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- OPEN ACCESSThe vast diversity of bacteria that inhabit the gastrointestinal tract strongly influence host physiology, not only nutrient metabolism but also immune system development and function. The complexity of the microbiota is matched by the complexity of the host immune system, where they have coevolved to maintain homeostasis ensuring the mutualistic host-microbial relationship. Numerous studies in recent years investigating the gut-brain axis have demonstrated an important role for the gut microbiota in modulating brain development and function, with the immune system serving as an important coordinator of these interactions. Gut bacteria can modulate not only gut-resident immune cells but also brain-resident immune cells. Activation of the immune system in the gut and in the brain are implicated in responses to neuroinflammation, brain injury, as well as changes in neurogenesis and plasticity. Impairments in this bidirectional communication are implicated in the etiopathogenesis of psychiatric and neurodevelopmental diseases and disorders, including autism spectrum disorders, or comorbidities associated with Gastrointestinal diseases, including inflammatory bowel diseases, where dysbiosis is commonly seen. Consequently, probiotics, or beneficial microbes, are being recognized as promising therapeutic targets to modulate behavior and brain development by modulating the gut microbiota. Here we review the role of microbiota-immune interactions in the gut and the brain during homeostasis and disease and their impact on gut-brain communication, brain function, and behavior as well as the use of probiotics in central nervous system alterations.Statement of novelty: The microbiota-gut-brain axis is increasingly recognized as an important physiological pathway for maintaining health and impacting the brain and central nervous system. Increasing evidence suggests that the immune system is crucial for gut-brain signaling. In this review, we highlight the critical studies in the literature that identify the key immune pathways involved.
- OPEN ACCESSAsthma is a heterogeneous condition in which multiple pathological pathways manifest with similar symptoms. Severe asthma (SA) is challenging to manage and comprises a significant health and economic burden. Many studies have been conducted in an attempt to define different clinical phenotypes that translate into biological endotypes, with the goal of tailoring treatment based on precision medicine. This review summarizes the current evidence for the treatments of SA, and in particular, the biologic treatments that are currently available: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. We found only limited high-quality direct evidence regarding treatment with anti-IgE (omalizumab) in SA patients. Data regarding anti-interleukin (IL)-5 (mepolizumab, reslizumab and benralizumab) showed beneficial effects in severe eosinophilic asthma (SEA) with different levels of blood eosinophils used in clinical trials. Dupilumab, anti-IL-4/IL-13, was shown to be effective in SEA and is the only agent currently FDA-approved for the indication of oral corticosteroid dependent asthma, regardless of the blood eosinophil level. This review also summarizes the existing knowledge regarding the characteristics of the patient who may respond to the different therapies. As of today, more studies are needed to better understand the diverse mechanisms that underlie SA phenotypes. We have not yet adequately reached the goal of precision medicine. Additional studies are necessary in order to find novel surrogate markers that can predict the response to a specific biologic therapy, especially in patients who are oral corticosteroid dependent. In addition, efforts must be invested into research looking for new treatment options for patients with non-type-2 inflammation SA.Statement of novelty: we review the current evidence regarding tailored treatment therapies in SA, with a particular focus on the knowledge regarding patient selection for specific biologic treatments.
- OPEN ACCESSPioneered in 1968, hematopoietic stem cell transplantation (HSCT) first cured a patient with severe combined immune deficiency (SCID) transplanted from a matched sibling, bringing hope for this previously fatal disease. Since then, HSCT has become the standard of care treatment for SCID with thousands of patients transplanted successfully worldwide. Initially successful mainly in patients with a matched sibling donor and in specific easier to transplant types of SCID, nowadays, most patients with SCID undergo successful transplantation due to HSCT technique advances. These include refined human leukocyte antigen (HLA)-tissue typing, use of alternative donors, availability of new stem cell sources such as umbilical cord blood, less toxic chemotherapeutic conditioning, as well as improved graft-versus-host disease (GvHD) prophylaxis. Other factors contributing to the success of transplantation include the improvement of supportive care by molecular detection of viral infections, enabling preemptive antiviral treatment before organ damage occurs. Increased awareness for primary immunodeficiency disorders (PID), leading to earlier diagnosis and referral to specialist centers, has been another important factor in successfully transplanting SCID patients. A major game changer in the last decade has been the implementation of neonatal screening for SCID. This increased early diagnosis, allowing for this disease to be almost universally diagnosed soon after birth in countries which included this test in their newborn screening program. As a result, early and optimal transplant timing and conditions could be achieved. However, very early diagnosis also raised new questions regarding SCID patients with a “leaky” phenotype, as well as dilemmas regarding transplant and conditioning regimens in very young infants. With improved diagnosis and treatment options, overall survival has increased to over 90% for SCID babies with a genoidentical donor and similar results are emerging for matched unrelated donor HSCT. Due to new advances, we hope to achieve similar results for those given HSCT from haploidentical donors as well. This review will focus on the new considerations in HSCT seen in recent years, and examines the effect they have had on treatment options and outcomes for SCID patients.Statement of novelty: The field of HSCT has advanced considerably since the first successful SCID bone marrow transplant in 1968. However, success rates have been limited due to delayed diagnosis and poor outcome of patients for which a HLA-matched donor could not be found. This review will discuss recent advances occurring in the last decade in HSCT for SCID, and our hopes to bring cure to this once fatal disease.
- OPEN ACCESSHistamine is a bioactive amine which is considered a key player in the allergic response. Thus, histamine receptor blockers (antihistamines) play an important role in the treatment of a number atopic diseases such as allergic rhinitis, conjunctivitis, and acute and chronic forms of urticaria. Histamine is produced by immune cells but also by bacteria in the gut. Beyond its role in the acute allergic response, histamine exerts numerous effects by binding to its 4 pleiotropic G-protein coupled histamine receptors. Here, we describe the roles of these histamine receptors and antihistamines in the human system, clinical applications, side effects, and novel concepts for the usage of antihistamines with different specificity based on guidelines and recommendations.Statement of novelty: This review provides an overview of histamine receptors and links it to clinical relevance of antagonizing their action in clinical routine.
- OPEN ACCESSChronic granulomatous disease (CGD) is a rare immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and to resolve inflammation. The last few years have witnessed major advances in pathogenesis and clinical management of the disease:Better understanding of 3 physiologic anti-inflammatory functions of NADPH oxidase-derived reactive oxygen species: Promotion of the clearance of dying host cells, suppression of inflammasomes, and regulation of type I interferon signalling. This insight is opening new avenues for targeted drug interventions.Advances in reduced intensity conditioning (RIC) for allogeneic hematopoietic stem cell transplantation (HSCT) make it a promising and safe procedure even for fragile patients with ongoing severe infection or hyperinflammation.Encouraging early data of a multicenter trial of gene-replacement therapy using a self-inactivated lentiviral vector.Combining targeted anti-infectious/anti-inflammatory measures and considering extended indications for curative HSCT are key to improving patient outcome further. Gene therapy will likely become a viable option for disease correction, but long-term assessment is not yet possible.Statement of novelty: We discuss important advances in pathogenesis and treatment of CGD that will change our approach to clinical management.
- OPEN ACCESSBackground: Cleaning and disinfecting agents are widely used in modern life, in homes, schools, public places, and workplaces as well as in recreational facilities such as swimming pools. Use has been for sanitizing purposes and to assist in reduction of infection as well as for deodorizing purposes. However, adverse respiratory effects have been associated with use of cleaning products ranging from effects in infancy and early childhood up to adults at home and work.Methods: This review summarizes recent published literature on the effects of cleaning agents used pre-natally, in childhood and adult life, at home, work, and in swimming pools.Results: Several studies have indicated that there is an increased risk of developing asthma among adults with frequent exposure to cleaning products at work and in the home. Potential mechanisms include sensitization and respiratory irritant effects. Exposure to irritant chlorine by-products from swimming pools have also been associated with respiratory effects and increased risk of asthma. Potential effects from maternal exposures to cleaning products on infants, and effects on early childhood atopy are less clear.Conclusions: Exposure to cleaning agents increases relative risks of asthma among workers, and adults using these agents in the home. Risks are also increased with exposure to chlorinated by-products from swimming pools, both in adults and children. Further studies are needed to understand the mechanisms of these associations.
- OPEN ACCESS
- Adi Ovadia and
- Ilan Dalal
Primary immunodeficiency (PID) is a group of genetic disorders which affects immune cell development, differentiation, and function. The affected individuals are highly susceptible to infection by a diverse array of pathogens. Epstein–Barr virus (EBV) infection is ubiquitous in humans and usually involves an asymptomatic or self-limiting clinical course. In rare cases, EBV can cause not only an acute infection but also a severe exaggerated immune response and lymphoproliferative disease.Furthermore, EBV infection in patients with PID can lead to immune dysregulation and increased risk of malignancies, in addition to the severe course of the acute infection. Recognition of the different genetic defects and their effect on immunological pathways provide us with fundamental insights into the pathophysiology of EBV infection and associated disease, and may lead to developing better targeted therapies in the future. Here, we review all of PIDs with an abnormal response to EBV disease.Statement of novelty: Here we provide a review of the current knowledge of all PIDs reported to be associated with abnormal response to EBV infection and associated disease, such as hemophagocytic lymphohistiocytosis. - OPEN ACCESSSevere bacterial infection (SBI) poses a significant clinical problem as its mortality and morbidity is still unacceptably high. A systematic literature analysis was performed with an emphasis on recent meta analyses examining the specificity and sensitivity of conventional inflammation biomarkers (C-reactive protein, procalcitonin, interleukin-6, interleukin-8) for diagnosing SBI. Most inflammation biomarkers do not show high sensitivity and are of limited value regarding SBI detection. To the practicing clinician, the sole use of inflammation markers is not useful for differentiating between viral or bacterial origin of infection in an individual patient. Thus, only in combination with clinical biometric markers, taken from patient history and physical examination, is the analysis of inflammation biomarkers to some degree helpful in clinical practice. To date, their sensitivity and specificity have been best captured in the field of neonatology, where levels of interleukin-6 have been measured in combination with relevant perinatal factors. The indiscriminate use of inflammation biomarkers for the diagnosis of SBI may lead to over diagnosis. Novel technologies for pathogen detection and more precise measurement of the host-response using microarrays, allowing for simultaneous detection of multiple genes or proteins, promise to improve the value of laboratory biomarkers for the diagnosis of SBI.Statement of novelty: Presented here is an up-to-date systematic analysis of C-reactive protein and inflammation biomarkers with regard to their use in the diagnosis of SBI. I question whether a broad use of C-reactive protein is useful in patients presenting with infection. The results of the systematic analysis are put into context with recent concerns about over-diagnosing in medicine. This paper is adapted from a publication in the German journal Monatsschrift Kinderheilkunde.
- OPEN ACCESSHaemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome, triggered by the excessive stimulation of lymphocytes and macrophages producing abnormally increased levels of cytokines. The diagnosis can be challenging due to overlapping signs and symptoms with other diseases. Therefore, early detection and prompt initiation of treatment is crucial for better survival. There are mainly 2 forms of HLH, primary (genetic) and secondary (acquired). Recent advances in the diagnosis and treatment modalities have led to better understanding of HLH. Here, we present a concise review of the literature with recent updates in pathogenesis, diagnostic modalities, and treatment of HLH.Statement of novelty: In this concise review of HLH, we discuss from the historical background to contemporary diagnostic modalities, as well as recent updates on treatment.
- OPEN ACCESSEosinophilic esophagitis is an antigen-mediated chronic disease that has been increasing in prevalence for the last few decades. A plethora of research has been done recently studying the pathophysiology and potential treatments for the disease. This review paper highlights the epidemiology, diagnosis, pathophysiology, and treatment of eosinophilic esophagitis including new diagnostic and treatment modalities for the disorder.Statement of novelty: We review the epidemiology, diagnosis, pathophysiology, and treatment of eosinophilic esophagitis, and include new diagnostic and treatment modalities for the disorder.
- OPEN ACCESSChronic mucocutaneous candidiasis (CMCC) encompasses a heterogeneous group of syndromes associated with persistent or recurrent Candida infections of the skin, nails, and mucous membranes. While chronic candidiasis can present by itself or as part of a complex, including endocrinopathy, autoimmune manifestations, bone marrow failure and neoplastic diseases, it is often regarded as a warning sign for immunodeficiency. Here, we review the processes involved in host-microbial recognition of Candida and highlight underlying genetic causes of CMCC—including those that are monogenic (such as mutations in AIRE and STAT1) as well as polymorphisms that increase susceptibility to candidal infection.Statement of novelty: This review provides an overview of the pathophysiology of Candida fungal infection as well as genetic defects that have been identified to cause CMCC.
- OPEN ACCESSThe nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was similar to that after reduced intensity conditioning, although donor cells engraftment and immune reconstitution after HSCT was not complete in some patients. The effects of HSCT on organ dysfunction associated with NFκB defects, such as liver toxicity or bowel inflammation, are still not clear. Earlier identification and transplantation of affected patients, as well as better understanding of the pathogenesis and complications of the different NFκB mutations, might improve outcome of HSCT for specific patient populations.Statement of novelty: This review highlights the current indications, regimens, and outcome of HSCT for inherited defects involving various components of the canonical and non-canonical NFκB pathways.
- OPEN ACCESS
- Richard Y. Wu,
- Michael P. Jeffrey,
- Kathene C. Johnson-Henry,
- Julia M. Green-Johnson, and
- Philip M. Sherman
Increasing evidence indicates that gut microorganisms impact multiple aspects of the innate and adaptive mucosal immune system. Current research focuses on the potential of prebiotics (non-digestible fibres that nourish beneficial bacteria) and probiotics (beneficial live bacteria) to promote health, prevent disease, and for use as a treatment strategy for a variety of immune-mediated conditions. The immune modulatory effects of probiotics and prebiotics are strain- or structure-specific and vary with disease state, age, and sex. Prebiotics and live beneficial bacteria, including their metabolic products or soluble mediators, have the ability to affect the composition of the intestinal microbiota. As well, they influence the integrity and functions of intestinal epithelial cells and antigen presenting cells, including dendritic cells and macrophages, by both direct and indirect mechanisms of action.Statement of novelty: This review serves to highlight select advances related to the impact of prebiotics, probiotics, and gut microbe-derived metabolites on host immune function. - OPEN ACCESSWhole exome and whole genome sequencing are next generation sequencing (NGS) applications that enable investigation of all coding variants (around 20 000) or all variants (around 4 million) in the human genome. They provide an extremely powerful tool for detecting variants with an established implication in Mendelian disorders as well as for discovering new disease variants and genes. The large number of variants generated requires elaborate databases, prediction models, and integrated workflows to identify which variants are more likely to contribute to disease. We discuss the whole exome and whole genome options, review the sequencing platforms and variant calling pipelines available for different variant types, and devote most of the review to how genetic variants can be annotated and prioritized to identify the ones likely contributing to disorder. The application focus will be Mendelian disorders; disorders caused by rare or common variants with a more complex genetic architecture will only be discussed briefly. For variant annotation and interpretation, we will concentrate on smaller variants (substitutions, insertions, and deletions), only briefly reviewing structural and copy number variation.
- OPEN ACCESSInfections represent an ongoing challenge for immunocompromised patients. Children are particularly vulnerable because of several age-related issues that relate in part to immune prematurity. This review addresses the challenges in managing infections among immunocompromised children and highlights several general principles that guide management.Statement of novelty: This work provides important guidance to clinicians who are involved in the management of pediatric patients with an ever-expanding spectrum of immunocompromising disorders.
- OPEN ACCESSDendritic cells (DC) are professional antigen-presenting cells that play a key role in linking the innate and adaptive arms of the immune system. In vitro, DC perform critical functions such as antigen uptake and processing, priming of naïve T cells and production of cytokines to regulate other immune cells. In vivo experimental systems support a central role for DC in inducing protective immune responses but the effect of DC deficiency in existing whole animal models is smaller than would be predicted. Studies of human primary immunodeficiency disorders (PID) have significantly advanced our understanding of the development and function of other immune cells and provide some important information about DC. Although only a small number of rare monogenic PID that cause DC deficiency have been described to date, impaired DC function forms part of the immunophenotype of several PID and is likely to contribute to clinical presentation. This review focuses on what is known so far about the role of DC in PID and what implications this has for basic DC biology.
- OPEN ACCESSThe history of providing antibodies to treat diseases began in the 19th century with the discovery of tetanus and diphtheria toxins and the demonstration that immunity to tetanus and diphtheria infections could be transferred by immune sera. Characterization of the mediators of this immunity resulted in the discovery that antibodies are proteins that can be isolated and used to protect against infectious diseases. Development of a method to isolate antibodies from human plasma that could be safely injected into people initiated the development of human gamma globulin preparations to provide antibodies to patients with inherited antibody deficiencies. To overcome the limitations imposed by intramuscular injection of gamma globulin, intravenous gamma globulin preparations were developed that began to be used in a wide variety of clinical conditions. Thus the original clinical indication for infection prevention was expanded to several other indications that employ large doses to suppress inflammatory and autoimmune disorders. The most recent development in immunoglobulin therapy is the production of concentrated immune globulins for subcutaneous injection. Home infusions of subcutaneous immunoglobulin are increasingly used to treat immunodeficient patients and are being studied for other clinical applications.
- OPEN ACCESSPrimary immunodeficiencies (PID) can present with recurrent infections, autoimmunity, inflammation, or malignancy and each of these conditions can be associated with elevated immunoglobulin. A high level of immunoglobulin G (IgG) is an uncommon finding, especially in pediatrics, and does not rule out primary immunodeficiency. Deficiencies in varied aspects of immune response have been described with high IgG. Reported PID conditions with elevated IgG include defects in humoral, cellular, and innate immunity. Some of these immunodeficiencies can have fatal outcomes, some require hematopoetic stem cell transplantation, and some require systemic medications. The mechanisms driving elevated IgG are not well understood, but in some cases abnormal cytokine production has been proposed. The evaluation of a patient with high IgG is guided by the patient's history and a physical examination, with special attention to autoimmunity in pediatrics and malignancy and liver disease in adults. In the setting of autoimmunity, chronic gastrointestinal disease, or chronic infections, the measurement of specific antibodies to evaluate the function of the IgG should be considered. An increased appreciation of elevation in IgG reflecting immune dysregulation may lead to earlier PID diagnoses.
- OPEN ACCESS
- Ana V.M. Marin,
- Beatriz Garcillán,
- Anaïs Jiménez-Reinoso,
- Miguel Muñoz-Ruiz,
- Alejandro C. Briones,
- Edgar Fernández-Malavé,
- Maria J. Recio, and
- José R. Regueiro
Immunodeficiencies of most T-cell receptor (TCR) components (TCRID) have been reported in almost 40 patients worldwide who have also, at times, shown signs of autoimmunity. We updated their clinical, immunological, and molecular features with an emphasis on practical diagnosis, as the range of the disorder grows in complexity with new partial defects. Cellular and animal models are also reviewed and in some cases reveal their limitations for predicting TCRID immunopathology. - OPEN ACCESSThe mammalian gut is the richest immune organ in the body and serves as a central location for immune system development, processing, and education. Inflammatory bowel diseases (IBD) provide excellent models for studying both innate and adaptive responses to gut microbes and the host-immune system – microbe interactions in the gut. Microbes are linked to almost all of the known disease-associated genetic polymorphisms in IBD and are critical mediators of environmental effects (through food, hygiene, and infection). Human and animal-based research supports the central role of microbes in IBD pathogenesis at multiple levels. Animal models of IBD only develop in the presence of microbes, and co-housing mice that are genetically susceptible to gut inflammation with normal mice can lead to the development of bowel injury. Recent advances in research technologies, such as deep-sequencing that enables detailed compositional analyses, have revolutionized the study of host–microbe interactions in the gut; however, knowing which bacteria are present in the bowel is likely not sufficient. The function of the microbiota as a community is recognized as a critical factor for gut homeostasis. Animal models of IBD have provided critical insight into basic biology and disease pathogenesis, especially regarding the role of microbes in IBD pathogenesis. Although many of these recent discoveries on host–microbe interactions are not yet applied to patient care, these basic observations will certainly revolutionize patient care in the future. Using such data, we may be able to predict risk of disease, define biological subtypes, establish tools for prevention, and even cure IBD using microbes or their products. A broad spectrum of therapeutic tools spanning from fecal transplantation, probiotics, prebiotics, and microbial products to microbe-tailored diets may supplement current IBD treatments.
