut luminal content contributes to determine normal GI function and on the therapeutic possibilities arising from modulating its impact on gut physiology and immunity using probiotic bacteria. In this issue of Neurogastroenterology and Motility, two papers explore the effect of specific probiotic bacteria on spinal neuronal activation and in vitro muscle contractility. These papers support the notion that the composition of the intestinal microbiota can influence gut neuro-motor function and enhance our understanding on the mechanisms of action underlying the effects of specific probiotics on gut functional disorders.

This paper summarizes studies on antibody formation in the bone marrow and the suppressive effects of intravenous immunization with allogeneic blood cells on T-cell function in mice. The latter studies were extended by employing the limiting dilution culture system developed in Ivan Lefkovits' laboratory and implemented in collaboration with Lucien Aarden. Thereby, the functional data were complemented with frequencies of alloantigen-activated helper (Th) and suppressor T cells after intravenous alloimmunization. These results led the Rotterdam group to studies on the prevention of rejection of the foetal 'allograft'. Th cells are central in foetal allograft rejection and pregnancy success. Characteristic for human pregnancy is the production of the glycoprotein chorionic gonadotropin (hCG) hormone. The in vivo liberated peptide fragments originating from nicking of the sequence MTRVLQGVLPALPQ in the beta-chain of hCG were considered for their immunoregulating capacity related to pregnancy success. These peptides - prepared synthetically - (MTR, MTRV, LQG, LQGV, VLPALP and others) indeed showed a remarkable spectrum of biological effects (e.g. modulation of angiogenesis, inhibition of septic shock syndrome, prevention of diabetes and reduction of ischaemia-reperfusion damage). The paper interprets and generalizes these findings and projects them into various research directions, especially towards the proteomics framework studies built up in Ivan Lefkovits' laboratory in the nineties. During the time period, when Ivan spent a mini-sabbatical in Rotterdam (months after closing down the BII) more detailed discussions were intiated. This paper is meant to keep the discussions between the involved research groups going on.

This paper deals with the qualitative analysis of a model related to the description of two medical therapies which have been intensively developed in recent years. In particular, we refer to the modelling of the actions applied by proteins, to activate the immune defense, and to the control of angiogenesis, to contrast the growth of tumour cells by preventing the feeding actions of endothelial cells. The therapeutical actions which are object of the modelling process developed in this paper have to be regarded as applied within the framework of the competition between the immune system and tumour cells. We prove the existence of solutions to the Cauchy problem related to the model. The efficiency of the therapies and the asymptotic behaviour in time of our solutions is also investigated.

Prostasomes are submicron-sized, membrane-bound organelles produced by the epithelial cells of the prostate and normally found in the secretion in the gland ducts. Their physiological role is in the promotion of sperm-function in human reproduction. This thesis contains four papers dealing with the production of prostasomes and some possible applications in clinical urology of the prostasome. Paper I and II provided an ultrastructural description of the synthesis, storage and secretion of prostasomes in benign as well as in malignant tissue. Most notable were the extracellular appearances of prostasomes in metastatic lesions whereby the prostasomes become exposed to the immune system of the patient. This supported findings in earlier studies in which patients with advanced prostate cancer had elevated levels of anti-prostasome antibodies. The results of paper III reinforced the view of the prostate-unique origin of the prostasome. In particular, there were no indications in SDS-PAGE patterns or flow-cytometric studies of material from seminal vesicle secretion that it contained components that could be associated with a production of prostasomes. Some possible clinical functions of the prostasomes were investigated in paper IV. Exposure of prostasomes to the immune system through mechanical and thermal trauma to the prostate did not induce an evident formation of anti-prostasome autoantibodies. Furthermore, the serum levels of anti-prostasome antibodies registered by assays with preparations of prostasomes from seminal plasma as antigen did not correlate with existing prostate cancer. Seminal prostasomes seemed not to function as substitute markers for prostate cancer in the test kit used. A possible explanation could be underestimated differences in antigen properties between seminal or prostate gland-derived prostasomes and prostasomes from tumor tissue.

This paper discusses the following ten subtitles with the contents indicated. 1. To meet a microbe: discusses the four alternatives in host-microbe interactions. 2. Receptors and signal transduction giving gene activation: discusses the lipopolysaccharide receptor and the limitations of cell cultures versus use of live animals. 3. Effector molecules--antimicrobial peptides with and without cysteines. A data base exists with over 500 sequences. This paper gives a general overview of five classes of gene-encoded effector molecules, based on the absence or presence of cysteines. These molecules are peptide antibiotics with wide spectra against different microbes. They are synthesized as propeptides and post-translational modifications are common. 4. Effectors of innate immunity--lethal action without host damage: evaluates current opinions about the mode of action of peptide antibiotics and the fact that these effectors do not create host damage. 5. Genes, introns and movable elements. Two cecropin genes containing movable elements and the human cathelicidin gene for proFALL-39/hCAP18 are discussed. 6. The natural microflora. Hippos or frogs as model systems. This section includes the isolation of bacteria from the normal flora of frogs; Aeromonas hydrophila, the bacterium found on all five frog species studied; arguments and selected examples of frog-microbe interactions in vivo and in vitro; and the use of glucocorticoids as control for nuclear factor-kappa B/I kappa B alpha regulation of effector genes. 7. The use of germ-free mice--hard facts from hard work: summarizes new findings which indicate that germ-free mice are born with a set of antibacterial peptides in their small intestine. The intestine of germ-free mice monoinfected with A. hydrophila have peptide patterns that differ depending on a pretreatment with cortisone. 8. Looking back--an evolutionary perspective on innate immunity: arguments for an early evolutionary need for gene-encoded antibacterial factors. Caenorhabditis elegans should provide some answers. The finding of cecropin-like peptides in Helicobacter pylori and the indications that cecropins are derived from ribosomal protein L1. 9. What about viruses? Arguments for the lack of innate immunity against viruses. 10. Five questions floating in the pond of immunology. The normal microflora, its size and control are too often left out from immunological thinking. Animal model systems may sometimes invite misinterpretation. Which animal species are more equal than others?

This paper examines methods of adaptation among those faced with stress from chronic health problems. Studies of disabled older adults and those with muscular-skeletal disorders are described with special emphasis on the role of everyday life events, and the threats to well-being imposed by chronic stressors. Attention is paid not only to psychological distress as outcome of a failure to adapt, but also to indices of psychological well-being which provide evidence of the benefits for those who cope successfully with chronic illness. The paper examines evidence for the proposition that everyday stressors can influence physiological processes linked to disease course. The implications of these findings for social interventions are discussed from community and health psychology perspectives.

Progressive multifocal encephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), which occurs in immunocompromised individuals. Management of PML relies on restoration of immunity within the CNS. However, when this restoration cannot be readily achieved, PML has a grim prognosis. Innovative strategies have shown promise in promoting anti-JCV immune responses, and include T-cell adoptive transfer or immune checkpoint inhibitor therapies. Conversely, management of immune reconstitution inflammatory syndrome, particularly in iatrogenic PML, remains a major challenge. In this paper, we review recent development in the treatment of PML. ANN NEUROL 2021;90:865-873.

Molecular genetic analyses of P. falciparum have led to the cloning and sequencing of a number of antigens that are potential candidates for vaccination against malaria. Seroepidemiological studies in endemic areas have attempted to assess the relative importance of these antigens in protection against malaria. In this paper, we attempt to evaluate the relative contributions of conserved and strain-specific immune responses by modelling their influence of age-specific patterns of infection and disease. The modelling exercises in this paper clearly demonstrate that the observed patterns of age-prevalence are best explained by proposing that the accumulation to a threshold of an immune response against a conserved determinant is required for protection against infection, while 'anti-disease' immunity develops more linearly with exposure. This is compatible with the conjecture that the parasite population is structured into several independently transmitted strains, that each confers some degree of 'anti-disease' immunity, but does not protect against further infection by the same strain. Within this framework, the average duration of parasitaemia increases with age, as previously encountered strains endure for longer periods at a subclinical level. Indirect evidence for the increase in duration of parasitaemia with age may be obtained from a comparison of age-prevalence curves between dry and rainy seasons. By using mathematical methods to structure epidemiological and immunological information, we provide a coherent theoretical framework for the dissection of the important components of naturally acquired immunity to malaria.