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The microbiota can play important roles in the development of human immunity and the establishment of immune homeostasis. Lifestyle factors including diet, hygiene, and exposure to viruses or bacteria, and medical interventions with antibiotics or anti‐ulcer medications, regulate phylogenetic variability and the quality of cross talk between innate and adaptive immune cells via mucosal and skin epithelia. More recently, microbiota and their composition have been linked to protective effects for health. Imbalance, however, has been linked to immune‐related diseases such as allergy and cancer, characterized by impaired, or exaggerated immune tolerance, respectively. In this AllergoOncology position paper, we focus on the increasing evidence defining the microbiota composition as a key determinant of immunity and immune tolerance, linked to the risk for the development of allergic and malignant diseases. We discuss novel insights into the role of microbiota in disease and patient responses to treatments in cancer and in allergy. These may highlight opportunities to improve patient outcomes with medical interventions supported through a restored microbiome. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the effects of bleached kraft mill effluent on selected physiological and hematological endpoints in fingerling largemouth bass ( Micropterus salmoides). Fish were exposed for 35 days to surface water collected at sites up- and downstream from a pulp and paper mill treatment-effluent discharge. The condition factor, spleen somatic index, and pronephros cellularity were statistically significantly decreased in fish exposed to the downstream site, compared to the upstream site. There was also a shift from lymphocytes to neutrophils in peripheral blood of fish exposed to the downstream site. Hematocrit values and the liver somatic index were statistically significantly increased in fish in the downstream exposure. These results indicate that in-stream exposure to elemental-chlorine-free pulp and paper mill effluents produce a generalized stress response, leading to potential immunosuppression in fish. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors have revolutionized cancer therapy and improved clinical outcomes. Immunotherapy is now increasingly combined with chemotherapy and other conventional treatments, such as radiation therapy, as part of the multimodal treatment of earlier-stage cancers. Although generally well tolerated and capable of inducing long-lasting responses, immunotherapy for thymic epithelial tumors can be challenging due to defects in immune self-tolerance, which increase the risk of immune-mediated toxicity. In order to improve the safety of immunotherapy and maximize clinical benefit in patients with thymic cancers, there is a pressing need to identify potential biomarkers of response and toxicity for this patient population. In this paper, we review the current role of immunotherapy for thymic cancers and discuss future applications across the spectrum of stage and histology of these diseases. Thymic epithelial tumors are a histologically diverse group of cancers arising from the epithelial compartment of the thymus. These tumors are characterized by a low tumor mutation burden, a lack of actionable genomic changes, and, especially with thymomas, defects in immune tolerance. Surgery is the mainstay of the management of resectable disease, whereas advanced, unresectable tumors are treated with platinum-based chemotherapy. Disease recurrence can occur months to years after frontline treatment. Although several options are available for conventional treatment of recurrent thymic tumors, response rates are generally low, and treatment-related toxicity can affect quality of life. A subset of patients benefit from biologic therapies, but there remains an unmet need for the development of new treatments. Immune checkpoint inhibitors are safe, clinically active, and have contributed to an improvement in survival for patients with a wide variety of cancers. However, the application of these revolutionary treatments for thymic cancers is limited to their use for the management of recurrent thymic carcinoma because of the risk of immune toxicity. In this paper, we review the current uses of immunotherapy for the management of thymic epithelial tumors and highlight potential strategies to improve safety and broaden the application of these treatments for patients with thymic cancers. [ABSTRACT FROM AUTHOR]

Immunosenescence, the gradual deterioration of immune function with age, holds profound implications for our understanding and management of multiple sclerosis (MS), a chronic autoimmune disease affecting the central nervous system. Traditionally diagnosed in young adults, advancements in disease-modifying therapies and increased life expectancy have led to a growing number of older individuals with MS. This demographic shift underscores the need for a deeper investigation into how age-related alterations in immune function shape the course of MS, influencing disease progression, treatment effectiveness, and overall patient outcomes. Age-related immunosenescence involves changes such as shifts in cytokine profiles, the accumulation of senescent immune cells, and compromised immune surveillance, collectively contributing to a state known as "inflammaging". In the context of MS, these immunological changes disturb the intricate balance between inflammatory and regulatory responses, thereby impacting mechanisms of central immune tolerance and peripheral regulation. This paper stands out by combining the most recent advancements in immunosenescence with both pathophysiological and treatment perspectives on multiple sclerosis, offering a cohesive and accessible discussion that bridges theory and practice, while also introducing novel insights into underexplored concepts such as therapy discontinuation and the latest senolytic, neuroprotective, and remyelination therapies. Enhancing our understanding of these complexities will guide tailored approaches to MS management, ultimately improving clinical outcomes for affected individuals. [ABSTRACT FROM AUTHOR]

Features abstracts of articles presented at the Sixteenth Annual British Society for Histocompatibility and Immunogenetics CONFERENCE held from September 7 to 9, 2005 in Plymouth, England. "Definition of Acceptable Mismatches for Highly Sensitised Patients," by E. L. Buchanan, A. J. Robson, J. E. Worthington and S. Martin; "Identification Of Permissible HLA Mismatches In Highly Sensitised Renal Patients Using HLA Matchmaker And Single Specificity HLA Antibody Detection Beads," by R. S. Goodman, C. M. O'Rourke, C. J. Taylor and T. Key; "A Failure to Characterise HLA-C Specific Antibody Using Luminex," by M. Hathaway and D. C. Briggs; "Cactus, A Population Genetics Analysis Environment," by H. M. Torres, J. Robinson, J. A. Madrigal and S. G. E. Marsh; Others.

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Minimum information models are reporting frameworks that describe the essential in-formation that needs to be provided in a publication, so that the work can be repeated or compared to other work. In 2016, Minimum Information about Tolerogenic Antigen-Presenting cells (MITAP) was created to standardize the reporting on tolerogenic antigen-presenting cells, including tolerogenic dendritic cells (tolDCs). tolDCs is a generic term for dendritic cells that have the ability to (re-)establish immune tolerance; they have been developed as a cell therapy for autoimmune diseases or for the prevention of transplant rejection. Because protocols to generate these therapeutic cells vary widely, MITAP was deemed to be a pivotal reporting tool by and for the tolDC community. In this paper, we explored the impact that MITAP has had on the tolDC field. We did this by examining a subset of the available literature on tolDCs. Our analysis shows that MITAP is used in only the minority of relevant papers (14%), but where it is used the amount of metadata available is slightly increased over where it is not. From this, we conclude that MITAP has been a partial success, but that much more needs to be done if standardized reporting is to become common within the discipline. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this review is to discuss the significance of IL-17 in SLE and the potential of IL-17-targeted therapy. Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs and tissues throughout the body. It is characterized by overactive B and T cells and loss of immune tolerance to autoantigens. Interleukin-17 (IL-17) is a cytokine that promotes inflammation and has been implicated in the pathogenesis of several autoimmune diseases as well as inflammatory diseases. In in vitro cellular experiments in lupus susceptible mice or SLE patients, there is substantial evidence that IL-17 is a highly promising therapeutic target. Methods: We searched papers from PubMed database using the search terms, such as interleukin-17, systemic lupus erythematosus, treatment targets, T cells, lupus nephritis, and other relevant terms. Results: We discuss in this paper the molecular mechanisms of IL-17 expression, Th17 cell proliferation, and the relationship between IL-17 and Th17. The significance of IL-17 in SLE and the potential of IL-17-targeted therapy are further discussed in detail. Conclusion: IL-17 has a very high potential for the development as a star target in SLE. [ABSTRACT FROM AUTHOR]

Simple Summary: Penile cancer is a rare and aggressive disease. Current treatment options when the cancer is locally advanced are suboptimal and potentially mutilating. Insight into the immune dysregulation necessary for the emergence of penile cancer could suggest innovative ways to manipulate the immune system which have already demonstrated efficacy in other, more common malignancies. In this paper, we use multiplex immunofluorescence, a novel technology, to investigate the immune microenvironment of penile cancer for the first time. We describe a pattern of immune exhaustion as cancer becomes more advanced and identify tumor-associated macrophages as a potential key player in regulating this process. Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status. [ABSTRACT FROM AUTHOR]

This paper summarizes key features of the dose‐finding strategies used in the development of 11 approved new molecular entities that are first‐in‐class enzyme replacement therapy (ERT), with a goal to gain insight into the dose exploration approaches to inform efficient dose‐finding in future development of biological products for Inborn Errors of Metabolism (IEM). Dose exploration should preferably begin in in vitro studies, followed by testing multiple doses in an appropriate animal disease model, when available, which can provide important information for dose assessment in humans. Performing adequate dose‐finding in early phase clinical studies in a well‐defined study population, including pediatric subjects, is generally critical to inform dose selection for pivotal trials; alternatively, additional dose exploration can be incorporated as part of a pivotal trial. Two important considerations for successful dose selection include (1) identifying appropriate disease‐specific endpoints, including pharmacodynamic (PD) end points and intermediate clinical end points or clinical end points, and (2) designing a study with adequate treatment durations for evaluating these end points. Appropriately selected PD biomarkers is useful for dose selection, and early development of these biomarkers can facilitate the overall clinical development program. Optimization of ERT doses, as well as evaluations of patient intrinsic factors and/or immune tolerance strategies may be necessary to overcome antibody responses or increase efficacy in IEM. [ABSTRACT FROM AUTHOR]

The high-burden regions of Sub-Saharan Africa, which accounted for greater than 70% of the HIV epidemic, are disproportionately affected by the high rates of TB coinfection. This might be explained by, the low immune tolerance of the population due to malnutrition and chronic infections aggravating immune suppression. In this review, we discuss the immunopathogenesis of this common co-infection that causes significant morbidity and mortality in people living with HIV globally. We used published studies using a two-step search strategy. Initial search of Pub Med Central and Google Scholar was undertaken followed by an analysis of the keywords. A second search using all the reference list of all identified reports and articles was searched for additional studies. Literature published as of January 1, 1981, that meets the inclusion criteria were considered. Qualitative data was extracted from papers included in the review. Mortality occurs at both ends of the immunological spectrum of TB at one end HIV uninfected patient dies from asphyxiation from acute massive hemoptysis due to cavitary TB; at the other end, and far more frequently HIV-infected patient with disseminated TB dies from overwhelming infection with less evidence of focal pathology. There is no clear sign that the HIV-TB epidemic is slowing, especially considering the emergence of increasingly drug-resistant strains of MTB. A major challenge for the future is to discover immune correlates of TB protection and TB disease risk. Failure to define this conclusively has hindered TB prevention strategies, including the design of new TB vaccines to replace BCG, which provides only shortlived efficacy, prevents severe forms of the extra-pulmonary disease and is contraindicated in PLHIV. Understanding TB and HIV infection through immunological advances needs to be combined to describe the complex interactions between TB and HIV and the effects of ART. The complex interactions between the individual components of innate and acquired immune responses to TB and HIV infection is also likely to be the next step forward. [ABSTRACT FROM AUTHOR]

Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In contrast to other pathogens, the enhanced survival in primed animals does not correlate with decreased E. faecalis load. Further analysis shows that primed organisms tolerate, rather than resist infection. Using RNA-seq of immune tissues, we found many genes were upregulated in only primed flies, suggesting a distinct transcriptional program in response to initial and secondary infections. In contrast, few genes continuously express throughout the experiment or more efficiently re-activate upon reinfection. Priming experiments in immune deficient mutants revealed Imd is largely dispensable for responding to a single infection but needed to fully prime. Together, this indicates the fly's innate immune response is plastic—differing in immune strategy, transcriptional program, and pathway use depending on infection history. Author summary: Most animals, like the fruit fly Drosophila melanogaster, lack an adaptive immune system and react to infection using only an innate immune response. In this paper, we study how previous infection with the bacterium Enterococcus faecalis changes the immune response to a second infection with the same bacterium, through a phenomenon called immune priming. We find that primed flies tend to survive more, tolerate a higher bacterial load, and undergo priming-specific gene expression reprogramming compared to non-primed flies. We also find that eliminating a key component of the Imd pathway, which is not canonically related to response to E. faecalis lowered priming ability in flies. These experiments highlight the true complexity of fly immune response and provide a basis for further exploring the interrelatedness of multiple known innate immune pathways in regulating a complex phenomenon like immune priming. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has a rapidly expanding role for the treatment of several cancers due to durable clinical activity and favorable tolerability. However, the unique biology of thymic epithelial tumors (TETs) increases the risk of immune-mediated toxicity. In this paper we review the biology of thymic cancers and its impact on the potential benefits and risks of immunotherapy. We describe the results of completed clinical trials of immune checkpoint inhibitors for advanced TETs and provide an overview of potential biomarkers of response or toxicity of immunotherapy that might influence future development of immunotherapeutic modalities for the treatment of advanced thymoma and thymic carcinoma. Thymic epithelial tumors (TETs) are rare thoracic cancers that are broadly classified as thymomas and thymic carcinomas. Surgery is the cornerstone of management for early-stage disease. There are a limited number of effective treatment options for patients with advanced or recurrent disease. The occurrence of paraneoplastic autoimmune disorders in patients with TETs, especially thymomas, creates significant challenges for the development of immunotherapy, including immune checkpoint inhibitors, as a feasible treatment option. In addition, patients with TETs are at increased risk for the development of immune-mediated toxicity with a predilection for musculoskeletal and neuromuscular adverse events upon treatment with immunotherapy. The identification of biomarkers of response and toxicity is expected to play a key role in harnessing the benefits of immunotherapy for patients with TETs. In this paper we review the biology of TETs and the potential effects on the tolerability of immunotherapy. The results of clinical trials of immune checkpoint inhibitors for the treatment of advanced TETs are described to understand the potential risks and benefits of immunotherapy. We also provide an overview of future avenues for treatment with novel immunotherapeutic modalities and opportunities to develop biomarkers to improve the safety and tolerability of immunomodulatory treatments in patients with TETs. [ABSTRACT FROM AUTHOR]

Food allergy has become a major public health problem all over the world. Evidence showed that allergic reactions induced by food proteins often lead to disturbances in the gut microbiota (symbiotic bacteria). Gut microbiota plays an important role in maintaining the balance between intestinal immune tolerance and allergic reactions. Dietary intervention has gradually become an important method for the prevention and treatment of allergic diseases, and changing the composition of gut microbiota through oral intake of prebiotics and probiotics may serve as a new effective adjuvant treatment measure for allergic diseases. In this paper, the main mechanism of food allergy based on intestinal immunity was described firstly. Then, the clinical and experimental evidence showed that different prebiotics and probiotics affect food allergy by changing the structure and composition of gut microbiota was summarized. Moreover, the molecular mechanism in which the gut microbiota and their metabolites may directly or indirectly regulate the immune system or intestinal epithelial barrier function to affect food immune tolerance of host were also reviewed to help in the development of food allergy prevention and treatment strategies based on prebiotics and probiotics. [ABSTRACT FROM AUTHOR]

Programmed death-ligand 1 (PD-L1) is the primary ligand of the receptor programmed death-1 (PD-1) which is constitutively expressed or activated in myeloid, lymphoid (T, B and NK), normal epithelial cells, and cancer. The PD-1/PD-L1 interaction is crucial for the physiological development of immunological tolerance but also in the development of the cancer. Among these, malignant melanoma represents a tumour in which the immunohistochemical expression of PD-L1 is important to guide future therapeutic choices based on the presence/absence of expression. Various clones have been used over time for immunohistochemical determination, and different results and heterogeneity remain among the various studies in the literature. We perform a narrative review of the present studies in order to discuss and take stock of what certain achievements have been made in this field, what challenges remain, and what possible solutions can be found. [ABSTRACT FROM AUTHOR]

Allergies affect approximately 10–30% of people worldwide, with an increasing number of cases each year; however, the underlying mechanisms are still poorly understood. In recent years, extracellular vesicles (EVs) have been suggested to play a role in allergic sensitization and skew to a T helper type 2 (Th2) response. The aim of this review is to highlight the existing evidence of EV involvement in allergies. A total of 22 studies were reviewed; 12 studies showed EVs can influence a Th2 response, while 10 studies found EVs promoted a Th1 or Treg response. EVs can drive allergic sensitization through up-regulation of pro-Th2 cytokines, such as IL-4 and IL-13. In addition, EVs from MRSA can induce IgE hypersensitivity in mice towards MRSA. On the other hand, EVs can induce tolerance in the immune system; for example, pre-exposing OVA-loaded EVs prevented OVA sensitization in mice. The current literature thus suggests that EVs play an essential role in allergy. Further research utilizing human in vitro models and clinical studies is needed to give a reliable account of the role of EVs in allergy. [ABSTRACT FROM AUTHOR]

This paper offers a historical analysis of the American plastic surgeon and Nobel laureate Joseph E. Murray's kidney transplantation. After succeeding in the first kidney transplantation between monozygotic twins in 1954, he transplanted kidneys between genetically distinct people after X-radiation and immunosuppressants. Amid these achievements, however, Murray encountered numerous failures, which he thought were closely intertwined with each patient's physiological and pathological individuality. As he appropriated his expertise in plastic surgery for kidney transplantation, this individuality became a major issue that he had to cope with in his efforts to avoid failures. To him, kidney transplantation could fail because of each individual's immunological barrier or constitutional singularity that could engender unexpected complications. Although he could neither explain nor control many of these failures, I argue that his unsuccessful work and patient individuality played multiple roles in shaping his operations as a plastic surgeon. They structured the path of his surgical research, made sense of it, defended him from criticism, and formed the way that he presented the results of his work with an immunological implication. Consequently, Murray, with little scientific training, articulated an important dimension of immunological tolerance relevant to clinical settings. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are characterized by a breakdown of immune tolerance, leading to inflammation and irreversible end-organ tissue damage. Platelet extracellular vesicles are cellular elements that are important in blood circulation and actively participate in inflammatory and immune responses through intercellular communication and interactions between inflammatory cells, immune cells, and their secreted factors. Therefore, platelet extracellular vesicles are the "accelerator" in the pathological process of autoimmune diseases; however, this robust set of functions of platelet extracellular vesicles has also prompted new advances in therapeutic strategies for autoimmune diseases. In this review, we update fundamental mechanisms based on platelet extracellular vesicles communication function in autoimmune diseases. We also focus on the potential role of platelet extracellular vesicles for the treatment of autoimmune diseases. Some recent studies have found that antiplatelet aggregation drugs, specific biological agents can reduce the release of platelet extracellular vesicles. Platelet extracellular vesicles can also serve as vehicles to deliver drugs to targeted cells. It seems that we can try to silence or inhibit microRNA carried by platelet extracellular vesicles transcription and regulate the target cells to treat autoimmune diseases as platelet extracellular vesicles can transfer microRNA to other cells to regulate immune-inflammatory responses. Hopefully, the information presented here will provide hope for patients with autoimmune diseases. Autoimmune diseases patients are characterized by autoimmune disorders, whose immune system cannot distinguish between auto- and foreign-antigens. Autoimmune diseases is the third significant disease threatening human health after cardiovascular disease and cancer. However, the exact etiology of autoimmune diseases has yet to be fully elucidated. Several studies have shown that platelet extracellular vesicle content is elevated in multiple autoimmune disorders and positively correlates with disease activity. However, our knowledge about the details of the mechanisms still remains limited and fragmentary. This article updates the communication function of platelet extracellular vesicles in accelerating autoimmune and inflammatory responses. The interesting thing is every coin has two sides. We put forward a new treatment idea for AD based on the particular volume and powerful intercellular communication function of platelet extracellular vesicles. Inhibition of the communication function of platelet extracellular vesicles seems to be considered in the future, or silence or block miRNA of platelet extracellular vesicles involved in the pathogenesis of AD. We can even use it as a drug carrier to deliver the drug to the relevant target cells, thereby enhancing the role of the medicine in regulating immune response and inhibiting inflammation. This paper not only provides a deeper understanding of the pathogenesis of autoimmune diseases but also provides theoretical support for the use of platelet extracellular vesicles to achieve targeted therapy. [ABSTRACT FROM AUTHOR]

There is a pregnant maternal immunological tolerance that protects the fetus and promotes its growth, and nuclear factor kappa B (NF-κB) family participates in the regulation of innate immune and adaptive immune responses. The thymus is related to establishing central tolerance, and early pregnancy has effects on expression of a good number of genes and proteins in the maternal thymus in sheep. However, it is unclear whether early pregnancy changes expression of NF-κB subunits in the ovine thymus. In this study, the thymic samples were collected from day 16 of non-pregnant ewes, and days 13, 16 and 25 of pregnant ewes, and the expression of NF-κB members (NF-κB1, NF-κB2, RelA, RelB and c-Rel) was analyzed through real-time quantitative PCR, Western blot and immunohistochemical analysis. The results showed that c-Rel mRNA and protein upregulated at day 25 of pregnancy, and NF-κB1 mRNA and proteins increased at days 16 and 25 of pregnancy, and RelB mRNA and proteins enhanced during early pregnancy. However, expression levels of NF-κB2 and RelA were decreased during early pregnancy, but upregulated from day 13 to 25 of pregnancy. In addition, the RelA protein was located in the epithelial reticular cells, capillaries and thymic corpuscles. This paper reported for the first time that early pregnancy induced expression of NF-κB1, RelB and c-Rel, but inhibited expression of NF-κB2 and RelA in the maternal thymus during early pregnancy, which is involved in the central immune tolerance, and helpful for successful pregnancy in sheep. [ABSTRACT FROM AUTHOR]

Glycyrrhizae Radix et Rhizoma (GRER) has been used as a medicinal plant and dietary supplements for its beneficial effect in immunomodulatory effects. Sulfur fumigation (SF) processing was widely used in the storage and maintenance of Chinese medicine because of its convenience and cheapness. However, the disadvantage of SF has been reported, but the systematic study of SF on GRER was deficient. In this paper, the active ingredients, sulfur-fumigated products, immunomodulatory effect, and liver injury of SF-GRER were studied. After SF, the liquiritin decreased from 4.49 ± 0.03 mg/g to 3.94 ± 0.08 mg/g (P < 0.01). Compared with the NSF-GRER group, the SF-GRER group showed a decreased immunoregulation in the thymus index, spleen index, and serum IL-6 and SOD levels (P < 0.05). After 2 weeks of continuous intragastric administration of SF-GRER in healthy mice, the level of serum aspartate aminotransferase (AST) significantly increased (P < 0.05) and the area of liver lesion significantly increased compared with the NSF-GRER (P < 0.05) group. The sulfonated products (m/z, 631.13) corresponding to liquiritin apioside (m/z, 551.17) and isoliquiritin apioside (m/z, 551.17) were screened out in SF-GRER by using UPLC-Orbitrap-MS. The sulfonated products provided in this paper were discovered for the first time and could be powerfully applied for the identification of SF-GRER. SF destroyed the chemical composition of GRER, inhibited immunoregulation, and induced liver injury. The feasibility of this processing method needs to be reconsidered. [ABSTRACT FROM AUTHOR]

The autonomic nervous system can control immune cell activation via both sympathetic adrenergic and parasympathetic cholinergic nerve release of norepinephrine and acetylcholine. The hypothesis put forward in this paper suggests that autonomic nervous system dysfunction leads to dysregulation of immune tolerance mechanisms in brain-resident and peripheral immune cells leading to excessive production of proinflammatory cytokines such as Tumor Necrosis Factor alpha (TNF-a). Inactivation of Glycogen Synthase Kinase-3b (GSK3b) is a process that takes place in macrophages and microglia when a toll-like receptor 4 (TLR4) ligand binds to the TLR4 receptor. When Damage-Associated Molecular Patterns (DAMPS) and Pathogen-Associated Molecular Patterns (PAMPS) bind to TLR4s, the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway should be activated, leading to inactivation of GSK3b. This switches the macrophage from producing pro-inflammatory cytokines to antiinflammatory cytokines. Acetylcholine activation of the a7 subunit of the nicotinic acetylcholine receptor (a7 nAChR) on the cell surface of immune cells leads to PI3K/Akt pathway activation and can control immune cell polarization. Dysregulation of this pathway due to dysfunction of the prenatal autonomic nervous system could lead to impaired fetal immune tolerance mechanisms and a greater vulnerability to Maternal Immune Activation (MIA) resulting in neurodevelopmental abnormalities. It could also lead to the adult schizophrenia patient's immune system being more vulnerable to chronic stress-induced DAMP release. If a schizophrenia patient experiences chronic stress, an increased production of pro-inflammatory cytokines such as TNF-a could cause significant damage. TNF-a could increase the permeability of the intestinal and blood brain barrier, resulting in lipopolysaccharide (LPS) and TNF-a translocation to the brain and consequent increases in glutamate release. MIA has been found to reduce Glutamic Acid Decarboxylase mRNA expression, resulting in reduced Gammaaminobutyric acid (GABA) synthesis, which combined with an increase of glutamate release could result in an imbalance of glutamate and GABA neurotransmitters. Schizophrenia could be a "two-hit" illness comprised of a genetic "hit" of autonomic nervous system dysfunction and an environmental hit of MIA. This combination of factors could lead to neurotransmitter imbalance and the development of psychotic symptoms. [ABSTRACT FROM AUTHOR]

Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but highly potent endocrine organ. Hormonal activity of placenta is marked by its ability to continuously produce and secrete high levels of progesterone. Progesterone guards the well-being of the fetoplacental unit throughout the gestation and one of the proposed mechanisms of this principle involves the development of local and systemic immune tolerance mainly due to impediment of CD4+ lymphocyte activation. However, though these alterations are present and well-established, autoimmunity is not entirely rare and a wide spectrum of diseases can continue, or develop de novo , throughout the gestation or even after the delivery. Up-to-date data supports the existence of a relationship between the clinical course of chosen autoimmune diseases and levels of circulating sex steroids. The most common autoimmune endocrinopathies in pregnant women are Hashimoto's disease, Graves' disease, and, more rarely, primary adrenal insufficiency in the form of Addison's disease. Gestation can influence the clinical course of these endocrinopathies in patients who were diagnosed before conception. Multiple particles, like TSH-receptor stimulating antibodies, thyroid hormones, glucocorticoids, and anti-thyroid medications, can cross the placental barrier and evoke biological action in fetal tissues. Thyroid pathology in the form of postpartum thyroiditis is particularly prevalent in patients with positive anti-thyroperoxidase and anti-thyroglobulin antibodies. Certain populations are more at risk of developing numerous gestational complications and require regular follow-up. In our paper, we would like to address physiological, physiopathological, and clinical aspects of endocrine autoimmunity throughout human gestation, as well as special circumstances to consider in pregnant women. [ABSTRACT FROM AUTHOR]

Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for years, autoimmunity and cancer have been considered as two separate fields of research that do not have a lot in common. However, the discovery of immune checkpoints and the development of anti-cancer drugs targeting PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways proved that studying autoimmune diseases can be extremely helpful in the development of novel anti-cancer drugs. Therefore, autoimmunity and cancer seem to be just two sides of the same coin. In the current review, we broadly discuss how various regulatory cell populations, effector molecules, genetic predisposition, and environmental factors contribute to the loss of self-tolerance in autoimmunity or tolerance induction to cancer. With the current paper, we also aim to convince the readers that the pathways involved in cancer and autoimmune disease development consist of similar molecular players working in opposite directions. Therefore, a deep understanding of the two sides of immune tolerance is crucial for the proper designing of novel and selective immunotherapies. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are a broad spectrum of human diseases that are characterized by the breakdown of immune tolerance and the production of autoantibodies. Recently, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals. The main function of NLRP3 inflammasome is to promote secretion of interleukin (IL)-1β and IL-18, and pyroptosis mediated by caspase-1. Served as a checkpoint in innate and adaptive immunity, aberrant activation and regulation of NLRP3 inflammasome plays an important role in the pathogenesis of autoimmune diseases. This paper reviewed the roles of NLRP3 inflammasome in autoimmune diseases, which shows NLRP3 inflammasome may be a potential target for autoimmune diseases deserved further study. [ABSTRACT FROM AUTHOR]

'Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance', published in Philosophical Transactions B in 1956 by Peter Medawar and his colleagues, PhD graduate Leslie Brent and postdoctoral fellow Rupert Billingham, is a full description of the concept of acquired transplantation tolerance. Their 1953 Nature paper (Billingham RE et al. 1953 Nature 172, 603-606. (doi:10.1038/172603a0)) had provided initial evidence with experimental results from a small number of neonatal mice, with mention of similar findings in chicks. The Philosophical Transactions B 1956 paper is clothed with an astonishing amount of further experimental detail. It is written in Peter Medawar's landmark style: witty, perceptive and full of images that can be recalled even when details of the supporting information have faded. Those images are provided not just by a series of 20 colour plates showing skin graft recipient mice, rats, rabbits, chickens and duck, bearing fur or plumage of donor origin, but by his choice of metaphor, simile and analogy to express the questions being addressed and the interpretation of their results, along with those of relevant published data and his prescient ideas of what the results might portend. This work influenced both immunology researchers and clinicians and helped to lay the foundations for successful transplantation programmes. It led to the award of a Nobel prize in 1960 to Medawar, and subsequently to several scientists who advanced these areas. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society. [ABSTRACT FROM AUTHOR]

Phagocytic activity is an extremely important indicator that evaluates medicinal effects related to the immune system and functions to investigate the mechanism of how a drug works under conditions such as immunological regulation, immune tolerance, inflammation, cancer, etc. Current techniques based on flow cytometry, fluorescence imaging or numbering CFUs after cell lysis for detecting phagocytosis suffer from long terms of bacteria culturing and complex preparation steps for fluorescent labeling or require a large amount of cell samples to be tested. This study aims at developing a simple and fast method for testing the phagocytic activity of unlabeled and native cells, taking advantage of very high-resolution direct current insulator-based dielectrophoresis (DC-iDEP). The properties of cells are characterized by native whole cell biophysical properties. This strategy not only eliminates the time-consuming bacterial culture work after cell lysis, but also lowers the expenses of bacteria labeling. The introduction of microfluidics reduces the sample volume or reagent needed. The analysis of the biophysical property distributions of native cells and medicine treated cells may lead to a less expensive and rapid tool for evaluating medicinal effects. Furthermore, berberine was investigated for decreasing the phagocytic activity of macrophages and used for comparison of activities. This study works on establishing a label-free, unbiased, and non-destructive method to determine cell phagocytic activity and investigate its use in evaluating medicinal effects on phagocytosis in a single step within a short time. [ABSTRACT FROM AUTHOR]

Aim: The objective of this review is to describe the immunological mechanisms which facilitate maternal tolerance at the maternal‐placental interface, and to discuss how these mechanisms are disrupted in pre‐eclampsia. Methods: A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the immunological mechanisms which facilitate maternal tolerance in healthy pregnancy and pre‐eclampsia are presented in this article. Results: The maternal‐placental interface is the site where the immune tolerance begins and develops. Within the innate immunity, natural killer cells, macrophages and dendritic cells play a pivotal role in tolerance through regulation of inflammation. On the other hand, within the adaptive immunity, the correct increase of regulatory T cells is crucial for ensuring immune tolerance toward placental cells. Disturbances in maternal tolerance can lead to the appearance of pregnancy complications such as pre‐eclampsia, which has a considerable impact on perinatal morbidity and mortality. Conclusion: Our partial knowledge of immunological mechanisms involved in tolerance at the maternal‐placental interface indicates that pre‐eclampsia is characterized by alterations of this maternal immune tolerance, which could represent the origin of the disease. [ABSTRACT FROM AUTHOR]

Nowadays, the development of factor VIII and IX inhibitors in patients with hemophilia is considered as the most challenging in the treatment of hemophilia. Immune tolerance induction (ITI) therapy is an approach for eradication of inhibitors. Some ITI protocols are routinely in use for the eradication of inhibitors in patients with hemophilia. Moreover, such a therapeutic regimen may facilitate the tendency to reduced bone density in patients with inhibitor. This study scheduled to investigate whether that predisposing role of ITI protocols with an immunosuppressive agent has considered or not. By a literature review, published ITI protocols in hemophilia with inhibitors were evaluated. Among them, 51 papers found and studied thoroughly. None of them had performed the bone mineral examination in patients with hemophilia and inhibitor under treatment. Since there are 2 coexisting facilitating factors in these protocols, considering the bone mineral density study for patients with inhibitor who are undergoing ITI protocols with an immunosuppressive agent is recommended. [ABSTRACT FROM AUTHOR]

In the first of two papers we described the development in the field of allergy mechanisms as described by Clinical and Experimental Allergy in 2015. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered. A second paper will cover clinical aspects. [ABSTRACT FROM AUTHOR]

Regulatory T-cells (Tregs) are key players in successful pregnancy and their deficiencies are implicated in pregnancy complications such as preeclampsia (PE), but the results are inconsistent among studies. This study aims to compile an overview of the studies about the associations of Tregs and PE risk and to provide recommendations for future research. A sensitive search of three databases including PubMed, Scopus and Google scholar (from 1995 to January 9, 2015) identified 636 unique titles. An accurate process of study selection, data extraction and method qualification were independently conducted by authors on retrieved papers. Seventeen papers met the inclusion criteria and were included in quality assessment. Regarding the source of Tregs, 14 studies assessed Tregs in peripheral blood, 2 studies in peripheral blood and decidua and one study in peripheral blood and umbilical cord blood. Despite variation in the combinations of markers and other aspects of the studies designs, remarkable constancy in the results of studies that measured Tregs as CD4+FoxP3+ or CD4+CD25+FoxP3+ cells (but not CD4+CD25high/lowFoxP3+ markers) was found, which in broad terms showed a shift towards fewer Treg cells in PE. This review revealed an association between lower percentage of circulating CD4+FoxP3+ or CD4+CD25+FoxP3+ Tregs and the risk of PE. Given the above issue and regarding the high consistency of studies on reduction of suppressive activity of Tregs in PE, we have proposed a model in which the Tregs deficiency is a reflection of immune endocrine imbalance, which reverses maternal tolerance and results in development of preeclampsia. [ABSTRACT FROM PUBLISHER]

Radiotherapy, a precise modality for treating malignant tumors, has undergone rapid advancements in primary and clinical research. The mechanisms underlying tumor radioresistance have become significant research. With the introduction and in-depth study of cancer stem cells (CSCs) theory, CSCs have been identified as the primary factor contributing to the development of tumor radioresistance. The "stemness" of CSCs is a biological characteristic of a small subset of cells within tumor tissues, characterized by self-renewal solid ability. This characteristic leads to resistance to radiotherapy, chemotherapy, and targeted therapies, driving tumor recurrence and metastasis. Another study revealed that cellular autophagy plays a pivotal role in maintaining the "stemness" of CSCs. Autophagy is a cellular mechanism that degrades proteins and organelles to generate nutrients and energy in response to stress. This process maintains cellular homeostasis and contributes to CSCs radioresistance. Furthermore, ionizing radiation (IR) facilitates epithelial-to-mesenchymal transition (EMT), vascular regeneration, and other tumor processes by influencing the infiltration of M2-type tumor-associated macrophages (TAMs). IR promotes the activation of the classical immunosuppressive "switch," PD-1/PD-L1, which diminishes T-cell secretion, leading to immune evasion and promoting radioresistance. Interestingly, recent studies have found that the immune pathway PD-1/PD-L1 is closely related to cellular autophagy. However, the interrelationships between immunity, autophagy, and radioresistance of CSCs and the regulatory mechanisms involved remain unclear. Consequently, this paper reviews recent research to summarize these potential connections, aiming to establish a theoretical foundation for future studies and propose a new model for the network regulation of immunity, autophagy, and radioresistance of tumor cells. [Display omitted] • The property of radioresistance is part of the "stemness" of CSCs. • Autophagy can maintain the radioresistance of CSCs by reducing DNA damage in cancer cells. • Radiotherapy can also induce immunosuppression and enhance immune tolerance, weakening the immune response. • A close regulatory mechanism exists between the immune system and autophagy. • An essential signaling network likely links immunity, autophagy, and the radioresistance of cancer stem cells. [ABSTRACT FROM AUTHOR]

Vertebrate cell identity depends on the combined activity of scores of transcription factors (TF). While TFs have often been studied in isolation, a systematic perspective on their integration has been missing. Focusing on FoxP3+ regulatory T cells (Tregs), key guardians of immune tolerance, we combined single-cell chromatin accessibility, machine learning, and high-density genetic variation, to resolve a validated framework of diverse Treg chromatin programs, each shaped by multi-TF inputs. This framework identified previously unrecognized Treg controllers (Smarcc1) and illuminated the mechanism of action of FoxP3, which amplified a pre-existing Treg identity, diversely activating or repressing distinct programs, dependent on different regulatory partners. Treg subpopulations in the colon relied variably on FoxP3, Helios+ Tregs being completely dependent, but RORγ+ Tregs largely independent. These differences were rooted in intrinsic biases decoded by the integrated framework. Moving beyond master regulators, this work unravels how overlapping TF activities coalesce into Treg identity and diversity. [ABSTRACT FROM AUTHOR]

The functional outcomes and restoration of form after vascularized composite allotransplantation (VCA) have exceeded the results that could be achieved with current autologous surgical techniques. However, the longevity of VCA grafts has been limited due to the development of donor-specific antibodies (DSAs), and chronic rejection and graft failure occur despite long-term immunotherapy. Furthermore, despite widespread consensus that these non-life-saving transplants are beneficial for select patients, the application of VCA is limited by the need for lifelong immunosuppression. Therefore, attempts to achieve drug-free tolerance through safe and effective therapies are critical. This review highlights recent publications regarding alloantibody-mediated rejection (AMR) in various VCAs with a focus on the critical need for novel tolerance-inducing strategies. The development and implementation of effective methods of inducing tolerance, such as the use of anti-CD3 immunotoxins, could drastically improve VCA graft outcomes and recipient quality of life. [ABSTRACT FROM AUTHOR]

Cytokines coordinate the intricate choreography of the immune system, directing cellular activities that mediate inflammation, pathogen defense, pathology and tissue repair. Within this spectrum, the anti-inflammatory prowess of interleukin-10 (IL-10) predominates in immune homeostasis. In normal pregnancy, the dynamic shift of IL-10 across trimesters maintains maternal immune tolerance ensuring fetal development and pregnancy success. Unravelling the dysregulation of IL-10 in pregnancy complications is vital, particularly in the heightened inflammatory condition of preeclampsia. Of note, a reduction in IL-10 levels contributes to endothelial dysfunction. In human immunodeficiency virus (HIV) infection, a complex interplay of IL-10 occurs, displaying a paradoxical paradigm of being immune-protective yet aiding viral persistence. Genetic variations in the IL-10 gene further modulate susceptibility to HIV infection and preeclampsia, albeit with nuanced effects across populations. This review outlines the conceptual framework underlying the role of IL-10 in the duality of normal pregnancy and preeclampsia together with HIV infection, thus highlighting its regulatory mechanisms and genetic influences. Synthesizing these findings in immune modulation presents avenues for therapeutic interventions in pregnancy complications comorbid with HIV infection. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting cells that are important for initiating and regulating both innate and adaptive immune responses. As a crucial component of the immune system, DCs have a pivotal role in the pathogenesis and clinical treatment of CRC. DCs cross-present tumor-related antigens to activate T cells and trigger an antitumor immune response. However, the antitumor immune function of DCs is impaired and immune tolerance is promoted due to the presence of the tumor microenvironment. This review systematically elucidates the specific characteristics and functions of different DC subsets, as well as the role that DCs play in the immune response and tolerance within the CRC microenvironment. Moreover, how DCs contribute to the progression of CRC and potential therapies to enhance antitumor immunity on the basis of existing data are also discussed, which will provide new perspectives and approaches for immunotherapy in patients with CRC. [ABSTRACT FROM AUTHOR]

Skin‐resident antigen‐presenting cells (APC) play an important role in maintaining peripheral tolerance via immune checkpoint proteins and induction of T regulatory cells (Tregs). However, there is a lack of knowledge on how to expand or recruit immunoregulatory cutaneous cells without causing inflammation. Here, it is shown that administration of a non‐coding single‐stranded oligonucleotide (ssON) leads to CCR2‐dependent accumulation of CD45+CD11b+Ly6C+ cells in the skin that express substantial levels of PD‐L1 and ILT3. Transcriptomic analyses of skin biopsies reveal the upregulation of key immunosuppressive genes after ssON administration. Functionally, the cutaneous CD11b+ cells inhibit Th1/2/9 responses and promote the induction of CD4+FoxP3+ T‐cells. In addition, ssON treatment of imiquimod‐induced inflammation results in significantly reduced Th17 responses. It is also shown that induction of IL‐10 production in the presence of cutaneous CD11b+ cells isolated after ssON administrations is partly PD‐L1 dependent. Altogether, an immunomodulatory ssON is identified that can be used therapeutically to recruit cutaneous CD11b+ cells with the capacity to dampen Th cells. [ABSTRACT FROM AUTHOR]

Background: The absence of a safe and effective therapy for recurrent spontaneous abortion due to a maternofetal failure in immunological tolerance remains an intractable clinical obstacle for surgeons. Recently, traditional Chinese medicine has become a feasible alternative for certain diseases, including recurrent spontaneous abortion. However, because of the complex composition of the traditional Chinese medicine formula, its action mechanism remains unclear. Methods: We selected two isolated active ingredients (RAMP and baicalin) from the traditional Chinese medicine formula and used an abortion-prone CBA/J × DBA/2 model to simulate human RSA and compared the changes in fetal resorption rate, Treg cell percentage, and relevant cytokines before and after combination therapy. In addition, The mechanisms were preliminarily discussed using in vitro differentiation models. Results: In CBA/J × DBA/2 abortion-prone mice, the combination therapy resulted in a lower embryo resorption rate compared to that obtained with individual delivery of either RAMP or baicalin, thereby playing an embryo-protective role through the increase in Treg cells for the maintenance of maternal-fetal immune tolerance. In in vitro primary cell differentiation experiments, the concentration of Treg cells significantly increased from 11% to 17.9% after the combination therapy compared to that of the single administration group. Conclusion: the synergistic effects of RAMP and baicalin were responsible for Treg differentiation. The present study provides a solid basis for improving the applicability of traditional Chinese herbs in the treatment of recurrent spontaneous abortion. [ABSTRACT FROM AUTHOR]

Peanut allergy, a prevalent and potentially severe condition affecting millions worldwide, has been linked to specific human leukocyte antigens (HLAs), suggesting increased susceptibility. Employing an immunoinformatic strategy, we developed a "logo model" based on amino acid frequencies in the peptide binding core and used it to predict peptides originating from 28 known peanut allergens binding to HLA-DRB1*03:01, one of the susceptibility alleles. These peptides hold promise for immunotherapy in HLA-DRB1*03:01 carriers, offering reduced allergenicity compared to whole proteins. By targeting essential epitopes, immunotherapy can modulate immune responses with minimal risk of severe reactions. This precise approach could induce immune tolerance with fewer adverse effects, presenting a safer and more effective treatment for peanut allergy and other allergic conditions. [ABSTRACT FROM AUTHOR]

The development of inhibitors is a rare but severe complication for people living with haemophilia. This patient benefited from the concurrent use of ITI and emicizumab with reasonable bleeding control and inhibitor eradication, making it the first reported case of concurrent ITI and emicizumab in the rare population of haemophilia A carrier with inhibitor. Her father and elder brother have severe haemophilia A and two sisters who are known heterozygous carriers of haemophilia A mutation. [Extracted from the article]

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Abstract One of the ongoing challenges in lateral flow Immunochromatographic assays (LFIA), is lowering the limit of detection and enhancing their signal quality, i.e. the color intensity. There are a number of rather costly and complicated processes for this aim, such as the use of functionalized materials/membranes and additional spectroscopic readout units. Nonetheless, there are simple and easy to practice alternatives, to be uncovered by analyzing the essential parameters of immunological reactions. The color intensity of the test line is a function of analytes flow velocity and their reaction rate. Detection pad width and test line position impact the flow velocity and reaction rate kinetics, examined in this paper for the limit of detection (LOD) and test-line color intensity. Firstly, the impact of width on the LOD was examined for human chorionic gonadotropin (pregnancy biomarker). Test line color intensity was measured using five different widths of the detection pad (trapezoidal) and four different test line positions, and the trends observed were explained according to the measured evolution of the velocity along the chromatography paper. With a constant width absorbent pad, LOD was cut by half to 5 mIU/ml by using a narrowing width detection pad, which keeps the wicking velocity higher than normal strips, and compared to them, color intensity increase between 55 and 150%, depending on the concentration. Nevertheless, a widening detection pad might cut the color intensity up to 150%, compared to normal strips, due to a profound decline of the analyte to ligand ratio at the test line. In addition, adequately sending the test line away from the conjugate pad yields the highest possible color intensity, for up to 400% of increase, in lower concentrations and narrowing test pads. However, further distancing the test line downfalls the color intensity. Highlights • Width of detection pad and test line positioning impacts the performance of LFIAs. • Narrowing-width pads cut the detection limit by half to 5 mIU/ml. • Distancing the test line from conjugate pad augments color intensity up to 4 folds. • Narrowing-width effectively decelerates the flow-wise velocity drop of porous pads. [ABSTRACT FROM AUTHOR]

Background: The endolymphatic sac (ES) is endowed with a multitude of white blood cells that may trap and process antigens that reach the inner ear from nearby infection-prone areas, it thus serves as an immunologic defense organ. The human ES, and unexpectedly the rest of the inner ear, has been recently shown to contain numerous resident macrophages. In this paper, we describe ES macrophages using super-resolution structured fluorescence microscopy (SR-SIM) and speculate on these macrophages' roles in human inner ear defense. Material and Methods: After ethical permission was obtained, human vestibular aqueducts were collected during trans-labyrinthine surgery for acoustic neuroma removal. Tissues were placed in fixative before being decalcified, rapidly frozen, and cryostat sectioned. Antibodies against IBA1, cytokine fractalkine (CX3CL1), toll-like receptor 4 (TLR4), cluster of differentiation (CD)68, CD11b, CD4, CD8, and the major histocompatibility complex type II (MHCII) were used for immunohistochemistry. Results: A large number of IBA1-positive cells with different morphologies were found to reside in the ES; the cells populated surrounding connective tissue and the epithelium. Macrophages interacted with other cells, showed migrant behavior, and expressed immune cell markers, all of which suggest their active role in the innate and adaptive inner ear defense and tolerance. Discussion: High-resolution immunohistochemistry shows that antigens reaching the ear may be trapped and processed by an immune cell machinery located in the ES. Thereby inflammatory activity may be evaded near the vulnerable inner ear sensory structures. We speculate on the immune defensive link between the ES and the rest of the inner ear. [ABSTRACT FROM AUTHOR]

2013 was another exciting year for allergy in general and Clinical and Experimental Allergy in particular. In the field of asthma and rhinitis, there continued to be a focus on heterogeneity and phenotypes with increasing use of biostatistical techniques to determine clusters of similar populations. Obesity- and aspirin-associated disease are intriguing associations with asthma which were explored in a number of papers. We published a number of excellent papers on mechanisms of airway inflammation and how this relates to physiology, pathology, genetics and biomarkers in both human and experimental model systems. In terms of mechanisms, there is less on individual cell types in allergic disease at the moment, but the immunology of allergic disease continued to fascinate our authors. Another area that was popular both in the mechanisms and in the epidemiology sections was early life events and how these lead to allergic disease, with an increasing focus on the role of the microbiome and how this influences immune tolerance. In the clinical allergy section, oral immunotherapy for food allergy is clearly a major topic of interest at the moment as was in vitro testing to distinguish between sensitization and allergic disease. There was less on inhalant allergy this year, but a good representation from the drug allergy community including some interesting work on non-IgE-mediated mechanisms. In the allergen section, important new allergens continue to be discovered, but the major focus as in the last couple of years was on working out how component-resolved approaches can improve diagnosis and management of food and venom allergy. [ABSTRACT FROM AUTHOR]

For many years, the role of interleukin-2 (IL-2) in autoimmune responses was established as a cytokine possessing strong pro-inflammatory activity. Studies of the past few years have changed our knowledge on IL-2 in autoimmune chronic inflammation, suggesting its protective role, when administered at low-doses. The disrupted balance between regulatory and effector T cells (Tregs and Teffs, respectively) is a characteristic of autoimmune diseases, and is dependent on homeostatic cytokines, including IL-2. Actually, inherent defects in the IL-2 signaling pathway and/or levels leading to Treg compromised function and numbers as well as Th17 expansion have been attributed to autoimmune disorders. In this review, we discuss the role of IL-2 in the pathogenesis of autoimmune diseases. In particular, we highlight the impact of the dysregulated IL-2 pathway on disruption of the Treg/Th17 balance, reversal of which appears to be a possible mechanism of the low-dose IL-2 treatment. The negative effects of IL-2 on the differentiation of follicular helper T cells (Tfh) and pathogenic Th17 cells, both of which contribute to autoimmunity, is emphasized in the paper as well. We also compare the current IL-2-based therapies of animal and human subjects with immune-mediated diseases aimed at boosting the Treg population, which is the most IL-2-dependent cell subset desirable for sufficient control of autoimmunity. New perspectives of therapeutic approaches focused on selective delivery of IL-2 to inflamed tissues, thus allowing local activity of IL-2 to be combined with its reduced systemic and pleiotropic toxicity, are also proposed in this paper. [ABSTRACT FROM AUTHOR]

The timing of the introduction of complementary foods appears crucial to the development of allergic diseases later in life. The results from recent observational studies might be misinterpreted to suggest that introducing complementary food prior to the age of four months might have a beneficial effect on the induction of immune tolerance. Since these two recently published papers cannot completely account for reverse causation, as is the case for all observational studies, we recommend that the current ESPGHAN and American Academy of Pediatrics recommendations be maintained as long as new evidence from large randomized controlled intervention trials do not suggest otherwise. That is, complementary foods should be first introduced between the age of 17 to 26 weeks. [ABSTRACT FROM AUTHOR]

Allergic asthma and rhinitis are characterized by IgE-mediated inflammation consequent to the exposure to a specific allergen. Therefore, IgE production may be considered the hallmark of allergy. Actually, allergen immunotherapy (AIT) is the unique causal treatment for respiratory allergy. Indeed, successful AIT can induce a physiologic immune tolerance toward the causal allergen. There is evidence to show that AIT is safe and effective; its indication has been rigorously stated by robust position papers. AIT efficacy assessment is mainly based on symptom reduction and drug saving. AIT responder quote may range between 60 and 90% of AIT prescription. As AIT is expensive and long-lasting, the availability of a marker able to predict AIT responder is a crucial relevance. This issue has been the topic of several studies. Very recently, it has been preliminarly reported that a cut-off of serum specific IgE levels could define AIT-responder. However, further rigorous studies will confirm this view. [ABSTRACT FROM AUTHOR]

Summary: Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. ‘Bypassing agents’ may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at ‘good’ or ‘bad risk’ for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities. [ABSTRACT FROM AUTHOR]

Abstract: While desired for the cure of allergy, regulatory immune cell subsets and nonclassical Th2‐biased inflammatory mediators in the tumour microenvironment can contribute to immune suppression and escape of tumours from immunological detection and clearance. A key aim in the cancer field is therefore to design interventions that can break immunological tolerance and halt cancer progression, whereas on the contrary allergen immunotherapy exactly aims to induce tolerance. In this position paper, we review insights on immune tolerance derived from allergy and from cancer inflammation, focusing on what is known about the roles of key immune cells and mediators. We propose that research in the field of AllergoOncology that aims to delineate these immunological mechanisms with juxtaposed clinical consequences in allergy and cancer may point to novel avenues for therapeutic interventions that stand to benefit both disciplines. [ABSTRACT FROM AUTHOR]