DNA breaks can be induced by exogenous stimuli or by endogenous stress, but are also generated during recombination of V, D, and J genes (V(D)J recombination), immunoglobulin class switch ...recombination (CSR). Among various DNA breaks generated, DNA double strand break (DSB) is the most deleterious one. DNA damage response (DDR) is initiated when DSBs are detected, leading to DNA break repair by non-homologous end joining (NHEJ). The process is critically important for the generation of diversity for foreign antigens; and failure to exert DNA repair leads to immunodeficiency such as severe combined immunodeficiency and hyper-IgM syndrome. In V(D)J recombination, DSBs are induced by RAG1/2; and generated post-cleavage hairpins are resolved by Artemis/DNA-PKcs/KU70/KU80. DDR is initiated by ataxia-telangiectasia mutated as a master regulator together with MRE11/RAD50/NBS1 complex. Finally, DSBs are repaired by NHEJ. The defect of one of the molecules shows various degree of immunodeficiency and radiosensitivity. Upon CSR inducing signal, DSBs induced by activation-induced cytidine deaminase and endonucleases elicit DDR. Broken ends are repaired either by NHEJ or by mismatch repair system. Patients with radiosensitive SCID require hematopoietic cell transplantation as a curative therapy; but the procedures for eradication of recipient hematopoietic cells are often associated with severe toxicity.
We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents ...the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.
Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which ...accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.
Our understanding of the spatiotemporal regulation of cardiogenesis is hindered by the difficulties in modeling this complex organ currently by in vitro models. Here we develop a method to generate ...heart organoids from mouse embryonic stem cell-derived embryoid bodies. Consecutive morphological changes proceed in a self-organizing manner in the presence of the laminin-entactin (LN/ET) complex and fibroblast growth factor 4 (FGF4), and the resulting in vitro heart organoid possesses atrium- and ventricle-like parts containing cardiac muscle, conducting tissues, smooth muscle and endothelial cells that exhibited myocardial contraction and action potentials. The heart organoids exhibit ultrastructural, histochemical and gene expression characteristics of considerable similarity to those of developmental hearts in vivo. Our results demonstrate that this method not only provides a biomimetic model of the developing heart-like structure with simplified differentiation protocol, but also represents a promising research tool with a broad range of applications, including drug testing.
Monogenic diseases of the immune system, also known as inborn errors of immunity (IEIs), are caused by single-gene mutations and result in immune deficiency and dysregulation. More than 400 monogenic ...diseases have been described to date, and this number is rapidly expanding. The increasing availability of next-generation sequencing is now facilitating the diagnosis of IEIs. It is known that IEIs can predispose a person to not only infectious diseases but also cancer and immune disorders, such as inflammatory, autoimmune, and atopic diseases. IEIs with eosinophilia and atopic diseases can occur in several disorders. IEIs with eosinophilia have provided insights into human immunity and the pathogenesis of allergic diseases. Eosinophilia is not a rare finding in clinical practice, and it often poses problems in terms of etiologic research and differential diagnoses. Secondary eosinophilia is the most common form. The main underlying conditions are infectious diseases such as parasitic infections, allergic disorders, drug reactions, and of course IEIs. In clinical settings, the recognition of IEIs in the context of an allergic phenotype with eosinophilia is critical for prompt diagnosis and appropriate treatment aimed at modulating pathophysiological mechanisms and improving clinical symptoms.
The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in ...January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects.
We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and ...laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.
Changes of nuclear localization of lineage‐specific genes from a transcriptionally inert to permissive environment are a crucial step in establishing the identity of a cell. Noncoding RNA ...transcription‐mediated genome folding and activation of target gene expression have been found in a variety of cell types. Noncoding RNA ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T‐cell lineage commitment. The cessation of ThymoD transcription abolishes transcription‐mediated demethylation, recruiting looping factors such as the cohesin complex, CCCTC‐binding factor (CTCF), ultimately leading to the phenotype of severe combined immunodeficiency and T‐cell leukemia/lymphoma. In this review, we describe the functional role of RNA polymerase II‐mediated transcription at enhancers and in genome folding. We also highlight the involvement of faulty activation or suppression of enhancer transcription and enhancer‐promoter interaction in cancer development.
Noncoding RNA ThymoD (thymocyte differentiation factor) transcription at superenhancers is essential for mouse T‐cell lineage commitment. The cessation of ThymoD transcription abolishes transcription‐mediated demethylation, recruiting looping factors such as the cohesin complex, CTCF, ultimately leading to the phenotype of severe combined immunodeficiency and T‐cell leukemia/lymphoma.
Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and ...is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs.
Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.
AIOLOS is encoded by
and is a member of the IKAROS zinc finger transcription factor family. Heterozygous missense variants in the second zinc finger of AIOLOS have recently been reported to be found ...in the families of patients with inborn errors of immunity. The AIOLOS
variant was identified in patients with B-lymphopenia and familial Epstein-Barr virus-associated lymphoma. Early B-cell progenitors were significantly reduced in the bone marrow of patients with AIOLOS
. Another variant, AIOLOS
was identified in the patients presented with hypogammaglobulinemia, susceptibility to
pneumonia, and chronic lymphocytic leukemia. Patients with AIOLOS
had mostly normal B cell counts but showed increased levels of CD21
B cells, decreased CD23 expression, and abrogated CD40 response. Both variants were determined to be loss-of-function. Mouse models harboring the corresponding patient's variants recapitulated the phenotypes of the patients. AIOLOS is therefore a novel disease-causing gene in human adaptive immune deficiency.
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