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In this unprecedented crisis of severe acute respiratory syndrome coronavirus 2 and its associated coronavirus disease 2019 (COVID-19), polymerase chain reaction and then serological testing platforms have been massively developed to face the important screening demand. Polymerase chain reaction and serological testing platforms are not the only actors impacted by the crisis, transfusion services are facing important difficulties. A positive direct antiglobulin test is frequently observed for patients encountering COVID-19. Patients with severe symptoms may develop anaemia and become good candidates for blood transfusions. The interpretation of a positive direct antiglobulin test for patients recently transfused and suffering from COVID-19 is complex. The differentiation between COVID-19 induced antibodies and possible associated transfusion alloantibodies is therefore crucial. In this context, the elution technique incorporated in an appropriate decision-making process plays its full role. This intricate topic is presented through a case report followed by literature review and finally decision-making process for COVID-19 patients necessitating red blood cells administration.

Introduction The automated quantitative antigen test (QAT), which detects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is suitable for mass screening. However, its diagnostic capability differentiated by time from onset and potential contribution to infectivity assessment have not been fully investigated. Methods A retrospective, observational study using nasopharyngeal swab specimens from coronavirus disease (COVID-19) inpatients was conducted using LumipulseⓇ SARS-CoV-2 antigen test. Diagnostic accuracy was examined for the early (up to 10 days after onset) and late (over 10 days after onset) stages. Time-course QAT changes and reverse‐transcription quantitative polymerase chain reaction tests results were displayed as locally estimated scatterplot smoothing curve, and receiver operating characteristic curve (ROC) analysis was used to determine the appropriate cutoff value for differentiating the early and late stages. Results We obtained 100 specimens from 68 COVID-19 patients, including 51 early-stage and 49 late-stage specimens. QAT sensitivity and specificity were 0.82 (0.72–0.90) and 0.95 (0.75–0.99) for all periods, 0.93 (0.82–0.98) and 1.00 (0.39–1.00) for the early stage, and 0.66 (0.48–0.82) and 0.93 (0.69–0.99) for the late stage, respectively. The ROC analysis indicated an ideal cutoff value of 6.93 pg/mL for distinguishing early-from late-stage specimens. The sensitivity, specificity, positive predictive value, and negative predictive value for predicting the late stage were 0.76 (0.61–0.87), 0.76 (0.63–0.87), 0.76 (0.61–0.87), and 0.76 (0.63–0.87). Conclusions QAT has favorable diagnostic accuracy in the early COVID-19 stages. In addition, an appropriate cutoff point can potentially facilitate rapid identification of noncontagious patients.

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed., Graphical abstract Image 1, Highlights • In responsive to the changes in TME, nanoparticles target tumor microenvironment and enhance the therapeutic effect. • Nanoparticles modulate the activation and maturation of DC. • Nanoparticles could reprogram polarization of TAM and relieve hypoxia. • Nanoparticles could transfer the immunosuppressive TME to immunosupportive.

Middle East respiratory syndrome (MERS) is a threat to public health worldwide. A vaccine against the causative agent of MERS, MERS-coronavirus (MERS-CoV), is urgently needed. We previously identified a peptide ligand, Co4B, which can enhance antigen (Ag) delivery to the nasal mucosa and promote Ag-specific mucosal and systemic immune responses following intranasal immunization. MERS-CoV infects via the respiratory route; thus, we conjugated the Co4B ligand to the MERS-CoV spike protein receptor-binding domain (S-RBD), and used this to intranasally immunize C57BL/6 and human dipeptidyl peptidase 4-transgenic (hDPP4-Tg) mice. Ag-specific mucosal immunoglobulin (Ig) A and systemic IgG, together with virus-neutralizing activities, were highly induced in mice immunized with Co4B-conjugated S-RBD (S-RBD-Co4B) compared to those immunized with unconjugated S-RBD. Ag-specific T cell-mediated immunity was also induced in the spleen and lungs of mice intranasally immunized with S-RBD-Co4B. Intranasal immunization of hDPP4-Tg mice with S-RBD-Co4B reduced immune cell infiltration into the tissues of virus-challenged mice. Finally, S-RBD-Co4B-immunized mice exhibited were better protected against infection, more likely to survive, and exhibited less body weight loss. Collectively, our results suggest that S-RBD-Co4B could be used as an intranasal vaccine candidate against MERS-CoV infection.

Background Markedly elevated levels of pro-inflammatory cytokines and defective type-I interferon responses were reported in COVID-19 patients. Objective This study aimed to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. Methods Cytokine concentrations and SARS-CoV-2 antigen were measured at hospital admission in serum of symptomatic COVID-19 patients (N=115), classified at hospitalization into three respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS) and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N=86). Results At time of hospitalization, ECMO patients presented a dominant pro-inflammatory response with elevated levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-8 and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at one month was associated with higher levels of pro-inflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (Risk Ratio 24.3, p, Graphical abstract, Capsule SummaryDistinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality in different oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.

Understanding the dynamics of the human proteome is crucial for developing biomarkers to be used as measurable indicators for disease severity and progression, patient stratification, and drug development. The Proximity Extension Assay (PEA) is a technology that translates protein information into actionable knowledge by linking protein-specific antibodies to DNA-encoded tags. In this report we demonstrate how we have combined the unique PEA technology with an innovative and automated sample preparation and high-throughput sequencing readout enabling parallel measurement of nearly 1500 proteins in 96 samples generating close to 150,000 data points per run. This advancement will have a major impact on the discovery of new biomarkers for disease prediction and prognosis and contribute to the development of the rapidly evolving fields of wellness monitoring and precision medicine., Graphical Abstract, Highlights • Novel tool for protein discovery and quantification. • PEA technology in combination with high-throughput sequencing read-out. • Parallel measurement of nearly 1500 proteins. • Innovative, miniaturized, and automated sample preparation protocol., In Brief Wik et al. presents a groundbreaking method based on the PEA technology in combination with NGS readout to measure nearly 1500 validated proteins in parallel. The protocol contains an innovative and automated sample preparation workflow generating close to 150,000 data points per run while consuming minimal amount of sample. Using dual DNA tags as readout enables high multiplex detection with exceptional specificity. This protocol meets all the requirements for a proteomic tool of the 21st century healthcare.

Schistosomiasis is an acute and chronic tropical parasitic disease caused by blood dwelling worm of the genus Schistosoma. It is the most destructive disease globally and is a major cause of morbidity and mortality for developing countries. Three main species of schistosomes infect human beings from which S. mansoni is the most common and widespread. Over the last several decades, chemotherapy using praziquantel has been a commonly used strategy for the treatment and control of schistosomiasis. However, control programs focused exclusively on chemotherapy have been challenging because of the frequency and rapidity of reinfection and these programs were expensive. Thus, new schistosomiasis control strategies will be needed. Vaccination strategy would be an ideal tool for a significant and sustainable reduction in the transmission and disease burden of schistosomiasis. An effective anti schistosome vaccine would greatly contribute to decreasing schistosomiasis-associated morbidity via protective immune responses leading to reduced worm burdens and decreased egg production. Vaccine development is a long process that can take decades. There have been three candidate vaccines that have been produced by Good Manufacturing Procedure and entered human clinical trials for S. mansoni are Sm14, SmTSP-2, and Sm-p80. Other candidates that are in pre-clinical trials at various stages include paramyosin, Sm29, SmKI-1, and Sm23. Since the growth of several new technologies, including genomics, transcriptomics, microarrays, immunomic profiling, and proteomics, have helped in the identification of promising new target schistosome antigens. Therefore, this review considers the present status of protein vaccine candidates against Schistosoma mansoni and provides some insight on prospects vaccine design and discovery.

Background Literature describing triggers of GFAP astrocytopathy (GFAP-A) is limited. We report a case of GFAP-A in a patient with recent messenger ribonucleic acid (mRNA) severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) vaccination and discuss the possible pathogenesis. Case description A 45-year-old gentleman presented with features of meningoencephalitis 31 days after the first dose and 4 days after the second dose of mRNA SARS-CoV-2 vaccination. He sequentially developed brainstem/cerebellar, autonomic and cord dysfunction. Cerebrospinal fluid was positive for GFAP autoantibody. Clinical improvement occurred after intravenous methylprednisolone and immunoglobulins. Conclusion Although we are uncertain of a causal link of GFAP-A to mRNA vaccine, indirect activation of an underlying dysregulated immune milieu is plausible.

Plasmacytoid dendritic cells (pDCs) have been shown to both mediate and prevent autoimmunity, and the regulation of their immunogenic versus tolerogenic functions remains incompletely understood. Here we demonstrate that, compared to other cells, pDCs are the major expressors of Indoleamine-2,3-dioxygenase (IDO) in steady-state lymph nodes (LNs). IDO expression by LN pDCs was closely dependent on MHCII-mediated, antigen-dependent, interactions with Treg. We further established that IDO production by pDCs was necessary to confer suppressive function to Tregs. During EAE development, IDO expression by pDCs was required for the generation of Tregs capable of dampening the priming of encephalitogenic T cell and disease severity. Thus, we describe a novel crosstalk between pDCs and Tregs: Tregs shape tolerogenic functions of pDCs prior to inflammation, such that pDCs in turn, promote Treg suppressive functions during autoimmunity., Graphical abstract, Highlights • IDO expression by LN pDCs is closely dependent on MHCII-mediated, antigen-dependent, interactions with Tregs. • pDCs are the predominant source of IDO in both steady-state and inflamed lymph nodes. • IDO production by pDCs is necessary to confer suppressive function to Tregs in EAE.

Highlights • There is a risk even for dogs with limited time of exposure to obtain a vector-borne infection. • Prevention of vector-transferred pathogens in dogs travelling to endemic areas is important. • The owners should be educated regarding the vectors, diseases, risks and prophylaxis., Canine vector-borne infections gained in importance in Germany due to growing tourist traffic, the increased import of dogs from abroad and the changing of climatic conditions. The Mediterranean region and southeastern Europe are geographical areas where pathogens such as Leishmania (L.) infantum, Hepatozoon (H.) canis, Ehrlichia (E.) canis, Anaplasma (A.) platys and Dirofilaria (D.) spp. are endemic. Meanwhile, Babesia (B.) spp. and A. phagocytophilum are present in central and western Europe. The objective of this retrospective study was to evaluate whether dogs were exposed to a corresponding risk of infection when travelling to regions in the Mediterranean area and southeastern Europe, which are endemic for these pathogens. Medical records and laboratory test results of 303 dogs that travelled to 14 countries endemic for the mentioned canine vector-borne pathogens and that were presented to the Small Animal Clinic at Freie Universität Berlin between 2007 and 2018 were retrospectively reviewed. A total of 1174 test results from external laboratories were descriptively analysed including 525 test results of direct and 649 of indirect determination methods. Overall, 13% of the tested dogs (40/303) were positive for at least one pathogen. Concurrent infections with two pathogens were detected in 1% of the dogs (4/303). The positive results were: E. canis 8% (18/231 dogs; Polymerase chain reaction [PCR] 3/73, indirect immunofluorescence test [IFAT] 18/209 dogs), L. infantum 5% (14/260 dogs; PCR 5/80, IFAT or enzyme linked immunosorbent assay [ELISA] 11/251 dogs), Babesia spp. 5% (11/232 dogs; Babesia spp. PCR 3/127, B. canis/vogeli IFAT or ELISA 8/160, B. gibsoni IFAT 2/22), Dirofilaria spp. 1% (1/133 dogs; D. immitis antigen-ELISA 1/117, microfilariae PCR 0/16, Knott´s test 0/69 dogs). None of the dogs has been tested positive in a combined Babesia spp./Hepatozoon spp. PCR test (0/15 dogs) and for H. canis (0/17 dogs; PCR) or A. platys (0/11 dogs; PCR). There is a substantial risk for dogs travelling to areas endemic for vector-borne pathogens even with limited time of exposure to get infected. The data indicates the importance of owner education and prophylactic measurements against vector-borne infections in dogs travelling to endemic areas.

Female and male mice of the BTBR T+Itpr3tf/J (BTBR) strain have behaviors that resemble autism spectrum disorder. In comparison to C57BL/6 (B6) mice, BTBR mice have elevated humoral immunity, in that they have naturally high serum IgG levels and generate high levels of IgG antibodies, including autoantibodies to brain antigens. This study focused on the specificities of autoantibodies and the immune cells and their transcription factors that might be responsible for the autoantibodies. BTBR IgG autoantibodies bind to neurons better than microglia and with highest titer to nuclear antigens. Two of the antigens identified were alpha-enolase (ENO1) and dihydrolipoyllysine-residue succinyltransferase component of 2-oxoglutarate dehydrogenase complex, mitochondrial (DLST). Surprisingly based on IgG levels, the blood and spleens of BTBR mice have more CD4+ and CD8+ T cells, but fewer B cells than B6 mice. The high levels of autoantibodies in BTBR relates to their splenic T follicular helper (Tfh) cell levels, which likely are responsible for the higher number of plasma cells in BTBR mice than B6 mice. BTBR mice have increased gene expression of interleukin-21 receptor (Il-21r) and Paired Box 5 (Pax5), which are known to aid B cell differentiation to plasma cells, and an increased Lysine Demethylase 6B (Kdm6b)/DNA Methyltransferase 1 (Dnmt1) ratio, which increases gene expression. Identification of gene expression and immune activities of BTBR mice may aid understanding of mechanisms associated with autism since neuroimmune network interactions have been posited and induction of autoantibodies may drive the neuroinflammation associated with autism., Highlights • BTBR mice have more autoantibodies, e.g., anti-α-enolase and anti-DLST than B6 mice. • T follicular helper cells are increased in BTBR mice compared to B6 mice. • BTBR mice have more plasma cells with ​Pax5 ​and ​IL-21r ​than B6 mice. • A high ​Kdm6b ​to ​Dmnt1 ​ratio influences the BTBR’s increase in plasma cells.

Natural Killer (NK) cells constitute a major subset of innate lymphoid cells that do not express the T- and B-cell receptors and play an important role in antimicrobial defense. NK cells not only induce early and rapid innate immune responses, but also communicate with dendritic cells to shape the adaptive immunity, thus bridging innate and adaptive immunity. Although the functional biology of NK cells is well-documented in a variety of infections in humans and mice, their role in protecting domestic animals from infectious agents is only beginning to be understood. In this article, we summarize the current state of knowledge about the contribution of NK cells in pathogen defense in domestic animals, especially cattle and pigs. Understanding the immunobiology of NK cells will translate into strategies to manipulate these cells for preventive and therapeutic purposes.

The basis of Haemophilus influenzae type b (Hib) and Neisseria meningitidis serogroup C (MenC) glycoconjugates binding to aluminum-containing adjuvants was studied. By measuring the amount of polysaccharide and protein in the non-adsorbed supernatant, the adjuvant, aluminum phosphate, AlPO4, was found to be less efficient than aluminum hydroxide, Al(OH)3 at binding to the conjugates, at concentrations relevant to licensed vaccine formulations and when equimolar. At neutral pH, binding of TT conjugates to AlPO4 was facilitated through the carrier protein, with only weak binding of AlPO4 to CRM197 being observed. There was slightly higher binding of either adjuvant to tetanus toxoid conjugates, than to CRM197 conjugates. This was verified in AlPO4 formulations containing DTwP–Hib, where the adsorption of TT-conjugated Hib was higher than CRM197-conjugated Hib. At neutral pH, the anionic Hib and MenC polysaccharides did not appreciably bind to AlPO4, but did bind to Al(OH)3, due to electrostatic interactions. Phosphate ions reduced the binding of the conjugates to the adjuvants. These patterns of adjuvant adsorption can form the basis for future formulation studies with individual and combination vaccines containing saccharide-protein conjugates.

This study aimed to investigate thrombin-activatable fibrinolysis inhibitor (TAFI) Thr325Ile polymorphism and TAFI antigen (Ag) levels in breast cancer (BC) in the Egyptian population to clarify their role in relation to BC. A group of 300 females was recruited in this study; of these 150 unrelated patients with different stages of BC and 150 age-matched healthy controls. Plasma TAFI Ag was measured by ELISA and TAFI Thr325Ile (rs1926447) polymorphism was genotyped using TaqMan single nucleotide polymorphism (SNP) genotyping assay. The results showed the genotypes of the minor allele; Thr/Ile (CT) and Ile/Ile (TT) were significantly more frequent in patients compared to control group (50.0% and 22.0% vs. 42.0% and 13.3%, respectively) and were also associated with BC susceptibility [OR = 1.9 and 2.6; 95% CI: (1.1–3.3) and (1.3–5.5), respectively P = 0.01]. Ile325 allele carriers were more frequent in cases than in controls (47.0% vs. 34.0%) [OR = 1.7, (95% CI = 1.2–2.4), P = 0.001]. However, TAFI Thr325Ile polymorphism was not associated with BC stage or other clincopathological characteristics. TAFI Ag levels were correlated with advanced stages of BC, poor prognosis and risk of recurrence (P = 0.02, P = 0.04 and P, Highlights • TAFI Thr325Ile polymorphism associated with breast cancer in studied population • TAFI Thr325Ile polymorphism was significantly correlated with TAFI antigen levels. • High TAFI antigen levels were correlated with advanced stages of breast cancer. • High TAFI plasma level could be used to recognize tumor prognosis and risk of recurrence.

Transcutaneous immunization (TCI) systems that use the skin's immune function are promising needle-free, easy-to-use, and low-invasive vaccination alternative to conventional, injectable vaccination methods. To develop effective TCI systems, it is essential to establish fundamental techniques and technologies that deliver antigenic proteins to antigen-presenting cells in the epidermis and dermis while overcoming the barrier function of the stratum corneum. In this review, we provide an outline of recent trends in the development of techniques for the delivery of antigenic proteins and of the technologies used to enhance TCI systems. We also introduce basic and clinical research involving our TCI systems that incorporate several original devices.

The field of point-of-care (POC) testing technology is developing quickly and producing instruments that are increasingly reliable, while their size is being gradually reduced. Proteins are a common target for POC analyses and the detection of protein markers typically involves immunoassays aimed at detecting different groups of proteins such as tumor markers, inflammation proteins, and cardiac markers; but other techniques can also be used to analyze plasma proteins. In the case of nucleic acids, hybridization and amplification strategies can be used to record electromagnetic or electric signals. These techniques allow for the identification of specific viral or bacterial infections as well as specific cancers. In this review, we consider some of the latest advances in the analysis of specific nucleic acid and protein biomarkers, taking into account their trend toward miniaturization and paying special attention to the technology that can be implemented in future applications, such as lab-on-a-chip instruments.

JAA-F11 is a highly specific mouse monoclonal to the Thomsen-Friedenreich Antigen (TF-Ag) which is an alpha-O-linked disaccharide antigen on the surface of ~80% of human carcinomas, including breast, lung, colon, bladder, ovarian, and prostate cancers, and is cryptic on normal cells. JAA-F11 has potential, when humanized, for cancer immunotherapy for multiple cancer types. Humanization of JAA-F11, was performed utilizing complementarity determining regions grafting on a homology framework. The objective herein is to test the specificity, affinity and biology efficacy of the humanized JAA-F11 (hJAA-F11). Using a 609 target glycan array, 2 hJAA-F11 constructs were shown to have excellent chemical specificity, binding only to TF-Ag alpha-linked structures and not to TF-Ag beta-linked structures. The relative affinity of these hJAA-F11 constructs for TF-Ag was improved over the mouse antibody, while T20 scoring predicted low clinical immunogenicity. The hJAA-F11 constructs produced antibody-dependent cellular cytotoxicity in breast and lung tumor lines shown to express TF-Ag by flow cytometry. Internalization of hJAA-F11 into cancer cells was also shown using a surface binding ELISA and confirmed by immunofluorescence microscopy. Both the naked hJAA-F11 and a maytansine-conjugated antibody (hJAA-F11-DM1) suppressed in vivo tumor progression in a human breast cancer xenograft model in SCID mice. Together, our results support the conclusion that the humanized antibody to the TF-Ag has potential as an adjunct therapy, either directly or as part of an antibody drug conjugate, to treat breast cancer, including triple negative breast cancer which currently has no targeted therapy, as well as lung cancer.

Highlights • CD9+ germinal center B cells are in close proximity to follicular dendritic cells (FDC) in vivo. • CD9 improves the survival of GC-B cells in the presence of FDC in vitro. • CD9 enhances the binding of GC-B cells to soluble VCAM-1. • CD9 on GC-B cells may have a role in enhancing the affinity of VLA4 to VCAM-1 on FDC., The germinal center (GC) is a dynamic microenvironment where antigen (Ag)-activated B cells rapidly expand and differentiate, generating plasma cells (PC) that produce high-affinity antibodies. Precise regulation of survival and proliferation of Ag-activated B cells within the GC is crucial for humoral immune responses. The follicular dendritic cells (FDC) are the specialized stromal cells in the GC that prevent apoptosis of GC-B cells. Recently, we reported that human GC-B cells consist of CD9+ and CD9− populations and that it is the CD9+ cells that are committed to the PC lineage. In this study, we investigated the functional role of CD9 on GC-B cells. Tonsillar tissue section staining revealed that in vivo CD9+ GC-B cells localized in the light zone FDC area. Consistent this, in vitro CD9+ GC-B cells survived better than CD9− GC-B cells in the presence of HK cells, an FDC line, in a cell–cell contact-dependent manner. The frozen tonsillar tissue section binding assay showed that CD9+ GC-B cells bound to the GC area of tonsillar tissues significantly more than the CD9− GC-B cells did and that the binding was significantly inhibited by neutralizing anti-integrin β1 antibody. Furthermore, CD9+ cells bound to soluble VCAM-1 more than CD9− cells did, resulting in activation and stabilization of the active epitope of integrin β1. All together, our data suggest that CD9 on GC-B cells contributes to survival by strengthening their binding to FDC through the VLA4/VCAM-1 axis.

Spatial organisation of T cell receptor (TCR) and its coreceptor CD8 on the surface of live naïve and Ag-experienced CD8+ T cells was resolved by fluorescence lifetime cross-correlation microscopy. We found that exposure of naïve CD8+ T cells to antigen (Ag) causes formation of [TCR, CD8] functional ensembles on the cell surface which correlated with significantly enhanced sensitivity of these cells. In contrast, TCR and CD8 are randomly distributed on the surface of naïve cells. Our model suggests that close proximity of TCR and CD8 can increase Ag sensitivity of T cells by significant accelerating the TCR–peptide-major histocompatibility complex (pMHC) binding rate and stabilisation of this complex. We suggest that the proximity of these primary signalling molecules contributes to the mechanism of functional avidity maturation of CD8+ T cells by switching them from a low to high sensitivity mode.

Multiple sclerosis (MS) is a complex inflammatory disease of unknown etiology that affects the central nervous system (CNS) white matter, and for which no effective cure exists. Indeed, whether the primary event in MS pathology affects myelin or axons of the CNS remains unclear. Animal models are necessary to identify the immunopathological mechanisms involved in MS and to develop novel therapeutic and reparative approaches. Specifically, viral models of chronic demyelination and axonal damage have been used to study the contribution of viruses in human MS, and they have led to important breakthroughs in our understanding of MS pathology. The Theiler's murine encephalomyelitis virus (TMEV) model is one of the most commonly used MS models, although other viral models are also used, including neurotropic strains of mouse hepatitis virus (MHV) that induce chronic inflammatory demyelination with similar histological features to those observed in MS. This review will discuss the immunopathological mechanisms involved in TMEV-induced demyelinating disease (TMEV-IDD). The TMEV model reproduces a chronic progressive disease due to the persistence of the virus for the entire lifespan in susceptible mice. The evolution and significance of the axonal damage and neuroinflammation, the importance of epitope spread from viral to myelin epitopes, the presence of abortive remyelination and the existence of a brain pathology in addition to the classical spinal cord demyelination, are some of the findings that will be discussed in the context of this TMEV-IDD model. Despite their limitations, viral models remain an important tool to study the etiology of MS, and to understand the clinical and pathological variability associated with this disease. © 2012 Elsevier Ltd., The authors thank REEM (Red Española de Esclerosis Múltiple; RD 07/0010/0060) for its support and its funding of MM. This work was supported by the Plan Nacional, Ministerio de Ciencia e Innovación (SAF, 2011/17501) and Network of Biomedicine Research from the CAM, CANNAB Program S-2010/BDM-2308.

Interferons represent a protein family with pleiotropic functions including immunomodulatory, cytostatic, and cytotoxic activities. Based on these effects, interferons are involved in innate as well as adaptive immunity, thereby shaping the tumor host immune responses. These cytokines, alone or in combination, have been successfully implemented for the treatment of some malignancies. However, it has been recently demonstrated that tumor cells could be resistant to interferon treatment, which may be associated with an escape of tumor cells from immune surveillance. Therefore, the aim of this chapter is to summarize the frequency of impaired interferon signal transduction, their underlying molecular mechanisms, and their clinical relevance.

CD4+ T cells represent an entire arm of the immune system that has hitherto been incompletely understood, but their potential to act as both helper and effector may make them optimal protagonists in immunotherapeutic approaches to treat cancer. Cytokine therapy can activate this population in a manner that ensures maximal diversification of effector function for a robust immune response.

Biliary atresia (BA) is the most frequent identifiable cause of neonatal cholestasis, and the majority of patients will need liver transplantation for survival. Despite surgical intervention with the Kasai portoenterostomy, significant fibrosis and cirrhosis develop early in life. An increased understanding of what causes this inflammatory fibrosing cholangiopathy will lead to therapies aimed at protecting the intrahepatic biliary system from immune-mediated damage. This review focuses on studies pertaining to the role of the adaptive immune response in bile duct injury in BA, including cellular and humoral immunity. The neonatal presentation of BA prompts the question of what potential modifications of unique aspects of the neonatal immune system set the stage for the progressive biliary disease. This review also discusses the characteristics of neonatal immune response and the theories on how alterations of this response could contribute to the pathogenesis of BA. These include aberrant type 1 helper T-cell (TH1) and TH17 responses, deficiencies in regulatory T cells, activation of humoral immunity, and autoimmunity. To advance our understanding of the etiology of BA, future studies should focus on the unique aspects of the neonatal immune system that have gone awry. Keywords: Cholestasis, Adaptive Immunity, Neonatal Autoimmunity