In FY2019, we have identified a novel genetic defect (FCHO1 deficiency) causing combined immune deficiency (CID), and in collaboration with other groups we have contributed to the identification of other novel genetic defects associated with PID. Immune dysregulation, manifesting with autoimmunity or exaggerated inflammatory responses, has emerged as an important component of several forms of PID, and CID in particular. We have identified a novel molecular signature of T cell-mediated immune dysregulation in patients with RAG deficiency, and shownthat similar abnormalities in the mechanisms of T cell tolerance operate also in other genetic conditions associated with autoimmunity. We have expanded characterization of the clinical spectrum of Activated PI3-kinase delta syndrome (APDS), and taken advantage of mouse models of the disease to identify abnormalities of B and T cell tolerance. Finally, in FY2019, we have reviewed outcome in the largest North-American cohort of patients with Severe Combined Immune Deficiency (SCID) who have received hematopoietic cell transplantation (HCT), identified critical variables that determine the quality of long-term immune reconstitution, and established the need to develop conditioning regimens that are targeted to different forms of SCID. During FY2019, the following achievements have been obtained: 1) We have reported the first gene defect (FCHO1 deficiency) affecting the process of clathrin-mediated endocytosis in patients with CID (Publication #5). We have demonstrated that FCHO1 and its highly homologous protein FCHO2 have distinct patterns of expression, with expression in T cells being largely restricted to FCHO1. We have also demonstrated that FCHO1 deficiency does not affect internalization of the CD3/T cell receptor (TCR) complex, but does compromise internalization of the transferrin receptor, suggesting that abnormal iron utilization is a key mechanism of impaired T cell function in these patients. We have also shown that FCHO1 deficiency affects cell cycle progression and cell survival, thereby contributing to the profound immune deficiency of this condition. Finally, we have shown that HCT can rescue the cellular defect and correct the disease phenotype. 2) In collaboration with the Lenardo laboratory at NIAID, we have identified a novel form of CID due to IL2RB gene mutation (publication #29). Consistent with an important role for IL-2 signaling in peripheral immune homeostasis, we have shown that patients with this disease suffer from autoimmunity in addition to infections 3) We have also participated at larger collaborative studies aimed to identify novel genetic causes of PID. As part of this work, we have contributed to the identification of neomorphic variants in the CEBPE gene as a cause of an autoinflammatory disease (publication #11). We have reported heterogeneity of the clinical phenotype in Ligase 1 (LIG1) deficiency (publication #17). Finally, we have participated in the identification of a novel form of CID due to ARPC1B gene defects, and shown that the abnormalities of cytoskeleton rearrangement in this disease are also responsible for a broad spectrum of immunological defects, thereby explaining the wide range of phenotypic manifestations, including allergy, infections and inflammation (publications #4 and 28). 4) A major focus of research in our group is represented by the characterization of the molecular and cellular mechanisms of immune dysregulation in patients with PID, and CID in particular. During FY2019, we have reported on a novel clinical manifestation of immune dysregulation (severe myopathy with autologous T cells infiltrating skeletal muscles) in an adult with RAG deficiency (publication #13). We have also reported on the clinical and immunological phenotype in more than 400 patients with RAG deficiency, the largest series reported so far for this disorder (publication #8). In a multicenter study, we have shown that the manifestations of immune dysregulation in RAG deficiency are often refractory to first- and even second-line of treatment, while HCT is curative in most cases. (publication #9). We have reviewed the molecular and cellular mechanisms responsible for altered T and B cell tolerance in patients with hypomorphic RAG mutations (publication #27), and identified persistence of T cell clonotypes harboring central CDR3 cysteine residues as a novel biomarker of this condition (publication #7). Furthermore, in collaboration with the Lionakis group at NIAID, we have shown that the impaired cross-talk between developing thymocytes and thymic epithelial cells as a cause of altered central tolerance is not restricted to RAG deficiency, but is also seen in other forms of PID, such as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome (publication #10). In order to better define the thymic abnormalities that characterize inborn errors with immune dysregulation, we have initiated a study of thymuses that are removed at the time of heart surgery from infants with DiGeorge syndrome (DGS), Trisomy 21 (T21) or from infants with otherwise intact immune system. We have demonstrated that the thymus of T21 patients undergoes accelerated maturation and premature ageing, whereas DGS is characterized by impaired maturation of the thymic medulla (publication #18). 5) Taking advantage of the large cohort of patients with APDS that has been assembled by Dr. Uzel at the NIH Clinical Center, and of two newly developed mouse models of this disease, we have further investigated the phenotypic spectrum of the disease and the molecular and cellular bases of its immune dysregulation. We have reported on the occurrence of disseminated toxoplasmosis in a female with APDS and congenital toxoplasmosis in her affected fetus (publication #14). We have also demonstrated important B- and T-cell intrinsic abnormalities in APDS mice that mirror what observed in patients (publications #3 and 23). These mouse models may therefore represent a valuable tool to explore novel therapeutic modalities, especially considering the current limitations of HCT in this disorder (publication #21). 6) In a series of collaborative studies, we have expanded the knowledge of the phenotypic spectrum and of the molecular and cellular mechanisms of PID. These achievements include: i) identification of the Wiskott-Aldrich Syndrome protein as a tumor suppressor (publication #18); ii) description of life-threatening influenza in a patient with TLR3 deficiency (publication #16) and demonstration that TLR3 signaling does not protect trigeminal neurons from HSV-1 replication (publication #30); iii) identification of abnormal glycosylation as a novel mechanism accounting for deficiency of ADA2 (DADA2) syndrome (publication #22);and, iv) demonstration that DOCK2 deficiency is also characterized by neutrophil functional defects (publication #20). 7) We have reported outcome in the largest series of patients with SCID who have received HCT in North America (publication #12). We have demonstrated that the count of total and nave CD4 cells at 6 months post-transplant is predictive of long-term T cell immune reconstitution, and demonstrated that the need for second interventions varies depending on the nature of the underlying SCID genotype. As part of a group of experts, we defined optimal therapeutic approaches for patients with ADA deficiency (publication #15). Finally, we demonstrated that gene therapy in patients with X-linked SCID results in improved diversity of the T cell repertoire and correction of the microbiota (publication #6), and that gene therapy for Wiskott-Aldrich syndrome may correct platelet dysfunction (publication #26).
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