scholarly journals Gut Microbiota–Host Interactions in Inborn Errors of Immunity

2021 ◽  
Vol 22 (3) ◽  
pp. 1416
Author(s):  
Riccardo Castagnoli ◽  
Francesca Pala ◽  
Marita Bosticardo ◽  
Amelia Licari ◽  
Ottavia M. Delmonte ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Wide Spectrum ◽  
Adaptive Immune System ◽  
Clinical Feature ◽  
Inborn Errors ◽  
Mucosal Permeability ◽  
Microbial Dysbiosis ◽  
Inborn Errors Of Immunity ◽  
Key Aspects ◽  
And Function

Inborn errors of immunity (IEI) are a group of disorders that are mostly caused by genetic mutations affecting immune host defense and immune regulation. Although IEI present with a wide spectrum of clinical features, in about one third of them various degrees of gastrointestinal (GI) involvement have been described and for some IEI the GI manifestations represent the main and peculiar clinical feature. The microbiome plays critical roles in the education and function of the host’s innate and adaptive immune system, and imbalances in microbiota-immunity interactions can contribute to intestinal pathogenesis. Microbial dysbiosis combined to the impairment of immunosurveillance and immune dysfunction in IEI, may favor mucosal permeability and lead to inflammation. Here we review how immune homeostasis between commensals and the host is established in the gut, and how these mechanisms can be disrupted in the context of primary immunodeficiencies. Additionally, we highlight key aspects of the first studies on gut microbiome in patients affected by IEI and discuss how gut microbiome could be harnessed as a therapeutic approach in these diseases.

scholarly journals Thymic origins of autoimmunity—lessons from inborn errors of immunity

2021 ◽  
Author(s):  
Rosa Bacchetta ◽  
Kenneth Weinberg
Keyword(s):  
T Cell ◽  
Epigenetic Modification ◽  
Constitutive Expression ◽  
Abnormal Development ◽  
Thymic Epithelial Cells ◽  
Clonal Deletion ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity ◽  
Molecular Events ◽  
And Function

AbstractDuring their intrathymic development, nascent T cells are empowered to protect against pathogens and to be operative for a life-long acceptance of self. While autoreactive effector T (Teff) cell progenitors are eliminated by clonal deletion, the intrathymic mechanisms by which thymic regulatory T cell (tTreg) progenitors maintain specificity for self-antigens but escape deletion to exert their regulatory functions are less well understood. Both tTreg and Teff development and selection result from finely coordinated interactions between their clonotypic T cell receptors (TCR) and peptide/MHC complexes expressed by antigen-presenting cells, such as thymic epithelial cells and thymic dendritic cells. tTreg function is dependent on expression of the FOXP3 transcription factor, and induction of FOXP3 gene expression by tTreg occurs during their thymic development, particularly within the thymic medulla. While initial expression of FOXP3 is downstream of TCR activation, constitutive expression is fixed by interactions with various transcription factors that are regulated by other extracellular signals like TCR and cytokines, leading to epigenetic modification of the FOXP3 gene. Most of the understanding of the molecular events underlying tTreg generation is based on studies of murine models, whereas gaining similar insight in the human system has been very challenging. In this review, we will elucidate how inborn errors of immunity illuminate the critical non-redundant roles of certain molecules during tTreg development, shedding light on how their abnormal development and function cause well-defined diseases that manifest with autoimmunity alone or are associated with states of immune deficiency and autoinflammation.

scholarly journals Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

2022 ◽  
Vol 12 ◽  
Author(s):  
Ebe Schiavo ◽  
Beatrice Martini ◽  
Enrico Attardi ◽  
Filippo Consonni ◽  
Sara Ciullini Mannurita ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Genetic Disorders ◽  
Clinical Manifestations ◽  
Warning Signs ◽  
Inborn Errors ◽  
Multiparametric Flow Cytometry ◽  
First Line Therapy ◽  
Inborn Errors Of Immunity ◽  
Autoimmune Cytopenias ◽  
A Prospective Study

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

scholarly journals Monogenic Adult-Onset Inborn Errors of Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Frederik Staels ◽  
Tom Collignon ◽  
Albrecht Betrains ◽  
Margaux Gerbaux ◽  
Mathijs Willemsen ◽  
...  
Keyword(s):  
Pediatric Population ◽  
Adaptive Immune System ◽  
Adult Onset ◽  
Inborn Errors ◽  
Adaptive Immune ◽  
Delayed Onset ◽  
Inborn Errors Of Immunity ◽  
Heterogenous Group ◽  
Targeted Treatments ◽  
Generation Sequencing

Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate and/or adaptive immune system. The majority of these disorders are thought to have polygenic background. However, the use of next-generation sequencing in patients with IEI has led to an increasing identification of monogenic causes, unravelling the exact pathophysiology of the disease and allowing the development of more targeted treatments. Monogenic IEI are not only seen in a pediatric population but also in adulthood, either due to the lack of awareness preventing childhood diagnosis or due to a delayed onset where (epi)genetic or environmental factors can play a role. In this review, we discuss the mechanisms accounting for adult-onset presentations and provide an overview of monogenic causes associated with adult-onset IEI.

scholarly journals Endocrinopathies in Inborn Errors of Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Kei Takasawa ◽  
Hirokazu Kanegane ◽  
Kenichi Kashimada ◽  
Tomohiro Morio
Keyword(s):  
Adrenal Insufficiency ◽  
Growth Failure ◽  
Endocrine System ◽  
Autoimmune Response ◽  
Clinical Feature ◽  
Endocrine Disorders ◽  
Energy Regulation ◽  
Inborn Errors ◽  
Hematopoietic Stem ◽  
Inborn Errors Of Immunity

Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.

scholarly journals Inborn errors of immunity—recent advances in research on the pathogenesis

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Motoi Yamashita ◽  
Kento Inoue ◽  
Tsubasa Okano ◽  
Tomohiro Morio
Keyword(s):  
Immune System ◽  
Hematopoietic Cell Transplantation ◽  
Epigenetic Modification ◽  
Genetic Disorder ◽  
Loss Of Function ◽  
Inborn Errors ◽  
Whole Genome Analysis ◽  
Curative Therapy ◽  
Inborn Errors Of Immunity ◽  
Recent Advances

AbstractPrimary immunodeficiency (PID) is a genetic disorder with a defect of one of the important components of our immune system. Classical PID has been recognized as a disorder with loss of function of the immune system. Recent studies have unveiled disorders with immune dysfunction with autoimmunity, autoinflammation, allergy, or predisposition to malignancy. Some of them were caused by an augmented immune function or a defect in immune regulation. With this background, the term inborn errors of immunity (IEI) is now used to refer to PID in the International Union of Immunological Societies (IUIS) classification. More than 400 responsible genes have been identified in patients with IEI so far, and importantly, many of them identified lately were caused by a heterologous mutation. Moreover, the onset is not necessarily in childhood, and we started seeing more and more IEI patients diagnosed in adulthood in the clinical settings. Recent advances in genetic analysis, including whole-exome analysis, whole-genome analysis, and RNA-seq have contributed to the identification of the disease-causing gene mutation. We also started to find heterogeneity of phenotype even in the patients with the same mutation in the same family, leading us to wonder if modifier gene or epigenetic modification is involved in the pathogenesis. In contrast, we accumulated many cases suggesting genetic heterogeneity is associated with phenotypic homogeneity. It has thus become difficult to deduce a responsible gene only from the phenotype in a certain type of IEI. Current curative therapy for IEI includes hematopoietic cell transplantation and gene therapy. Other curative therapeutic modalities have been long waited and are to be introduced in the future. These include a small molecule that inhibits the gain-of-function of the molecule- and genome-editing technology. Research on IEI will surely lead to a better understanding of other immune-related disorders including rheumatic diseases and atopic disorders.

scholarly journals Human inborn errors of immunity to herpes viruses

2020 ◽  
Vol 62 ◽  
pp. 106-122 ◽  
Author(s):  
Emmanuelle Jouanguy ◽  
Vivien Béziat ◽  
Trine H Mogensen ◽  
Jean-Laurent Casanova ◽  
Stuart G Tangye ◽  
...  
Keyword(s):  
Herpes Viruses ◽  
Inborn Errors ◽  
Inborn Errors Of Immunity
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