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Summary: The factors responsible for the spectrum of coronavirus 19 (COVID‐19) disease severity and the genesis and nature of protective immunity against COVID‐19 remain elusive. Multiple studies have investigated the immune responses to COVID‐19 in various populations, including those without evidence of COVID‐19 infection. Information regarding innate and adaptive immune responses to the novel severe respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has evolved rapidly. Data are accumulating defining disease phenotypes that aid in rational and informed development of new therapeutic approaches for the treatment of patients infected with SARS‐CoV‐2 and the development of novel vaccines. In this paper, data on important innate immune responses are summarized, including cytokines, specifically interleukin (IL)‐6 and complement, and potential treatments are explored. Adaptive immune responses and derivative therapeutics such as monoclonal antibodies directed at spike proteins are also examined. Finally, data on real‐time assessments of adaptive immune responses are explored, which include CD4+/CD8+ T cells, natural killer (NK) T cells, memory B cells and T follicular cells with specificities for COVID‐19 peptides in infected and normal individuals. Data of two novel vaccines have been released, both showing > 95% efficacy in preventing SARS‐CoV‐2 infection. Analysis of humoral and cellular responses to the vaccines will determine the robustness and durability of protection. In addition, long‐term assessment of SARS‐CoV‐2 memory B and T cell‐mediated immune responses in patients recovering from an infection or those with cross‐reactive immunological memory will help to define risk for future SARS‐CoV infections. Finally, patients recovering from SARS‐CoV‐2 infection may experience prolonged immune activation probably due to T cell exhaustion. This will be an important new frontier for study. This review summarizes published data on the relevant innate and adaptive immune responses to SARS‐CoV‐2. Data characterizing innate and adaptive immune responses have rapidly led to informed therapeutic interventions, including vaccine development and recognition of dysfunctional immune responses that are likely responsible for post‐COVID‐19 autoimmunity. [ABSTRACT FROM AUTHOR]

Summary: The immune system plays a critical role in protecting the host against infection but is subject to numerous levels of control that are necessary to prevent pathological, tissue-damaging responses. Inappropriate inflammatory immune responses to self-antigens, innocuous commensal microorganisms, or environmental antigens can lead to chronic, debilitating, and degenerative diseases. Regulatory T cells have an essential, non-redundant, and dominant function in preventing pathological immune responses, as shown by the development of systemic fatal autoimmunity in humans and animals with a genetic deficiency in regulatory T cells. In addition to controlling immune responses, there is a growing understanding that regulatory T cells also contribute directly to tissue homeostasis by promoting tissue regeneration and repair. For these reasons, the prospect of enhancing regulatory T-cell numbers and/or function in patients represents an appealing therapeutic opportunity with potential applications in many diseases, including some where the pathological role of the immune system has only recently been recognized. Approaches to enhance regulatory T cells are now starting to be explored in clinical studies in humans. This review series brings together papers highlighting the Treg-enhancing approaches that are most advanced clinically and examples of therapeutic opportunities based on our growing understanding of regulatory T-cell functions. [ABSTRACT FROM AUTHOR]

Understanding the T-cell response to SARS-CoV-2 is key in patients who lack antibody production. We demonstrate the applicability of a functional assay to measure the T-cell response in a cohort of patients with immunodeficiency. T-cell responses to COVID are now linked to improved outcomes. This paper demonstrates a method to robustly test responses for routine diagnostic use in healthy controls and those unable to make a detectable antibody response due to underlying immune deficiency (primary or acquired). [ABSTRACT FROM AUTHOR]

Summary: Lung disease due to nontuberculous mycobacteria (NTM) occurs with disproportionate frequency in postmenopausal women with a unique phenotype and without clinically apparent predisposing factors. Dubbed 'Lady Windermere syndrome', the phenotype includes low body mass index (BMI), tall stature and higher than normal prevalence of scoliosis, pectus excavatum and mitral valve prolapse. Although the pathomechanism for susceptibility to NTM lung disease in these patients remains uncertain, it is likely to be multi‐factorial. A role for the immunomodulatory consequences of oestrogen deficiency and altered adipokine production has been postulated. Altered levels of adipokines and dehydroepiandrosterone have been demonstrated in patients with NTM lung disease. Case reports of NTM lung disease in patients with hypopituitarism support the possibility that altered endocrine function influences disease susceptibility. This paper catalogues the evidence for immunomodulatory consequences of predicted endocrine changes in Lady Windermere syndrome, with emphasis on the immune response to NTM. Collectively, the data warrant further exploration of an endocrine link to disease susceptibility in Lady Windermere syndrome. Lady Windermere syndrome is a phenotype of nontuberculous mycobacterial lung disease characterized by female sex, postmenopausal status and slender body habitus. This review article explores potential modulation of anti‐mycobacterial immunity by hormone changes as a mediator of disease susceptibility in this syndrome. [ABSTRACT FROM AUTHOR]

The article presents a notice of redundant publication on topics related to clinical and experimental immunology. The text and data of the paper "Peptide immunization in humans: a combined CD8+ T cell-targeted vaccine restimulates the memory CD4 T cell response but fails to induce cytoxic T lymphocytes (CTL)" is replicated without acknowledgement in the subsequent paper. The data indicate that the CTL peptide failed to stimulate a cytotoxic immune response.

In this paper we provide a detailed description of an experimental method for investigating the induction and resolution of recall immune response to antigen in humans in vivo. This involves the injection of tuberculin purified protein derivative ( PPD) into the skin, followed by inducing suction blisters at the site of injection, from which leucocytes and cytokines that are involved in the response can be isolated and characterized. Using this technique we found that although the majority of CD4+ T cells in the skin that are present early in the response express cutaneous lymphocyte antigen ( CLA), the expression of this marker is reduced significantly in later phases. This may enable these cells to leave the skin during immune resolution. Furthermore, interleukin ( IL)-2 production can be detected both in CD4+ T cells and also in the blister fluid at the peak of the response at day 7, indicating that mediators found in the blister fluid are representative of the cytokine microenvironment in vivo. Finally, we found that older humans have defective ability to respond to cutaneous PPD challenge, but this does not reflect a global immune deficit as they have similar numbers of circulating functional PPD-specific CD4+ T cells as young subjects. The use of the blister technology enables further characterization of the skin specific defect in older humans and also general mechanisms that govern immune regulation in vivo. [ABSTRACT FROM AUTHOR]

In Argentina, more than 3 million people suffer from asthma, with numbers rising. When asthma patients acquire viral infections which, in turn, trigger the asthmatic response, they may develop subsequent bacterial infections, mainly by Streptococcus (S.) pneumoniae. This encapsulated Gram+ bacterium has been considered historically a T cell-independent antigen. Nevertheless, several papers describe the role of T cells in the immune response to S. pneumoniae. We evaluated the response to S. pneumoniae and compared it to the response to Mycobacterium (M.) tuberculosis, a different type of bacterium that requires a T helper type 1 ( Th1) response, in cells from atopic asthmatic children, to compare parameters for the same individual under exacerbation and in a stable situation whenever possible. We studied asthma patients and a control group of age-matched children, evaluating cell populations, activation markers and cytokine production by flow cytometry, and cytokine concentration in serum and cell culture supernatants by enzyme-linked immunosorbent assay ( ELISA). No differences were observed in γδ T cells for the same patient in either situation, and a tendency to lower percentages of CD4+ CD25hi T cells was observed under stability. A significantly lower production of tumour necrosis factor ( TNF)-α and a significantly higher production of interleukin ( IL)-5 was observed in asthma patients compared to healthy individuals, but no differences could be observed for IL-4, IL-13 or IL-10. A greater early activation response against M. tuberculosis, compared to S. pneumoniae, was observed in the asthmatic patients' cells. This may contribute to explaining why these patients frequently acquire infections caused by the latter bacterium and not the former. [ABSTRACT FROM AUTHOR]

Summary: The Forkhead Box P3 (FOXP3) protein is an essential transcription factor for the development and function of regulatory T cells (Tregs), involved in the maintenance of immunological tolerance. Although extensive research over the last decade has investigated the critical role of FOXP3+ cells in preserving immune homeostasis, our understanding of their specific functions remains limited. Therefore, unveiling the molecular mechanisms underpinning the up- and downstream transcriptional regulation of and by FOXP3 is crucial for developing Treg-targeted therapeutics. Dysfunctions in FOXP3+ Tregs have also been found to be inherent drivers of autoimmune disorders and have been shown to exhibit multifaceted functions in the context of cancer. Recent research suggests that these cells may also be involved in tissue-specific repair and regeneration. Herein, we summarize current understanding of the thymic-transcriptional regulatory landscape of FOXP3+ Tregs, their epigenetic modulators, and associated signaling pathways. Finally, we highlight the contributions of FOXP3 on the functional development of Tregs and reflect on the clinical implications in the context of pathological and physiological immune responses. A subset of CD4+ T cells, recognized as FOXP3+ regulatory T (Treg) cells, are involved in preserving immune tolerance. Defects in these cells drive the pathogenesis of autoimmune diseases. In this review, we discuss the functions and dysfunctions in the developmental pathways of FOXP3+ Tregs, their emerging roles, and explore potential therapeutic targets. [ABSTRACT FROM AUTHOR]

The responses of thymocytes to Coneanavalin A (Con A), and interleukin 1 (IL-1), interleukin 2 (IL-2) and phorbol myristate acetate (PMA) were investigated. The enzyme 20-a-hydroxysteroid dehydrogenase (20αSDH) was used as a marker to distinguish between various populations of activated thymocytes. Thymocytes that were selected in Con A + pure or crude IL-2 expressed high 20αSDH activity, while those that were selected in Con A + recombinant IL-1 (rIL-1) or crude IL-1, or Con A + PMA expressed low 20αSDH activity. Both groups proliferate in response to Con A and had IL-2 receptors. After selection, the enzymatic phenotype was stable even if the cells were transferred from Con A + IL-2 to Con A + PMA (or IL-1) or vice versa. A third group was selected from thymocytes that were cultured in PMA + T cell growth factor (TCGF). This group expressed low levels of 20αSDH, had IL-2 receptors, but did not respond to Con A. This paper demonstrates that 20αSDH can be used as an enzymatic marker to distinguish between subpopulations of activated T cells, which have not been previously detected by the conventional surface markers. [ABSTRACT FROM AUTHOR]

This paper describes the effects of a single dose of cyclophosphamide on specific IgG production in rats during an established secondary immune response. (PVG × Agus)F1 rats were immunized twice (days 0 and 28) with chicken erythrocytes (CRBC), received cyclophosphamide (100 mg/m² of body surface area) on day 33 and were killed 8 days later. The production of anti-CRBC IgG antibodies was assessed by testing the supernatants of spleen cell cultures in a cytotoxicity assay with 51Cr-labelled CRBC as target cells and normal rat spleen cells as effector cells. In observations of fifty-nine pairs of treated and untreated rats from eight separate experiments, the administration of cyclophospharnide resulted in: (1) a decrease in the number of spleen cell to a median of 108.63 from a median of 108.7 (P < 0.0025); (2) an increase in the anti-CRBC IgG antibody titre of the supernatants of cultured spleen cells to a median of 100.67 from a median of 100.27 (P < 0.0025); and (3) the calculated anti-CRBC IgG antibody production per spleen to be increased in the drug-treated rats to a median of 102.26 from a median of 102.0 (P < 0.005). In a cyclophosphamide dose-response study, it was shown that some enhancement of antibody production was induced by doses between 12.5 and 50 mg/m² and consistently elevated levels of antibody production were associated with doses between 100 and 400 mg/m². [ABSTRACT FROM AUTHOR]

Using in vivo assays for alloreactivity, the responsiveness of maternal lymph node cells was shown to be increased when cells were harvested from both syngeneically and allogeneically pregnant mice. In addition, foetal liver and thymus cells induced a state of delayed type hypersensitivity to alloantigens whereas trophoblastic tissue, in the form of 12 to 15 day metrial glands, did not. The influence of mouse placenta on in vitro immune responses was tested using 7-day ectoplacental cones as sources of trophoblastic tissue. Ectoplacental cones increased a T cell dependent but not a T cell independent antibody response, whereas T cell dependent cytotoxicity was reduced. The findings reported in this paper suggest that murine ectoplacental cones are a particularly useful tissue with which to study both specific and non-specific immunological activities of the trophoblast in syngeneic and allogeneic pregnancies. [ABSTRACT FROM AUTHOR]

This paper describes the course of infection and certain pathological changes in thymus-deprived and normal CBA mice after oral infection with Trichinella spiralis. Greater morbidity was found among deprived mice and deaths due to trichiniasis occurred solely in this group. The local inflammatory response in the gut and skeletal muscles was defective in deprived animals: compared to normal mice it was slower to develop, contained fewer cells and was inadequately sustained. There was a striking paucity of tissue eosinophils and this was correlated with failure of deprived mice to develop a blood eosinophilia. The parasites appeared to persist longer in the gut of deprived animals and progressively more parasites were recovered from the carcasses of these mice at later stages of the infection. The present findings indicate that thymus-dependent cell populations are implicated in the host response to T. spiralis; and some possible modes of action of T cells are discussed. [ABSTRACT FROM AUTHOR]

Summary: The actions of the immune system are finely tuned, involving complex communication and coordination between diverse immune and non-immune cells across the tissues of the body. A healthy immune system requires a precise balance between immunity and tolerance. Regulatory T cells (Tregs) have long been appreciated as one of the master regulators of this balance; their importance is underscored by the autoimmunity that develops in mice and humans when Tregs are missing or dysfunctional. In addition to the immunoregulatory roles of Tregs in suppressing autoimmunity and inflammation via control of adaptive and innate immune responses, several non-immune modulatory functions of Tregs have been identified in recent years. In this review, we have highlighted the growing literature on the action of Tregs in metabolism, stem cell maintenance, tissue repair, and angiogenesis. Alongside Tregs' immune suppressive role, these non-suppressive activities comprise a key function of Tregs in regulating health and disease. As Tregs receive increasing attention as therapeutic targets, understanding their non-canonical functions may become an important feature of Treg-directed interventions. Diverse functions of Tregs beyond immune suppression. As detailed in the canonical suppression box, Tregs use several mechanisms to dampen proliferation and function of effector T cells and other immune cells. Tregs also have myriad effects on tissue repair, angiogenesis, basal metabolism, and maintenance of the stem cell niche. [ABSTRACT FROM AUTHOR]

Summary: Obesity increases the risk of type 2 diabetes mellitus, cardiovascular disease, fatty liver disease, and cancer. It is also linked with more severe complications from infections, including COVID-19, and poor vaccine responses. Chronic, low-grade inflammation and associated immune perturbations play an important role in determining morbidity in people living with obesity. The contribution of B cells to immune dysregulation and meta-inflammation associated with obesity has been documented by studies over the past decade. With a focus on human studies, here we consolidate the observations demonstrating that there is altered B cell subset composition, differentiation, and function both systemically and in the adipose tissue of individuals living with obesity. Finally, we discuss the potential factors that drive B cell dysfunction in obesity and propose a model by which altered B cell subset composition in obesity underlies dysfunctional B cell responses to novel pathogens. Obesity—a major risk factor for multiple disorders, including cardiovascular disease and cancer—has tripled globally in less than 50 years and is associated with a chronic inflammatory response. B cells play a central role in driving obesity-associated meta-inflammation, and here we provide a consolidated summary of human B cell dysregulation and the molecular switches potentially driving this B cell dysregulation. A new frontier within the obesity research field, highlighted by the COVID-19 pandemic, is that obesity impacts the ability to respond to and clear infections and we propose a model by which obesity establishes a new "set-point" in the B cell compartment which contributes to this. [ABSTRACT FROM AUTHOR]

B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. Indeed, similarly to T cells, there is significant heterogeneity in cytokine-driven responses by B cells, ranging from the production of pro-inflammatory effector cytokines such as IL-6, through to the release of immunosuppressive cytokines such as IL-10. In this review, focusing on human B cells, we summarize the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases. B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. In this review, focusing on human B cells, we summarise the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases. [ABSTRACT FROM AUTHOR]

To characterize the IgG and IgA responses to different SARS-CoV-2 proteins, we investigated the antibody responses to SARS-CoV-2 following natural infection and following a single dose of AZD1222 (Covishield), in Sri Lankan individuals. The IgG and IgA responses were assessed to S1, S2, RBD, and N proteins in patients at 4 weeks and 12 weeks since the onset of illness or following vaccination. Antibodies to the receptor-binding domain of SARS-CoV-2 wild type (WT), α, β, and λ and ACE2 (Angiotensin Converting Enzyme 2) receptor blocking antibodies were also assessed in these cohorts. For those with mild illness and in vaccines, the IgG responses to S1, S2, RBD, and N protein increased from 4 weeks to 12 weeks, while it remained unchanged in those with moderate/severe illness. In the vaccines, IgG antibodies to the S2 subunit had the highest significant rise (P < 0.0001). Vaccines had several-fold lower IgA antibodies to all the SARS-CoV-2 proteins tested than those with natural infection. At 12 weeks, the haemagglutination test (HAT) titres were significantly lower to the α in vaccines and significantly lower in those with mild illness and in vaccines to β and for λ. No such difference was seen in those with moderate/severe illness. Vaccines had significantly less IgA to SARS-CoV-2, but comparable IgG responses those with natural infection. However, following a single dose vaccines had reduced antibody levels to the VOCs, which further declined with time, suggesting the need to reduce the gap between the two doses, in countries experiencing outbreaks due to VOCs. Those with mild infection, vaccinees (AZD1222) and unexposed individuals had similar antibody levels to S2. Those with mild infection had highest antibody responses to S2, while hose with moderate/severe illness had highest responses to the receptor binding domain. Vaccinees had several fold lower IgA antibodies to all the SARS-CoV-2 proteins tested than those with natural infection. [ABSTRACT FROM AUTHOR]

Female genital tract chronic inflammation is common in clinics; the pathogenesis is not fully understood yet. House dust mite (HDM) involves the pathogenesis of many chronic diseases in human. This study aims to identify HDM-specific allergic response in the cervix of patients with cervical inflammation. Patients (n = 80) with chronic cervicitis (CC) and non-CC control (NC) subjects (n = 80) were recruited into this study. Vaginal lavage fluids (VLF) were collected from CC patients and NC subjects. Cellular components and fluid part of VLF were separated by centrifugation, and analyzed by flow cytometry and enzyme-linked immunosorbent assay. We found that a portion (52 out of 80) of CC patients responded to HDM, manifesting positive skin prick test, and HDM-specific IgE and IgG was detected in the VLF (designated CCp patients). VLF of CCp patients showed a Th2-dominant profile. HDM-specific Th2 cells were detected in VLF in CCp patients. Exposure to HDM in the culture induced proinflammatory cytokine release from CCp VLF CD4+ T cells. Exposure to CCp VLF CD4+ T cell-conditioned medium induced de novo Th2 response. Direct exposure to HDM induced allergic response in the cervix of CCp patients. In summary, a portion of CC patients respond to HDM challenge in the cervix. Exposure to HDM induces an allergy-like response in the cervix of CCp patients. We found that 52 out of 80 patients with chronic cervicitis showed allergic response to house dust mite. House dust mite-specific Th2 cells were detected in vagina lavage fluid. Direct exposure to house dust mite antigens induced allergic response in the cervix of patients with chronic cervicitis. [ABSTRACT FROM AUTHOR]

For treatment of several malignancies, transplantation of allogeneic haematopoietic stem cells (HSCT) derived from bone marrow or peripheral blood has been used as a therapeutic procedure for decades. In the past, HSCT has been suggested as a treatment option for infection with the human immunodeficiency virus type 1 (HIV-1), but these attempts were mostly unsuccessful. Today, after the introduction of an active anti-retroviral therapy, the lifetime expectancy of HIV-infected patients has improved substantially, but nevertheless the incidence rate of malignancies in these patients has increased considerably. Therefore, it can be assumed that there will be a rising necessity for HIV-1-infected patients with malignancies for allogeneic HSCT. At the same time, there is increasing interest in treatment methods which might target the HIV-1 reservoir more effectively, and the question has been raised as to whether allogeneic HSCT could be linked to such strategies. In this paper the data of more than 25 years experience with allogeneic HSCT in patients with HIV-1 are reviewed and analysed. [ABSTRACT FROM AUTHOR]

T cell lines with defined cytokine profiles are an invaluable tool for assessing the control of immune responses both in vitro and in vivo. Production of such cell lines can be complex and time-consuming. Here we present a powerful technique to assay the cytokines produced by T cells activated polyclonally or with specific antigens. This paper presents a detailed methodology for the identification and isolation of cytokine-producing T cells activated with the artificial superantigen, CytoStim, or viral and fungal antigens. These cells can be analysed for different cytokines simultaneously, or cultured further to rapidly establish T cell lines making known cytokine types. We highlight the enumeration, isolation and phenotype of interleukin-17-producing T cells, and the rapid generation of virus-specific Th1 T cell lines. [ABSTRACT FROM AUTHOR]

Gut inflammation is characterized by mucosal recruitment of activated cells from both the innate and adaptive immune systems. In addition to immune cells, inflammation in the gut is associated with an alteration in enteric endocrine cells and various biologically active compounds produced by these cells. Although the change in enteric endocrine cells or their products is considered to be important in regulating gut physiology (motility and secretion), it is not clear whether the change plays any role in immune activation and in the regulation of gut inflammation. Due to the strategic location of enteric endocrine cells in gut mucosa, these gut hormones may play an important role in immune activation and promotion of inflammation in the gut. This review addresses the research on the interface between immune and endocrine systems in gastrointestinal (GI) pathophysiology, specifically in the context of two major products of enteric endocrine systems, namely serotonin (5-hydroxytryptamine: 5-HT) and chromogranins (Cgs), in relation to immune activation and generation of inflammation. The studies reviewed in this paper demonstrate that 5-HT activates the immune cells to produce proinflammatory mediators and by manipulating the 5-HT system it is possible to modulate gut inflammation. In the case of Cgs the scenario is more complex, as this hormone has been shown to play both proinflammatory and anti-inflammatory functions. It is also possible that interaction between 5-HT and Cgs may play a role in the modulation of immune and inflammatory responses. In addition to enhancing our understanding of immunoendocrine interaction in the gut, the data generated from the these studies may have implications in understanding the role of gut hormone in the pathogenesis of both GI and non-GI inflammatory diseases which may lead ultimately to improved therapeutic strategies in inflammatory disorders. [ABSTRACT FROM AUTHOR]

Immunobiot assays showed that mycobacierial fibronectin-binding antigens are important targets of the humoral immune response in tuberculosis and leprosy. Using culture filtrate antigens of Mycobaeterium tuberculosis, strong reactivity with the fibronectin-binding of 30-31 kD (Fn 30-31) was demonstrated in 55.9% of tuberculosis sera and in 56.5% of lepromatous leprosy sera. Sera from patients with tuberculoid leprosy and control sera gave very weak binding. Reactivity of tuberculosis and lepromatous leprosy sera with the fibronectin-binding antigen of 58-60 kD (Fn 58-60) was less conspicuous. The ability to react with fibronectin of the antigens of 58-60 and 30-31 kD was demonstrated by parallel labelling with a fibronectin biotin conjugate. Fn 30-31 was purified to homogeneity by a two-step procedure and used for ELISA. Positive titres were found in 63% out of 65 tuberculosis sera and in 60.5% out of 43 lepromatous leprosy sera. Antibody titres in lepromatous leprosy sera were higher than in tuberculosis sera. Our observations indicate indirectly that M. leprae possess a highly immunogenic molecule homologous to M. tuberculosis Fn 30-31, which elicits a high antibody response in lepromatous leprosy but not in tubereuloid leprosy. In this investigation, direct evidence for the presence of this antigen in M. leprae was obtained by immunochemistry of lepromatous leprosy lesions with a monospecific antibody raised against M. tuberculosis Fn 30-31. [ABSTRACT FROM AUTHOR]

Clinical symptoms of immediate-type hypersensitivity (ITH) and specific IgE against Echinococcus granulosus antigens are frequently present in patients with hydatid cysts. In alveolar echinococcosis (AE) due to E. multilocularis, clinical manifestations related to ITH have never been reported. The IgE-dependent humoral immune response was evaluated in 30 patients with AE. Circulating specific IgE (sIgE) were determined with two different methods of radio-allergo-sorbent test. Scrum sIgE were determined sequentially in 18 patients over 15 months. Specific IgE bound to circulating basophils were assessed with two tests in vitro, measuring specific degranulation and histamine release. The respective abilities of E. granulosus and E. multilocularis antigens to reveal bound and circulating IgE antibodies were also assayed. Despite the absence of clinical symptoms of ITH and the frequent lack of circulating sIgE, an immunological response involving IgE was always present in human AE: basophil-bound sIgE were revealed in every patient by histamine release and degranulation tests: these tests were constantly negative in control subjects. Echinococcus granulosus extracts were more effective for detecting circulating sIgE; however E. multilocularis antigenic preparation induced a histamine release significantly higher than E. granulosus extracts. These results suggest that IgE-dependent humoral immune response could play a role in the host-parasite relationship in AE. Moreover, the sensitivity of the tests used to detect basophil-bound sIgE was higher than that of the usual serological tests, and the basophil degranulation test could be used to confirm diagnosis of AE in endemic countries. [ABSTRACT FROM AUTHOR]

The development of the cell-mediated immune response (CMIR) to antigens prepared from Salmonella typhi was investigated in patients suffering from typhoid fever and in normal healthy subjects. The leucocyte migration inhibition test, blast transformation of lymphocytes and active rosette-forming cells were used for detecting CMIR. Peripheral blood lymphocytes were analysed for the numbers and proportions of B lymphocytes, T lymphocytes and their subpopulations with receptors for IgM (Tμ) or IgG (Tγ) and cells with Fc receptors for IgG. These parameters were correlated with the duration and the severity of illness. The uncomplicated cases of typhoid fever were found to have an intact CMIR as compared to the complicated cases. The ratio of T lymphocyte subpopulations was grossly imbalanced in typhoid patients, the numbers of T lymphocytes and their subpopulations were further altered in the complicated cases as compared to uncomplicated cases. The present study demonstrates a depressed state of CMIR in complicated patients with typhoid fever. CMIR may thus emerge as the cardinal point for recovery in typhoid fever rather than the specific antibodies. The study further demonstrates that imbalance within the subsets of T lymphocytes may be responsible for the depressed state of CMIR in complicated cases of typhoid fever. [ABSTRACT FROM AUTHOR]

The article reports on the effects of the physical state of the antigen and of lymphoreticular cell proliferation on the response to intraperitoneal injection of bovine serum albumin in rabbits. A study was conducted to determine whether the time relationships of Corynebacterium parvum administration and antigen injection are important in particular to show whether it would produce same adjuvant effects as Corynebacterium parvum injected 6 days prior to the injection of the antigen. The result of the study reveals that higher affinity antibody especially if the quantity of antigen available causes specific lymphoid proliferation.

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

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

Summary: Mental illness exerts a major burden on human health, yet evidence‐based treatments are rudimentary due to a limited understanding of the underlying pathologies. Clinical studies point to roles for the immune system in psychiatric diseases, while basic science has revealed that the brain has an active and multi‐cellular resident immune system that interacts with peripheral immunity and impacts behavior. In this perspective, we highlight evidence of immune involvement in human psychiatric disease and review data from animal models that link immune signaling to neuronal function and behavior. We propose a conceptual framework for linking advances in basic neuroimmunology to their potential relevance for psychiatric diseases, based on the subtypes of immune responses defined in peripheral tissues. Our goal is to identify novel areas of focus for future basic and translational studies that may reveal the potential of the immune system for diagnosing and treating mental illnesses [ABSTRACT FROM AUTHOR]

Summary: Immunotherapies based on anti‐programmed death 1/programmed death ligand 1 (PD‐1/PD‐L1) pathway inhibitors may turn out effective in ovarian cancer (OC) treatment. They can be used in combination with standard therapy and are especially promising in recurrent and platinum‐resistant OC. There is growing evidence that the mechanism of the PD‐1/PD‐L1 pathway can be specific for a particular histological cancer type. Interestingly, the data have shown that the PD‐1/PD‐L1 pathway blockade may be effective, especially in the endometrioid type of OC. It is important to identify the cause of anti‐tumor immune response suppression and exclude its other mechanisms in OC patients. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival. The PD‐1/PD‐L pathway is a negative regulator of effector T cells. There is growing evidence that immunotherapies based on anti‐PD‐1/PD‐L1 mAbs can be effective in many cancer types, including OC. It is also necessary to conduct subsequent studies to confirm in which OC cases the treatment is effective and how to select patients and combine drugs to improve patient survival. [ABSTRACT FROM AUTHOR]

Summary: Meningococcal polysaccharide (Men‐Ps) vaccine immunogenicity following either primary immunization or revaccination in adults was evaluated. The study population consisted of subjects who have received tetravalent Men‐Ps vaccine once (group 1) or at least twice, with a 2–6 dose range (group 2). Human leucocyte antigen (HLA)‐typing was performed by polymerase chain reaction and specific immunoglobulin (Ig)G was measured by enzyme‐linked immunosorbent assay. Nine months post‐immunization, the percentages of individuals with levels of anti‐Men‐Ps IgG ≥ 2 µg/ml were comparable in both groups, with the exception of anti‐Men‐PsW135 IgG, which were significantly higher in group 2. The percentage of subjects doubling IgG levels at 9 months was significantly higher in group 1. The high baseline anti‐Men‐Ps antibody levels negatively influenced the response to revaccination, suggesting a feedback control of specific IgG. The calculated durability of anti‐Men‐Ps IgG was 2·5–4·5 years, depending on the Men‐Ps, following a single vaccine dose. No interference by other vaccinations nor HLA alleles association with immune response were observed. This study confirms that Men‐Ps vaccine in adults is immunogenic, even when administered repeatedly, and underlines the vaccine suitability for large‐scale adult immunization programmes that the higher costs of conjugate vaccines may limit in developing countries. Meningococcal polysaccharide (Men‐Ps) vaccine immunogenicity following either primary immunization or revaccination was evaluated in adult subjects who have received tetravalent Men‐Ps vaccine once (group 1) or at least twice, with a 2–6 dose range (group 2). Nine months post‐immunization, the percentages of individuals with levels of anti‐Men‐Ps immunoglobulin (Ig)G ≥ 2 µg/ml were comparable in both groups, with the exception of anti‐Men‐PsW135 IgG, which were significantly higher in individuals receiving booster doses. This study confirms that Men‐Ps vaccine in adults is immunogenic, even when repeatedly administered, and underlines the vaccine suitability for large‐scale adult immunization programmes that the higher costs of conjugate vaccines may limit in developing countries. [ABSTRACT FROM AUTHOR]

Summary: Programmed death‐1 (PD‐1) and interactions with PD‐ligand 1 (PD‐L1) play critical roles in the tumour evasion of immune responses through different mechanisms, including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumour‐infiltrating T cells and regulatory T cell (Treg) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti‐PD‐1 antibody, pembrolizumab, on various Treg subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD‐1 expression in both cohorts. We found that PD‐1 was expressed mainly on CD4+CD25+ T cells and pembrolizumab had a greater effect on PD‐1 expression in CD4+CD25− T cells, compared to CD4+CD25+ cells. In addition, pembrolizumab did not affect the expression levels of Treg‐related markers, including cytotoxic T lymphocyte antigen‐4 (CTLA‐4), CD15s, latency‐associated peptide (LAP) and Ki‐67. Moreover, we report that CD15s is expressed mainly on forkhead box P3 (FoxP3)−Helios+ Treg in HD, but it is expressed on FoxP3+Helios− Treg subset in addition to FoxP3−Helios+ Treg in PBC. Pembrolizumab did not affect the levels of FoxP3+/−Helios+/− Treg subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect Treg or change their phenotype or function but rather blocks signalling via the PD‐1/PD‐L1 axis in activated T cells. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) control immune responses by suppressing various inflammatory cells. Tregs in newborn babies may play an important role in preventing excessive immune responses during their environmental change. We examined the number and phenotype of Tregs during the neonatal period in 49 newborn babies. Tregs were characterized by flow cytometry using cord blood (CB) and peripheral blood (PB) from the early (7-8 days after birth) and late (2-4 weeks after birth) neonatal periods. CD4+forkhead box protein 3 (FoxP3+) T cells were classified into resting Tregs (CD45RA+FoxP3low), activated Tregs (CD45RA- FoxP3high) and newly activated T cells (CD45RA- FoxP3low). Compared with CB and PB during the late neonatal period, the percentage of Tregs and all Treg subpopulations in the CD4+ lymphocyte population were increased significantly during the early neonatal period. Furthermore, the proportion and absolute number of activated Tregs were increased markedly compared with other Treg subpopulations, such as resting Tregs and newly activated T cells (non-Tregs), in the early neonatal period. Increased Tregs concomitantly expressed the suppressive molecule cytotoxic T lymphocyte antigen-4 (CTLA-4). The up-regulated expression of chemokine receptor 4 (CCR4) and down-regulated expression of CCR7 were also observed in expanded Tregs. When cord blood cells were cultured in vitro with CD3 monoclonal antibodies (mAb) for 5 days, CD4+CD45RA-FoxP3high cells were increased significantly during the culture. Thus, the presence of increased activated Tregs in early neonates may play an important role in immunological regulation by suppressing excessive T cell activation caused by the immediate exposure to ubiquitous antigens after birth. [ABSTRACT FROM AUTHOR]

The pathogenesis of sepsis involves a dual inflammatory response, with a hyperinflammatory phase followed by, or in combination with, a hypoinflammatory phase. The adhesion molecules lymphocyte function-associated antigen (LFA-1) (CD11a/CD18) and macrophage-1 (Mac-1) (CD11b/CD18) support leucocyte adhesion to intercellular adhesion molecules and phagocytosis through complement opsonization, both processes relevant to the immune response during sepsis. Here, we investigate the role of soluble (s)CD18 in sepsis with emphasis on sCD18 as a mechanistic biomarker of immune reactions and outcome of sepsis. sCD18 levels were measured in 15 septic and 15 critically ill non-septic patients. Fifteen healthy volunteers served as controls. CD18 shedding from human mononuclear cells was increased in vitro by several proinflammatory mediators relevant in sepsis. sCD18 inhibited cell adhesion to the complement fragment iC3b, which is a ligand for CD11b/CD18, also known as Mac-1 or complement receptor 3. Serum sCD18 levels in sepsis non-survivors displayed two distinct peaks permitting a partitioning into two groups, namely sCD18 'high' and sCD18 'low', with median levels of sCD18 at 2158 mU/ml [interquartile range (IQR) 2093-2811 mU/ml] and 488 mU/ml (IQR 360-617 mU/ml), respectively, at the day of intensive care unit admission. Serum sCD18 levels partitioned sepsis non-survivors into one group of 'high' sCD18 and low CRP and another group with 'low' sCD18 and high C-reactive protein. Together with the mechanistic data generated in vitro, we suggest the partitioning in sCD18 to reflect a compensatory anti-inflammatory response syndrome and hyperinflammation, respectively, manifested as part of sepsis. [ABSTRACT FROM AUTHOR]

Persistent inflammatory response in cystic fibrosis (CF) airways is believed to play a central role in the progression of lung damage. Anti-inflammatory treatment may slow lung disease progression, but adverse side effects have limited its use. Vitamin D has immunoregulatory properties. We randomized 16 CF patients to receive vitamin D2, vitamin D3 or to serve as controls, and investigated the effect of vitamin D supplementation on soluble immunological parameters, myeloid dendritic cells (mDCs) and T cell activation. Three months of vitamin D treatment were followed by two washout months. Vitamin D status at baseline was correlated negatively with haptoglobin, erythrocyte sedimentation rate and immunoglobulin A concentration. Total vitamin D dose per kg bodyweight correlated with the down-modulation of the co-stimulatory receptor CD86 on mDCs. Vitamin D treatment was associated with reduced CD279 (PD-1) expression on CD4+ and CD8+ T cells, as well as decreased frequency of CD8+ T cells co-expressing the activation markers CD38 and human leucocyte antigen D-related (HLA-DR) in a dose-dependent manner. There was a trend towards decreased mucosal-associated invariant T cells (MAIT) cell frequency in patients receiving vitamin D and free serum 25-hydroxyvitamin D (free-s25OHD) correlated positively with CD38 expression by these cells. At the end of intervention, the change in free-s25OHD was correlated negatively with the change in CD279 (PD-1) expression on MAIT cells. Collectively, these data indicate that vitamin D has robust pleiotropic immunomodulatory effects in CF. Larger studies are needed to explore the immunomodulatory treatment potential of vitamin D in CF in more detail. [ABSTRACT FROM AUTHOR]

The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the adaptive immune response. Besides a role in inflammation, complement is also involved in physiological processes such as waste disposal and developmental programmes. The complement system comprises several soluble and membrane-bound proteins. The bulk of the soluble proteins is produced mainly by the liver. While several complement proteins are produced by a wide variety of cell types, other complement proteins are produced by only a few related cell types. As these data suggest that local production by specific cell types may have specific functions, more detailed studies have been employed recently analysing the local and even intracellular role of these complement proteins. Here we review the current knowledge about extrahepatic production and/or secretion of complement components. More specifically, we address what is known about complement synthesis by cells of the human immune system. [ABSTRACT FROM AUTHOR]

CD4+ T helper cells are a valuable component of the immune response towards cancer. Unfortunately, natural tumour-specific CD4+ T cells occur in low frequency, express relatively low-affinity T cell receptors (TCRs) and show poor reactivity towards cognate antigen. In addition, the lack of human leucocyte antigen (HLA) class II expression on most cancers dictates that these cells are often unable to respond to tumour cells directly. These deficiencies can be overcome by transducing primary CD4+ T cells with tumour-specific HLA class I-restricted TCRs prior to adoptive transfer. The lack of help from the co-receptor CD8 glycoprotein in CD4+ cells might result in these cells requiring a different optimal TCR binding affinity. Here we compared primary CD4+ and CD8+ T cells expressing wild-type and a range of affinity-enhanced TCRs specific for the HLA A*0201-restricted NY-ESO-1- and gp100 tumour antigens. Our major findings are: (i) redirected primary CD4+ T cells expressing TCRs of sufficiently high affinity exhibit a wide range of effector functions, including cytotoxicity, in response to cognate peptide; and (ii) optimal TCR binding affinity is higher in CD4+ T cells than CD8+ T cells. These results indicate that the CD4+ T cell component of current adoptive therapies using TCRs optimized for CD8+ T cells is below par and that there is room for substantial improvement. [ABSTRACT FROM AUTHOR]

West Nile virus (WNV) is the most important causative agent of viral encephalitis worldwide and an important public health concern in the United States due to its high prevalence, severe disease, and the absence of effective treatments. Infection with WNV is mainly asymptomatic, but some individuals develop severe, possibly fatal, neurological disease. Individual host factors play a role in susceptibility to WNV infection, including genetic polymorphisms in key anti-viral immune genes, but age is the most well-defined risk factor for susceptibility to severe disease. Ageing is associated with distinct changes in immune cells and a decline in immune function leading to increased susceptibility to infection and reduced responses to vaccination. WNV is detected by pathogen recognition receptors including Toll-like receptors (TLRs), which show reduced expression and function in ageing. Neutrophils, monocyte/macrophages and dendritic cells, which first recognize and respond to infection, show age-related impairment of many functions relevant to anti-viral responses. Natural killer cells control many viral infections and show age-related changes in phenotype and functional responses. A role for the regulatory receptors Mertk and Axl in blood-brain barrier permeability and in facilitating viral uptake through phospholipid binding may be relevant for susceptibility to WNV, and age-related up-regulation of Axl has been noted previously in human dendritic cells. Understanding the specific immune parameters and mechanisms that influence susceptibility to symptomatic WNV may lead to a better understanding of increased susceptibility in elderly individuals and identify potential avenues for therapeutic approaches: an especially relevant goal, as the world's populating is ageing. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) constitute a fascinating subpopulation of CD4+ T cells due to their ability to limit the immune response against self and non-self antigens. Murine models and antibodies directed against surface and intracellular molecules have allowed elucidation of the mechanisms that govern their development and function. However, these markers used to their classification lack of specificity, as they can be expressed by activated T cells. Similarly, there are slight differences between animal models, in steady state and pathological conditions, anatomical localization and strategy of analysis by flow cytometry. Here, we revised the most common markers utilized for Treg typification by flow cytometry such as CD25, forkhead box protein 3 (FoxP3) and CD127, along with our data obtained in different body compartments of humans, mice and rats. Furthermore, we revised and determined the expression of other molecules important for the phenotypical characterization of Treg cells. We draw attention to the drawbacks of those markers used in chronic states of inflammation. However, until a specific marker for the identification of Tregs is discovered, the best combination of markers will depend upon the tissue or the degree of inflammation from which Tregs derive. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4− HLA-DR4)+ woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3+ woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)−17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4+ twins, but not in the DR3+ RA. The collagen-specific activation of CD4+ T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4+ subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells. [ABSTRACT FROM AUTHOR]

Derailment of immune responses can lead to autoimmune type 1 diabetes, and this can be accelerated or even induced by local stress caused by inflammation or infection. Dendritic cells (DCs) shape both innate and adaptive immune responses. Here, we report on the responses of naturally occurring human myeloid BDCA1+ DCs towards differentially stressed pancreatic β cells. Our data show that BDCA1+ DCs in human pancreas-draining lymph node (pdLN) suspensions and blood-derived BDCA1+ DCs both effectively engulf β cells, thus mimicking physiological conditions. Upon uptake of enterovirus-infected, but not mock-infected cells, BDCA1+ DCs induced interferon (IFN)-α/β responses, co-stimulatory molecules and proinflammatory cytokines and chemokines. Notably, induction of stress in β cells by ultraviolet irradiation, culture in serum-free medium or cytokine-induced stress did not provoke strong DC activation, despite efficient phagocytosis. DC activation correlated with the amount of virus used to infect β cells and required RNA within virally infected cells. DCs encountering enterovirus-infected β cells, but not those incubated with mock-infected or stressed β cells, suppressed T helper type 2 (Th2) cytokines and variably induced IFN-γ in allogeneic mixed lymphocyte reaction (MLR). Thus, stressed β cells have little effect on human BDCA1+ DC activation and function, while enterovirus-infected β cells impact these cells significantly, which could help to explain their role in development of autoimmune diabetes in individuals at risk. [ABSTRACT FROM AUTHOR]

Neurocysticercosis is caused by the establishment of Taenia solium cysticerci in the central nervous system. It is considered that, during co-evolution, the parasite developed strategies to modulate the host's immune response. The action mechanisms of regulatory T cells in controlling the immune response in neurocysticercosis are studied in this work. Higher blood levels of regulatory T cells with CD4+CD45RO+forkhead box protein 3 (FoxP3)high and CD4+CD25highFoxP3+CD95high phenotype and of non-regulatory CD4+CD45RO+FoxP3med T cells were found in neurocysticercosis patients with respect to controls. Interestingly, regulatory T cells express higher levels of cytotoxic T lymphocyte antigen 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1) and glucocorticoid-induced tumour necrosis factor receptor (GITR), suggesting a cell-to-cell contact mechanism with dendritic cells. Furthermore, higher IL-10 and regulatory T cell type 1 (Tr1) levels were found in neurocysticercosis patients' peripheral blood, suggesting that the action mechanism of regulatory T cells involves the release of immunomodulatory cytokines. No evidence was found of the regulatory T cell role in inhibiting the proliferative response. Suppressive regulatory T cells from neurocysticercosis patients correlated negatively with late activated lymphocytes (CD4+CD38+). Our results suggest that, during neurocysticercosis, regulatory T cells could control the immune response, probably by a cell-to-cell contact with dendritic cells and interleukin (IL)-10 release by Tr1, to create an immunomodulatory environment that may favour the development of T. solium cysticerci and their permanence in the central nervous system. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) participate in the innate immune response and trigger the immune responses of the body. Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology, characterized by an excessive autoimmune response in the body affecting the connective tissues. The disease is possibly triggered by both environmental aetiological factors and pathological organic processes such as exposure to sunlight, chronic infectious processes and genetic factors. Conversely, periodontal disease is an infectious disease caused by microorganisms in the oral cavity, resulting in a chronic inflammatory process which continuously stimulates the immune response, thus causing damage to the periodontal tissues. The expression of both TLR-2 and TLR-4 receptors are increased in both SLE and periodontal disease. Periodontitis might trigger excessive activation of immune response occurring in SLE by maintaining a high expression of TLRs, leading in turn to the acceleration of the onset and progression of autoimmune reactions. In addition, periodontal treatment is able to reduce the expression of these receptors and therefore the symptoms of SLE. Here we discuss the possible interaction between SLE and periodontitis, and suggest further studies evaluating common features in both factors that could explored, due to morbidity and mortality of SLE and the high incidence of periodontal infections around the world. [ABSTRACT FROM AUTHOR]

Noroviruses (NoV) are the most common cause of epidemic gastroenteritis worldwide. The acute immune response to NoV in humans is poorly understood, hindering research on prevention and treatment. To elucidate the acute immune response and test for cytokine predictors of susceptibility to infection, serum samples from two human NoV challenge studies were tested for 16 cytokines. Subjects who became infected ( n = 26) were age-matched with subjects who remained uninfected following NoV challenge ( n = 26). Samples were tested from prechallenge and days 1-4 post-challenge. Cytokine responses were compared between infected and uninfected groups. Overall, infected individuals exhibited an elevation in T helper type 1 (Th1) and Th2 cytokines, as well as chemokines interleukin (IL)-8 and monocyte chemoattractant protein (MCP-1), compared to uninfected individuals (all P < 0·05). Most cytokines peaked on day 2 post-challenge in infected subjects, and tumour necrosis factor (TNF)-α, IL-8, and IL-10 remained elevated to day 3. The only cytokine elevated significantly among infected subjects to day 4 post-challenge was IL-10 ( P = 0·021). Prechallenge cytokine concentrations were not predictive of infection status post-challenge. There were no significant changes in serum cytokines among NoV-challenged subjects who remained uninfected. These results suggest that NoV infection elicits a Th1-type response, with some Th2 activation. Persistent elevation of IL-10 among infected subjects is consistent with activation of adaptive immune responses, such as B cell expansion, as well as down-regulation of Th1 cytokines. This study presents the first comprehensive description of the acute cytokine response to GI.1 NoV in humans. [ABSTRACT FROM AUTHOR]

Although it is widely believed that interleukin ( IL)-27 is anti-inflammatory, its role in controlling human immune responses is not fully established. In particular, its interactions with T helper type 17 ( Th)17 cytokines are unclear. Our aims were to establish the relationships between IL-27 and proinflammatory cytokines, including IL-17 A, in human sera and cultures of peripheral blood mononuclear cells. Plasma IL-27 levels in 879 healthy humans from 163 families varied widely, but with relatively low heritability (19%). Despite IL-27 including a subunit encoded by Epstein- Barr virus-induced gene 3 ( EBI3), there was no correlation of levels with serological evidence of infection with the virus. Although IL-27 has been reported to inhibit IL-17 A production, we demonstrated a strong positive correlation in sera, but lower correlations of IL-27 with other proinflammatory cytokines. We verified that IL-27 inhibited IL-17 A production by human peripheral blood T cells in vitro, but not that it stimulated IL-10 secretion. Importantly, addition of IL-17 A decreased IL-27 production by stimulated T cells but had the opposite effect on resting T cells. Together, these data suggest a model whereby IL-27 and IL-17 A exerts complex reciprocal effects to boost inflammatory responses, but restrain resting cells to prevent inappropriate activation. [ABSTRACT FROM AUTHOR]

Increasing evidence suggested that Toll-like receptors ( TLRs) were critically involved in immune responses of anti-neutrophil cytoplasmic antibody ( ANCA)-associated vasculitis ( AAV). The current study aimed to investigate the expression of TLR-2, TLR-4 and TLR-9 in kidneys of patients with ANCA-associated vasculitis. Renal biopsy specimens were collected from 24 patients with AAV. The expression of TLR-2, TLR-4 and TLR-9 in kidneys was detected by immunohistochemistry. Double immunofluorescence staining was performed to detect the expression of TLRs on various kinds of cells. In renal specimens, immunohistochemical examination revealed that expression of TLR-2 and TLR-4 could be detected in the glomeruli of AAV patients, while TLR-2 and TLR-4 were scarcely detected in the glomeruli of normal controls. Double immunofluorescence staining of TLR-2, TLR-4 and CD31 indicated that TLR-4 and TLR-2 were expressed on endothelial cells in the glomeruli. In the tubulointerstitial compartment, expression of TLR-2, TLR-4 and TLR-9 could be detected in both AAV patients and normal controls. The mean optical density of TLR-2 and TLR-4 in the tubulointerstitial compartment in AAV patients were significantly higher than that in normal controls. Among AAV patients, correlation analysis showed that the mean optical density of TLR-4 in the glomeruli correlated inversely with the initial serum creatinine, the proportion of total crescents and the proportion of cellular crescents in renal specimens ( r = −0·419, P = 0·041; r = −0·506, P = 0·012; r = −0·505, P = 0·012, respectively). The expression of TLR-2 and TLR-4 was dysregulated in kidneys of AAV patients. The expression of TLR-4 in glomeruli was associated with the severity of renal injury. [ABSTRACT FROM AUTHOR]

Aryl hydrocarbon receptor ( Ah R) is well known for mediating the toxic effects of dioxin-containing pollutants, but has also been shown to be involved in the natural regulation of the immune response. In this study, we investigated the effect of AhR activation by its endogenous ligands 6-formylindolo[3,2-b]carbazole ( FICZ) and 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester ( ITE) on the differentiation, maturation and function of monocyte-derived DCs in Behçet's disease ( BD) patients. In this study, we showed that Ah R activation by FICZ and ITE down-regulated the expression of co-stimulatory molecules including human leucocyte antigen D-related ( HLA-DR), CD80 and CD86, while it had no effect on the expression of CD83 and CD40 on DCs derived from BD patients and normal controls. Lipopolysaccharide ( LPS)-treated dendritic cells ( DCs) from active BD patients showed a higher level of interleukin ( IL)-1β, IL-6, IL-23 and tumour necrosis factor ( TNF)-α production. FICZ or ITE significantly inhibited the production of IL-1β, IL-6, IL-23 and TNF-α, but induced IL-10 production by DCs derived from active BD patients and normal controls. FICZ or ITE-treated DCs significantly inhibited the T helper type 17 ( Th17) and Th1 cell response. Activation of AhR either by FICZ or ITE inhibits DC differentiation, maturation and function. Further studies are needed to investigate whether manipulation of the AhR pathway may be used to treat BD or other autoimmune diseases. [ABSTRACT FROM AUTHOR]

An increased activation of interleukin ( IL)-17 A-producing immune cells is a well-established feature of Crohn's disease ( CD). Mechanisms that contribute to this aberrant immune activation are, however, less clear. Given that an enhanced induction of innate-immunity associated cytokines IL-6 and IL-23, which promote IL-17 immunity, is also clearly implicated in CD, we hypothesized that monocyte-derived dendritic cells (mo DCs) of CD patient origin would mount exaggerated IL-17 A responses in T cells. However, we found a significantly attenuated up-regulation of the IL-17 A response in allogeneic T helper memory cells in the presence of culture media from lipopolysaccharide ( LPS)-stimulated mo DCs of CD patients when compared with mo DCs of control subjects (median fold-increase in IL-17 A m RNA expression 1·09 versus 1·44, P = 0·038). This was accompanied by a lower expression of IL-1β and IL-6 transcripts in the LPS-treated mo DCs (median 9·55 versus 13·9 relative units, P = 0·042, and 2·66 versus 9·06 relative units, P = 0·049, respectively). In addition, the up-regulation of autophagy-related LC3 transcripts was decreased in mo DCs of CD patients (median fold-increase in m RNA expression 1·22 versus 1·52, P = 0·029). Our findings reveal similar immunological aberrancies in CD in the general population as reported in CD patients with mutated intracellular bacterial sensor NOD2, namely attenuated activation of innate cytokines and impaired autophagy, combined with a reduced capacity to up-regulate the T helper type 17 ( Th17) response. The results presented here emphasize a defective anti-microbial response in the pathogenesis of CD. The increased mucosal Th1 and Th17 responses, which may contribute to the pathogenesis, could be the consequences of primary defects in the innate immunity. [ABSTRACT FROM AUTHOR]

Few concepts in recent years have garnered more disease research attention than that of the intestinal (i.e. 'gut') microbiome. This emerging interest has included investigations of the microbiome's role in the pathogenesis of a variety of autoimmune disorders, including type 1 diabetes ( T1 D). Indeed, a growing number of recent studies of patients with T1 D or at varying levels of risk for this disease, as well as in animal models of the disorder, lend increasing support to the notion that alterations in the microbiome precede T1 D onset. Herein, we review these investigations, examining the mechanisms by which the microbiome may influence T1 D development and explore how multi-disciplinary analysis of the microbiome and the host immune response may provide novel biomarkers and therapeutic options for prevention of T1 D. [ABSTRACT FROM AUTHOR]

Cytomegalovirus ( CMV) usually causes lifelong asymptomatic infection, but over time can distort immune profiles. Recent reports describe selective expansion of Vδ2neg γδ T cells in healthy and immunocompromised CMV carriers. Having shown previously that virus-specific CD8+ and CD4+ T cell responses are increased significantly in elderly CMV carriers, probably driven by chronic stimulation, we hypothesized that Vδ2neg γδ T cells may also be expanded with age. Our results show that Vδ2neg γδ T cells are increased significantly in CMV-seropositive healthy individuals compared to CMV-seronegative controls in all age groups. The differences were most significant in older age groups ( P < 0·0001). Furthermore, while Vδ2neg γδ T- cells comprise both naive and memory cells in CMV-seronegative donors, highly differentiated effector memory cells are the dominant phenotype in CMV carriers, with naive cells reduced significantly in numbers in CMV-seropositive elderly. Although phenotypically resembling conventional CMV-specific T cells, Vδ2neg γδ T cells do not correlate with changes in magnitude of CMV-specific CD4+ or CD8+ T cell frequencies within those individuals, and do not possess ex-vivo immediate effector function as shown by CMV-specific CD4+ and CD8+ T cells. However, after short-term culture, Vδ2neg γδ T cells demonstrate effector T cell functions, suggesting additional requirements for activation. In summary, Vδ2neg γδ T cells are expanded in many older CMV carriers, demonstrating a further level of lymphocyte subset skewing by CMV in healthy individuals. As others have reported shared reactivity of Vδ2neg γδ T cells towards tumour cells, the composition of γδ T cell subsets may also have implications for risk of developing cancer in elderly people. [ABSTRACT FROM AUTHOR]

Allergen-specific immunotherapy ( SIT) is a clinically effective therapy for immunoglobulin ( Ig)E-mediated allergic diseases. To reduce the risk of IgE-mediated side effects, chemically modified allergoids have been introduced. Furthermore, adsorbance of allergens to aluminium hydroxide (alum) is widely used to enhance the immune response. The mechanisms behind the adjuvant effect of alum are still not completely understood. In the present study we analysed the effects of alum-adsorbed allergens and allergoids on their immunogenicity in vitro and in vivo and their ability to activate basophils of allergic donors. Human monocyte derived dendritic cells ( DC) were incubated with native Phleum pratense or Betula verrucosa allergen extract or formaldehyde- or glutaraldehyde-modified allergoids, adsorbed or unadsorbed to alum. After maturation, DC were co-cultivated with autologous CD4+ T cells. Allergenicity was tested by leukotriene and histamine release of human basophils. Finally, in-vivo immunogenicity was analysed by IgG production of immunized mice. T cell proliferation as well as interleukin ( IL)-4, IL-13, IL-10 and interferon ( IFN)-γ production were strongly decreased using glutaraldehyde-modified allergoids, but did not differ between alum-adsorbed allergens or allergoids and the corresponding unadsorbed preparations. Glutaraldehyde modification also led to a decreased leukotriene and histamine release compared to native allergens, being further decreased by adsorption to alum. In vivo, immunogenicity was reduced for allergoids which could be partly restored by adsorption to alum. Our results suggest that adsorption of native allergens or modified allergoids to alum had no consistent adjuvant effect but led to a reduced allergenicity in vitro, while we observed an adjuvant effect regarding IgG production in vivo. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease ( COPD) is characterized by an abnormal innate immune response. We have investigated the changes in the innate immune response of COPD alveolar macrophages exposed to both cigarette smoke and Toll-like receptor ( TLR) stimulation. COPD and control alveolar macrophages were exposed to cigarette smoke extract ( CSE) followed by TLR-2, -4 and -5 ligands [ Pam3 CSK4, lipopolysaccharide ( LPS) and phase I flagellin ( FliC), respectively] or non-typeable Haemophilus influenzae ( NTHi). CSE exposure suppressed TLR-induced tumour necrosis factor ( TNF)-α, interleukin ( IL)-6, IL-10 and regulated on activation, normal T cell expressed and secreted (RANTES) production in both COPD and control alveolar macrophages, but had no effect on interleukin 8 ( CXCL8) production. Similarly, CSE suppressed NTHi-induced TNF-α but not NTHi-induced CXCL8 production in COPD alveolar macrophages. Gene expression analysis showed that CSE suppressed LPS-induced TNF-α transcription but not CXCL8 transcription in COPD alveolar macrophages. The dampening effect of CSE on LPS-induced cytokine production was associated with a reduction in p38, extracellular signal regulated kinase (ERK) and p65 activation. In conclusion, CSE caused a reduced innate immune response in COPD alveolar macrophages, with the exception of persistent CXCL8 production. This could be a mechanism by which alveolar macrophages promote neutrophil chemotaxis under conditions of oxidative stress and bacterial exposure. [ABSTRACT FROM AUTHOR]