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Anna Villa - One of the best experts on this subject based on the ideXlab platform.
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447. Lentiviral Gene Therapy in a Preclinical Model of Omenn Syndrome
Molecular Therapy, 2015Co-Authors: Maria Carmina Castiello, Virginia Maina, Marita Bosticardo, Valentina Capo, Elena Draghici, Niek P. Van Til, Gerard Wagemaker, Anna VillaAbstract:Patients with Omenn Syndrome (OS), carrying hypomorphic recombination activating genes (RAG) mutations, develop a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. RAG1 and RAG2 genes play an essential role in the generation of antigen receptors during lymphocyte development. HLA-matched bone marrow transplantation is curative, however, hematopoietic stem cell gene therapy (GT) could represent an alternative treatment for patients lacking a suitable donor. The aim of the present study was to investigate the efficacy of GT in a knock-in murine model carrying the Rag2 R229Q mutation that mimics most of the symptoms of human OS. To this aim, we are testing a lentiviral vector encoding for codon optimized human RAG2 (hRAG2co-LV vector) under the control of the ubiquitous chromatin opening element (UCOE).We initially measured the efficiency of transduction of Rag2R229Q/R229Q lineage negative (lin-) cells by testing the presence of the integrated viral vector by real-time PCR in lin- cells transduced at a multiplicity of infection (MOI) 5 and 10 and in vitro cultured for 8 days. We observed that the hRAG2co-LV vector transduced Rag2R229Q/R229Q lin- cells very efficiently at MOI 5. Then, we tested the in vivo efficacy of hRAG2co-LV-mediated GT infusing transduced lin- BM cells isolated from male Rag2R229Q/R229Q mice in lethally irradiated females. Control Rag2R229Q/R229Q mice received wild-type (BMT-WT) or untransduced (BMT-OS) lin- BM cells. Analysis of immune cells in peripheral blood was evaluated overtime starting from six weeks after the treatment. GT-treated mice showed the appearance and progressive increase of B cells and amelioration of T cell frequency and absolute count as compared to BMT-OS mice. In parallel, the frequency of myeloid cells started to decrease 13 weeks after GT indicating a normalization of peripheral immune cell distribution. Our preliminary data demonstrate the feasibility of GT in the preclinical model of OS. Additional experiments aimed at evaluating long-term efficacy and safety are ongoing.
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Omenn Syndrome does not live by V(D)J recombination alone.
Current Opinion in Allergy and Clinical Immunology, 2011Co-Authors: Veronica Marrella, Virginia Maina, Anna VillaAbstract:Purpose of reviewDuring the past decade, easy access to sequence analyses has allowed us to increase our understanding of the pathogenesis of severe combined immunodeficiencies. Here, we describe the expanding clinical and immunological spectrum associated with Omenn Syndrome phenotype. In particula
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analysis of mutations from scid and Omenn Syndrome patients reveals the central role of the rag2 phd domain in regulating v d j recombination
Journal of Clinical Investigation, 2010Co-Authors: Chrystelle Couedel, Anna Villa, Paolo Vezzoni, Christopher Roman, Alison Jones, Patricia CortesAbstract:Rag2 plays an essential role in the generation of antigen receptors. Mutations that impair Rag2 function can lead to severe combined immunodeficiency (SCID), a condition characterized by complete absence of T and B cells, or Omenn Syndrome (OS), a form of SCID characterized by the virtual absence of B cells and the presence of oligoclonal autoreactive T cells. Here, we present a comparative study of a panel of mutations that were identified in the noncanonical plant homeodomain (PHD) of Rag2 in patients with SCID or OS. We show that PHD mutant mouse Rag2 proteins that correspond to those found in these patients greatly impaired endogenous recombination of Ig gene segments in a Rag2-deficient pro-B cell line and that this correlated with decreased protein stability, impaired nuclear localization, and/or loss of the interaction between Rag2 and core histones. Our results demonstrate that point mutations in the PHD of Rag2 compromise the functionality of the entire protein, thus explaining why the phenotype of cells expressing PHD point mutants differs from those expressing core Rag2 protein that lacks the entire C-terminal region and is therefore devoid of the regulation imposed by the PHD. Together, our findings reveal the various deleterious effects of PHD Rag2 mutations and demonstrate the crucial role of this domain in regulating antigen receptor gene assembly. We believe these results reveal new mechanisms of immunodeficiency in SCID and OS.
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Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn Syndrome
Blood, 2009Co-Authors: Pietro Luigi Poliani, Anna Villa, Chaim M. Roifman, Andrew R. Gennery, Fabio Facchetti, Maria Ravanini, Lucia Dora NotarangeloAbstract:Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with T-negative severe combined immunodeficiency, reticular dysgenesis, and Omenn Syndrome. The latter also showed virtual absence of thymic Foxp3+ T cells. In contrast, an IL2RG-R222C hypomorphic mutation permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3+ T cells. Our data provide evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn Syndrome.
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Omenn Syndrome with Mutation in RAG1 Gene
The Indian Journal of Pediatrics, 2008Co-Authors: I. Cherkaoui Jaouad, Anna Villa, Karim Ouldim, S. Ali Ou Alla, Y. Kriouile, Abdelaziz SefianiAbstract:Omenn Syndrome is a form of severe combined immunodeficiency associated with erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. Inherited hypomorphic mutations in the recombination activating genes 1 and 2 (RAG1 and RAG2) and in ARTEMIS genes and more recently defects in IL7RA, and RMRP genes have been described to be responsible of this peculiar immunodeficiency. The authors report here a Moroccan patient of four-months-old with classical features of Omenn Syndrome, carrying a deletion at the N terminal part of RAG1. Early recognition of this condition is important for genetic counseling and early treatment.
Akihiro Yachie - One of the best experts on this subject based on the ideXlab platform.
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Omenn Syndrome and DNA recombination defects.
Japanese Journal of Clinical Immunology, 2017Co-Authors: Akihiro YachieAbstract:Mutations in the RAG1/RAG2 genes are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to various autoimmune diseases. The diversity of the clinical symptoms is determined not only by the residual RAG recombinase enzyme activity as determined by the mutations, but also by multiple environmental factors and, in rare cases, by second site mutations within the RAG1/RAG2 genes. The residual recombinase activity is responsible for the oligoclonal expansion of autoreactive T cells. Omenn Syndrome is the result of intense Th2 type inflammation involving the skin and multiple other organs triggered by these T cells. In this review, the molecular pathology of diseases caused by RAG1/RAG2 mutations, in particular Omenn Syndrome, will be discussed. Furthermore, abnormalities in other molecules involved in V(D)J recombination will be discussed in relation to Omenn-like Syndrome.
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Syndrome atypical x linked severe combined immunodeficiency mimicking Omenn detection of t lymphocytes with a second site mutation in skin lesions of
2013Co-Authors: Yoshihito Kasahara, Akihiro Yachie, Shoichi Koizumi, Taizo Wada, Masahiro Yasui, Tomoko Toma, Yuko Nakayama, Masami Inoue, Keisei Kawa, Mika NishidaAbstract:Abstract X-linked severe combined immunodeficiency (XSCID) is caused by mutations of the common gamma chain (γc) and usually characterized by the absence of T and natural killer (NK) cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn Syndrome-like manifestations. The patient carried a splice-site mutation (IVS1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation and result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn Syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression. From bloodjournal.hematologylibrary.org by guest on June 5, 2013. For personal use only.
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Omenn Syndrome—Review of Several Phenotypes of Omenn Syndrome and RAG1/RAG2 Mutations in Japan
Allergology International, 2006Co-Authors: Masahiko Kato, Yasushi Ishida, Hirokazu Kimura, Mitsuru Seki, Akira Shimada, Yasuhide Hayashi, Tomohiro Morio, Satoru Kumaki, Yoshiro Kamachi, Akihiro YachieAbstract:ABSTRACT Omenn Syndrome (OS) is a form of severe combined immunodeficiency (SCID) characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients with OS, B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes either 1 or 2 ( RAG1 / 2 ) have been detected in most OS patients. We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1 -deficient SCID. In this review, we will focus on the variation of several phenotypes of OS.
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Omenn Syndrome review of several phenotypes of Omenn Syndrome and rag1 rag2 mutations in japan
Allergology International, 2006Co-Authors: Masahiko Kato, Yasushi Ishida, Hirokazu Kimura, Mitsuru Seki, Akira Shimada, Yasuhide Hayashi, Tomohiro Morio, Satoru Kumaki, Yoshiro Kamachi, Akihiro YachieAbstract:ABSTRACT Omenn Syndrome (OS) is a form of severe combined immunodeficiency (SCID) characterized by erythrodermia, hepatosplenomegaly, lymphadenopathy, and alopecia. In patients with OS, B cells are mostly absent, T-cell counts are normal to elevated, and T cells are frequently activated and express a restricted T-cell receptor (TCR) repertoire. Thus far, inherited hypomorphic mutations of the recombination activating genes either 1 or 2 ( RAG1 / 2 ) have been detected in most OS patients. We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1 -deficient SCID. In this review, we will focus on the variation of several phenotypes of OS.
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Novel adopted immunotherapy for mixed chimerism after unrelated cord blood transplantation in Omenn Syndrome
European Journal of Haematology, 2005Co-Authors: Daisuke Tomizawa, Akihiro Yachie, Masahiko Kato, Tomohiro Morio, Yuki Aoki, Masayuki Nagasawa, Michiko Kajiwara, Teruaki Sekine, Norio Shimizu, Shuki MizutaniAbstract:Omenn Syndrome is a variant form of severe combined immunodeficiency. It is fatal unless treated by allogeneic stem cell transplantation (SCT), which is the only curative approach. However, both treatment-related complications and graft rejection are major obstacles to treatment success. This report describes a case with Omenn Syndrome who developed mixed chimerism after unrelated cord blood transplantation (UCBT). This case was successfully treated by altering the patient's immunosuppression and donor lymphocyte infusion (DLI) with donor cord blood-derived activated CD4+ T cells ex vivo expanded from the cord blood cell residues in an infused bag. This novel development to expand CD4+ T-lymphocytes from the donor cord blood unit for the use of DLI would serve as a useful method to overcome the risk of graft rejection in SCT for primary immunodeficiency disorders with residual cell-mediated immunity without compounding graft-vs.-host disease, especially in the UCBT setting.
Veronica Marrella - One of the best experts on this subject based on the ideXlab platform.
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Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn Syndrome.
Journal of Allergy and Clinical Immunology, 2020Co-Authors: Rosita Rigoni, Waleed Al-herz, Veronica Marrella, Virginia Maina, Elena Fontana, Kerry Dobbs, Valentina Taverniti, Amanda Facoetti, Giovanna D’amico, Mario Ernesto Cruz-munozAbstract:Background Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn Syndrome (OS). Objective The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified. Methods We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2R229Q/R229Q (Rag2R229Q) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt. Results We show that memory/activated T cells from patients with OS and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad T h 1/T h 2/T h 17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2R229Q mice results in increased frequency of Ccr4+ splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by T h 1 effector T cells. Conclusions These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.
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Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn Syndrome: therapeutic implications
Blood, 2012Co-Authors: Veronica Marrella, Virginia Maina, Pietro Luigi Poliani, Anna Casati, Barbara Cassani, Francesca Schena, Elena Fontana, Francesca Ficara, Manuela Cominelli, Marianna PaulisAbstract:Omenn Syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3e monoclonal antibody (mAb) treatment in RAG2−/− mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3e mAb administration in the RAG2R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2R229Q progenitors into RAG2−/− animals previously conditioned with anti-CD3e mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3e mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity.
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Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn Syndrome : therapeutic implications
'American Society of Hematology', 2012Co-Authors: Veronica Marrella, Pietro Luigi Poliani, Francesca Ficara, Manuela Cominelli, E. Fontana, A. Casati, V. Maina, B. Cassani, F. Schena, Marianna PaulisAbstract:Omenn Syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre- T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3ε monoclonal antibody (mAb) treatment in RAG2 -/- mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3ε mAb administration in the RAG2 R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2 R229Q progenitors into RAG2 -/- animals previously conditioned with anti-CD3ε mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3ε mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity
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Omenn Syndrome does not live by V(D)J recombination alone.
Current Opinion in Allergy and Clinical Immunology, 2011Co-Authors: Veronica Marrella, Virginia Maina, Anna VillaAbstract:Purpose of reviewDuring the past decade, easy access to sequence analyses has allowed us to increase our understanding of the pathogenesis of severe combined immunodeficiencies. Here, we describe the expanding clinical and immunological spectrum associated with Omenn Syndrome phenotype. In particula
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Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn Syndrome
Journal of Experimental Medicine, 2010Co-Authors: Barbara Cassani, Dario Strina, Veronica Marrella, Pietro Luigi Poliani, Maria Ravanini, Francesca Schena, Aisha V. Sauer, Christian E. Busse, Stephan Regenass, Hedda WardemannAbstract:Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn Syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2R229Q knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2R229Q knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis.
Pietro Luigi Poliani - One of the best experts on this subject based on the ideXlab platform.
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Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn Syndrome: therapeutic implications
Blood, 2012Co-Authors: Veronica Marrella, Virginia Maina, Pietro Luigi Poliani, Anna Casati, Barbara Cassani, Francesca Schena, Elena Fontana, Francesca Ficara, Manuela Cominelli, Marianna PaulisAbstract:Omenn Syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3e monoclonal antibody (mAb) treatment in RAG2−/− mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3e mAb administration in the RAG2R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2R229Q progenitors into RAG2−/− animals previously conditioned with anti-CD3e mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3e mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity.
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Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn Syndrome : therapeutic implications
'American Society of Hematology', 2012Co-Authors: Veronica Marrella, Pietro Luigi Poliani, Francesca Ficara, Manuela Cominelli, E. Fontana, A. Casati, V. Maina, B. Cassani, F. Schena, Marianna PaulisAbstract:Omenn Syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre- T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3ε monoclonal antibody (mAb) treatment in RAG2 -/- mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3ε mAb administration in the RAG2 R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2 R229Q progenitors into RAG2 -/- animals previously conditioned with anti-CD3ε mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3ε mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity
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expansion of immunoglobulin secreting cells and defects in b cell tolerance in rag dependent immunodeficiency
Journal of Experimental Medicine, 2010Co-Authors: Jolan E Walter, Francesca Rucci, Stephan Regenass, Laura Patrizi, Mike Recher, Tiziana Paganini, Marton Keszei, Itai M Pessach, Philipp A Lang, Pietro Luigi PolianiAbstract:The contribution of B cells to the pathology of Omenn Syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro–B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP–keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4+ T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell–activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn Syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.
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Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn Syndrome
Journal of Experimental Medicine, 2010Co-Authors: Barbara Cassani, Dario Strina, Veronica Marrella, Pietro Luigi Poliani, Maria Ravanini, Francesca Schena, Aisha V. Sauer, Christian E. Busse, Stephan Regenass, Hedda WardemannAbstract:Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn Syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2R229Q knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2R229Q knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis.
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Defect of regulatory T cells in patients with Omenn Syndrome
Journal of Allergy and Clinical Immunology, 2010Co-Authors: Barbara Cassani, Cristina Sobacchi, Silvia Giliani, Veronica Marrella, Pietro Luigi Poliani, Daniele Moratto, Laura Imperatori, Donatella Vairo, Alessandro Plebani, Paolo VezzoniAbstract:Background Omenn Syndrome (OS) is an autosomal-recessive disorder characterized by severe immunodeficiency and T-cell–mediated autoimmunity. The disease is caused by hypomorphic mutations in recombination-activating genes that hamper the process of Variable (V) Diversity (D) Joining (J) recombination, leading to the generation of autoreactive T cells. We have previously shown that in OS the expression of autoimmune regulator, a key factor governing central tolerance, is markedly reduced. Objective Here, we have addressed the role of peripheral tolerance in the disease pathogenesis. Methods We have analyzed forkhead box protein P3 (FOXP3) expression in peripheral blood T cells of 4 patients with OS and in lymphoid organs of 8 patients with OS and have tested the suppressive activity of sorted CD4 + CD25 high peripheral blood T cells in 2 of these patients. Results We have observed that CD4 + CD25 high T cells isolated ex vivo from patients with OS failed to suppress proliferation of autologous or allogenic CD4 + responder T cells. Moreover, despite individual variability in the fraction of circulating FOXP3 + CD4 cells in patients with OS, the immunohistochemical analysis of FOXP3 expression in lymph nodes and thymus of patients with OS demonstrated a severe reduction of this cell subset compared with control tissues. Conclusion Overall, these results suggest a defect of regulatory T cells in OS leading to a breakdown of peripheral tolerance, which may actively concur to the development of autoimmune manifestations in the disease.
Chaim M. Roifman - One of the best experts on this subject based on the ideXlab platform.
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Early defects in human T-cell development severely affect distribution and maturation of thymic stromal cells: possible implications for the pathophysiology of Omenn Syndrome
Blood, 2009Co-Authors: Pietro Luigi Poliani, Anna Villa, Chaim M. Roifman, Andrew R. Gennery, Fabio Facchetti, Maria Ravanini, Lucia Dora NotarangeloAbstract:Thymocytes and thymic epithelial cell (TEC) cross-talk is crucial to preserve thymic architecture and function, including maturation of TECs and dendritic cells, and induction of mechanisms of central tolerance. We have analyzed thymic maturation and organization in 9 infants with various genetic defects leading to complete or partial block in T-cell development. Profound abnormalities of TEC differentiation (with lack of AIRE expression) and severe reduction of thymic dendritic cells were identified in patients with T-negative severe combined immunodeficiency, reticular dysgenesis, and Omenn Syndrome. The latter also showed virtual absence of thymic Foxp3+ T cells. In contrast, an IL2RG-R222C hypomorphic mutation permissive for T-cell development allowed for TEC maturation, AIRE expression, and Foxp3+ T cells. Our data provide evidence that severe defects of thymopoiesis impinge on TEC homeostasis and may affect deletional and nondeletional mechanisms of central tolerance, thus favoring immune dysreactive manifestations, as in Omenn Syndrome.
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Matched unrelated bone marrow transplant for Omenn Syndrome
Immunologic Research, 2009Co-Authors: Amit Nahum, Brenda Reid, Eyal Grunebaum, Chaim M. RoifmanAbstract:Little information is currently available on the outcome and the long-term restoration of immune function in infants with Omenn Syndrome (OS) treated with bone marrow transplantation (BMT). We prospectively followed patients with OS who received matched unrelated donor (MUD) BMT at our center. Engraftment, immune reconstitution, and transplant-related complications were recorded. Humoral and cellular immunity were evaluated. Six patients with OS were diagnosed at a mean age of 4.6 months and received a matched unrelated donor BMT as the first BMT at the mean age of 9.4 months. All six patients are alive and well at a mean 95 months after transplant. All patients have evidence of full hemopoetic engraftment and robust immune function. We have shown here that matched unrelated donor BMT is highly effective in curing patients with OS regardless of their genotype. This mode of treatment should be preferred for patients with OS when a related identical donor is not available.
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Reduced central tolerance in Omenn Syndrome leads to immature self-reactive oligoclonal T cells
Journal of Allergy and Clinical Immunology, 2009Co-Authors: Raz Somech, Ilan Dalal, Ninette Amariglio, Gideon Rechavi, Amos J. Simon, Atar Lev, Zvi Spirer, Itamar Goldstein, Meital Nagar, Chaim M. RoifmanAbstract:Background Omenn Syndrome (OS) is characterized by a peculiar severe T-cell immune deficiency associated with autoimmunelike manifestations. Dysregulations of the central and peripheral immune tolerance, mediated by the protein autoimmune regulator (AIRE) and regulatory T cells, respectively, were proposed as possible mechanisms of this aberrant inflammatory process. Objective We studied mechanisms of central and peripheral tolerance in patients with OS and also examined the gene expression profile associated with OS features. Methods T-cell receptor diversity, DNA rearrangement, and the expression of AIRE and forkhead box P3 mRNA as well as the expression of regulatory T cells in cells obtained from patients with OS were studied. Characterization of gene expression in these cells was carried out by using the TaqMan Low-Density Array. Results Transcript expression of peripheral blood AIRE but not forkhead box P3 was reduced in patients with OS. The expression of natural killer T and regulatory T cells was normal, although the latter showed an abnormal CD4-negative population. Patients with OS have oligoclonal T cells with limited DNA recombination activity, including the presence of early but not late T-cell maturation events, regardless of the genetic defect underlying the Syndrome. The transcriptional profile associated with OS features reveals significant changes in 25.5% of the tested genes compared with normal control. Conclusion Our findings suggest that T-cell oligoclonal expansion in OS emanates from an incomplete block before the maturation stage of negative selection, which may explain escape of autoreactive T cells from the thymus. Dysregulated genes in patients with OS are closely involved with self-tolerance and autoimmunity.
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Omenn Syndrome: inflammation in leaky severe combined immunodeficiency.
Journal of Allergy and Clinical Immunology, 2008Co-Authors: Anna Villa, Luigi D. Notarangelo, Chaim M. RoifmanAbstract:Omenn Syndrome (OS) was reported until recently as a distinct form (phenotype and genotype) of severe combined immunodeficiency (SCID). Similar to other patients with SCID, patients with OS present early in infancy with viral or fungal pneumonitis, chronic diarrhea, and failure to thrive. Unlike typical SCID, patients with OS have enlarged lymphoid tissue, severe erythroderma, increased IgE levels, and eosinophilia. The inflammation observed in these patients is believed to be triggered by clonally expanded T cells, which are predominantly of the T H 2 type. These abnormal T cells, in the absence of proper regulation by other components of the immune system, secrete a host of cytokines that promote autoimmune as well as allergic inflammation. The emergence of these T-cell clones occurs in patients with hypomorphic mutations in recombination activating gene 1 or 2, but not in patients with deleterious mutations in these enzymes which render them inactive. Recently, OS was also identified in a growing list of other leaky SCIDs with mutations in RNA component of mitochondrial RNA processing endoribonuclease , adenosine deaminase , IL-2 receptor γ , IL-7 receptor α , ARTEMIS , and DNA ligase 4 . This new information revealed OS is a distinct inflammatory process that can be associated with genetically diverse leaky SCIDS.
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Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn Syndrome.
Journal of Allergy and Clinical Immunology, 2006Co-Authors: Chaim M. Roifman, Amos CohenAbstract:Background Omenn Syndrome is a variant of severe combined immunodeficiency disease, which most prominently presents with erythroderma, eosinophilia, and susceptibility to various pathogens. Mutations in the nucleases of recombination activating genes 1 and 2 (RAG1/RAG2) or Artemis were found in some, but not all, patients with Omenn Syndrome. We identified 2 patients who presented with clinical features consistent with Omenn Syndrome but had no mutations in RAG or Artemis. Both patients also had cartilage-hair hypoplasia (CHH). Objectives We sought to define the molecular basis and characterize the features of severe combined immunodeficiency and Omenn Syndrome in these patients. Methods We have studied humoral and cellular immunity using standard assays. T-cell repertoire was investigated by quantitating Vβ families. The RNase mitochondrial RNA processing ( RMRP ) RNA gene was sequenced by using standard techniques. Results Sequence analysis of the RMRP RNA gene showed that each patient had an insertion-duplication on one allele and a point mutation on the other allele. These point mutations were novel, and they might be related to the unusual presentation of Omenn Syndrome in addition to CHH in these patients. Indeed, analysis of the thymus showed residual mature T lymphocytes. This leaky thymus might be responsible for the skewed release of some T-cell clones into the circulation, which might trigger the phenotype of Omenn Syndrome. Conclusion We have demonstrated that mutations in the RMRP RNA gene might be associated with Omenn Syndrome. Clinical implications This discovery will aid clinicians in the early recognition and treatment of CHH-associated Omenn Syndrome.
