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Journal of Clinical Immunology Jul 2020"X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease is an inborn error of glycosylation and immunity... (Review)
Review
"X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV) infection, and neoplasia" (XMEN) disease is an inborn error of glycosylation and immunity caused by loss of function mutations in the magnesium transporter 1 (MAGT1) gene. It is a multisystem disease that strongly affects certain immune cells. MAGT1 is now confirmed as a non-catalytic subunit of the oligosaccharyltransferase complex and facilitates Asparagine (N)-linked glycosylation of specific substrates, making XMEN a congenital disorder of glycosylation manifesting as a combined immune deficiency. The clinical disease has variable expressivity, and impaired glycosylation of key MAGT1-dependent glycoproteins in addition to Mg abnormalities can explain some of the immune manifestations. NKG2D, an activating receptor critical for cytotoxic function against EBV, is poorly glycosylated and invariably decreased on CD8 T cells and natural killer (NK) cells from XMEN patients. It is the best biomarker of the disease. The characterization of EBV-naïve XMEN patients has clarified features of the genetic disease that were previously attributed to EBV infection. Extra-immune manifestations, including hepatic and neurological abnormalities, have recently been reported. EBV-associated lymphomas remain the main cause of severe morbidity. Unfortunately, treatment options to address the underlying mechanism of disease remain limited and Mg supplementation has not proven successful. Here, we review the expanding clinical phenotype and recent advances in glycobiology that have increased our understanding of XMEN disease. We also propose updating XMEN to "X-linked MAGT1 deficiency with increased susceptibility to EBV-infection and N-linked glycosylation defect" in light of these novel findings.
Topics: Animals; CD8-Positive T-Lymphocytes; Cation Transport Proteins; Cytotoxicity, Immunologic; Drosophila Proteins; Epstein-Barr Virus Infections; Glycosylation; Herpesvirus 4, Human; Humans; Killer Cells, Natural; Magnesium Deficiency; Mutation; Neoplasms; Phenotype; X-Linked Combined Immunodeficiency Diseases
PubMed: 32451662
DOI: 10.1007/s10875-020-00790-x -
Frontiers in Immunology 2022
Topics: Humans; Adenosine Deaminase; Intercellular Signaling Peptides and Proteins; Vasculitis; Polyarteritis Nodosa
PubMed: 36569902
DOI: 10.3389/fimmu.2022.1108853 -
British Journal of Haematology Jun 2021Primary immunodeficiencies (PIDs) are a group of rare inherited disorders of the immune system. Many PIDs are devastating and require a definitive therapy to prevent... (Review)
Review
Primary immunodeficiencies (PIDs) are a group of rare inherited disorders of the immune system. Many PIDs are devastating and require a definitive therapy to prevent progressive morbidity and premature mortality. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative for many PIDs, and while advances have resulted in improved outcomes, the procedure still carries a risk of mortality and morbidity from graft failure or graft-versus-host disease (GvHD). Autologous haematopoietic stem cell gene therapy (HSC GT) has the potential to correct genetic defects across haematopoietic lineages without the complications of an allogeneic approach. HSC GT for PID has been in development for the last two decades and the first licensed HSC-GT product for adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is now available. New gene editing technologies have the potential to circumvent some of the problems associated with viral gene-addition. HSC GT for PID shows great promise, but requires a unique approach for each disease and carries risks, notably insertional mutagenesis from gamma-retroviral gene addition approaches and possible off-target toxicities from gene-editing techniques. In this review, we discuss the development of HSC GT for PID and outline the current state of clinical development before discussing future developments in the field.
Topics: Agammaglobulinemia; Autografts; Gene Editing; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Severe Combined Immunodeficiency
PubMed: 33336808
DOI: 10.1111/bjh.17269 -
Clinical Immunology (Orlando, Fla.) Oct 2023Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who...
Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34 cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment.
Topics: Humans; Paired Box Transcription Factors; Phenotype; T-Lymphocytes; Thymus Gland; Severe Combined Immunodeficiency
PubMed: 37689091
DOI: 10.1016/j.clim.2023.109757 -
The Journal of Clinical Investigation Jan 2022Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive....
Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II-restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.
Topics: Animals; Antigen Presentation; B-Lymphocytes; Female; Histocompatibility Antigens Class II; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Severe Combined Immunodeficiency; T-Lymphocytes, Regulatory
PubMed: 34813502
DOI: 10.1172/JCI150985 -
Frontiers in Immunology 2023Mutations in the recombination activating gene 1 () and in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to... (Review)
Review
Mutations in the recombination activating gene 1 () and in humans are associated with a broad spectrum of clinical phenotypes, from severe combined immunodeficiency to immune dysregulation. Partial (hypomorphic) RAG deficiency (pRD) in particular, frequently leads to hyperinflammation and autoimmunity, with several underlying intrinsic and extrinsic mechanisms causing a break in tolerance centrally and peripherally during T and B cell development. However, the relative contributions of these processes to immune dysregulation remain unclear. In this review, we specifically focus on the recently described tolerance break and B cell abnormalities, as well as consequent molecular and cellular mechanisms of autoantibody production in patients with pRD.
Topics: Humans; Homeodomain Proteins; Severe Combined Immunodeficiency; Autoimmunity; Phenotype; Autoantibodies
PubMed: 37475856
DOI: 10.3389/fimmu.2023.1155380 -
Frontiers in Immunology 2023The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for... (Review)
Review
The mature lymphocyte population of a healthy individual has the remarkable ability to recognise an immense variety of antigens. Instead of encoding a unique gene for each potential antigen receptor, evolution has used gene rearrangements, also known as variable, diversity, and joining gene segment (V(D)J) recombination. This process is critical for lymphocyte development and relies on recombination-activating genes-1 (RAG1) and RAG2, here collectively referred to as RAG. RAG serves as powerful genome editing tools for lymphocytes and is strictly regulated to prevent dysregulation. However, in the case of dysregulation, RAG has been implicated in cases of cancer, autoimmunity and severe combined immunodeficiency (SCID). This review examines functional protein domains and motifs of RAG, describes advances in our understanding of the function and (dys)regulation of RAG, discuss new therapeutic options, such as gene therapy, for RAG deficiencies, and explore and methods for determining RAG activity and target specificity.
Topics: Homeodomain Proteins; Recombinases; Gene Rearrangement; Lymphocytes; Genes, RAG-1
PubMed: 37497222
DOI: 10.3389/fimmu.2023.1210818 -
Frontiers in Pediatrics 2022In this article we revised the literature on Inborn Errors of Immunity (IEI) keeping our focus on those diseases presenting with intrauterine or perinatal clinical... (Review)
Review
In this article we revised the literature on Inborn Errors of Immunity (IEI) keeping our focus on those diseases presenting with intrauterine or perinatal clinical manifestations. We opted to describe our findings according to the IEI categories established by the International Union of Immunological Societies, predominantly addressing the immunological features of each condition or group of diseases. The main finding is that such precocious manifestations are largely concentrated in the group of primary immune regulatory disorders (PIRDs) and not in the group of classical immunodeficiencies. The IEI categories with higher number of immunological manifestations or in perinatal period are: (i) diseases of immune dysregulation (HLH, IPEX and other Tregopathies, autosomal recessive ALPS with complete lack of FAS protein expression) and (ii) autoinflammatory diseases (NOMID/CINCA, DIRA and some interferonopathies, such as Aicardi-Goutières syndrome, AGS, and USP18 deficiency). Regarding the other IEI categories, some patients with Omenn syndrome (an atypical form of SCID), and a few X-linked CGD patients present with clinical manifestations at birth associated to immune dysregulation. The most frequent clinical features were hydrops fetalis, intrauterine growth retardation leading to fetal loss, stillbirths, and prematurity, as in HLH and IPEX. Additionally, pseudo-TORCH syndrome was observed in AGS and in USP18 deficiency. The main goal of our review was to contribute to increasing the medical awareness of IEI with intrauterine and perinatal onset, which has obvious implications for diagnosis, treatment, and genetic counseling.
PubMed: 35601409
DOI: 10.3389/fped.2022.891343