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Background: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts., Objective: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system., Methods: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded., Results: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency., Conclusions: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)

Background: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections., Objective: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency., Methods: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment., Results: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8 + T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities., Conclusion: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities., Objectives: We sought to characterize the underlying genetic cause of this syndrome., Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing., Results: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell., Conclusions: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Expression of the pre-B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre-B-cell receptor result in early B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre-B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified., Methods: B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo., Results: Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK, which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre-BI- to pre-BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)