38 results on '"Csomos K"'
Search Results
2. DIAGNOSIS AND MANAGEMENT OF CTLA-4 VARIANT IMMUNE DYSREGULATION
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Ishmael, L., primary, Westermann-Clark, E., additional, Uzel, G., additional, Eatrides, J., additional, Csomos, K., additional, and Walter, J., additional
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- 2022
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3. Congenital Immunodeficiency Diseases
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Farmer, J., primary, Csomos, K., additional, Bacchetta, R., additional, and Walter, J.E., additional
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- 2016
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4. Contributors
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Agua-Doce, A., primary, Awe, O., additional, Azevedo, R.I., additional, Bacchetta, R., additional, Bortell, R., additional, Brehm, M.A., additional, Burska, A.N., additional, Csomos, K., additional, Denny, J.C., additional, Dudley, J.T., additional, Farmer, J., additional, Getts, D.R., additional, Graca, L., additional, Greiner, D.L., additional, Harrison, S.R., additional, Hillion, S., additional, Kaplan, M.H., additional, Kidd, B.A., additional, Lacerda, J.F., additional, Lee, Y.N., additional, Miller, S.D., additional, Monteiro, M., additional, Ponchel, F., additional, Shultz, L.D., additional, Simon, Q., additional, Smarr, C.B., additional, Ueno, H., additional, Verma, M., additional, Walter, J.E., additional, Warner, J.L., additional, and Yang, Jianfei, additional
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- 2016
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5. Tissue transglutaminase contributes to the all-trans retinoic acid induced differentiation syndrome phenotype in the NB4 model of acute promyelocytic leukemia: B4.65
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Csomos, K., Balajthy, Z., Fesus, L., and Nemet, I.
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- 2010
6. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency
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Lawless, D, Geier, CB, Farmer, JR, Lango Allen, H, Thwaites, D, Atschekzei, F, Brown, M, Buchbinder, D, Burns, SO, Butte, MJ, Csomos, K, Deevi, SVV, Egner, W, Ehl, S, Eibl, MM, Fadugba, O, Foldvari, Z, Green, DM, Henrickson, SE, Holland, SM, John, T, Klemann, C, Kuijpers, TW, Moreira, F, Piller, A, Rayner-Matthews, P, Romberg, ND, Sargur, R, Schmidt, RE, Schröder, C, Schuetz, C, Sharapova, SO, Smith, KGC, Sogkas, G, Speckmann, C, Stirrups, K, Thrasher, AJ, Wolf, HM, Notarangelo, LD, Anwar, R, Boyes, J, Ujhazi, B, NIHR BioResource - Rare Diseases Consortium, Thaventhiran, J, Walter, JE, Savic, S, Lango Allen, Hana [0000-0002-7803-8688], Smith, Kenneth [0000-0003-3829-4326], Johnson, Kathleen [0000-0002-6823-3252], Thaventhiran, James [0000-0001-8616-074X], and Apollo - University of Cambridge Repository
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Adult ,DNA-Binding Proteins ,Homeodomain Proteins ,Immunologic Deficiency Syndromes ,Prevalence ,Humans ,Nuclear Proteins - Published
- 2018
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7. Cultivation and characterization of corneal limbal epithelial stem cells on lens capsule in animal material-free medium
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ALBERT, R, primary, VEREB, Z, additional, CSOMOS, K, additional, MOE, MC, additional, JOHNSEN, EO, additional, NICOLAISSEN, B, additional, RAJNAVOLGYI, E, additional, FESUS, L, additional, BERTA, A, additional, and PETROVSKI, G, additional
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- 2012
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8. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency
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Je, Walter, Lb, Rosen, Csomos K, Jm, Rosenberg, Mathew D, Keszei M, Ujhazi B, Chen K, Yn, Lee, Tirosh I, Dobbs K, Al-Herz W, Mj, Cowan, Puck J, and Ld, Notarangelo
9. Time course transcriptomic analysis of all-trans retinoic acid (ATRA)-treated NB4 cells
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Csomos, K, primary
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10. Time course transcriptomic analysis of all-trans retinoic acid (ATRA)-treated NB4 cells
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Csomos, K, primary, Balajthy, Z, additional, Nagy, I, additional, and Fesus, L, additional
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11. Impaired B-cell function in ERCC2 deficiency.
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Rossmanith R, Sauerwein K, Geier CB, Leiss-Piller A, Stemberger RF, Sharapova S, Gruber RW, Bergler H, Verbsky JW, Csomos K, Walter JE, and Wolf HM
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- Humans, Male, Female, Trichothiodystrophy Syndromes genetics, Trichothiodystrophy Syndromes immunology, DNA Repair, Child, Lymphocyte Activation genetics, Child, Preschool, Adolescent, B-Lymphocytes immunology, Xeroderma Pigmentosum Group D Protein genetics, Xeroderma Pigmentosum Group D Protein deficiency, Mutation
- Abstract
Background: Trichothiodystrophy-1 (TTD1) is an autosomal-recessive disease and caused by mutations in ERCC2 , a gene coding for a subunit of the TFIIH transcription and nucleotide-excision repair (NER) factor. In almost half of these patients infectious susceptibility has been reported but the underlying molecular mechanism leading to immunodeficiency is largely unknown., Objective: The aim of this study was to perform extended molecular and immunological phenotyping in patients suffering from TTD1., Methods: Cellular immune phenotype was investigated using multicolor flow cytometry. DNA repair efficiency was evaluated in UV-irradiation assays. Furthermore, early BCR activation events and proliferation of TTD1 lymphocytes following DNA damage induction was tested. In addition, we performed differential gene expression analysis in peripheral lymphocytes of TTD1 patients., Results: We investigated three unrelated TTD1 patients who presented with recurrent infections early in life of whom two harbored novel ERCC2 mutations and the third patient is a carrier of previously described pathogenic ERCC2 mutations. Hypogammaglobulinemia and decreased antibody responses following vaccination were found. TTD1 B-cells showed accumulation of γ-H2AX levels, decreased proliferation activity and reduced cell viability following UV-irradiation. mRNA sequencing analysis revealed significantly downregulated genes needed for B-cell development and activation. Analysis of B-cell subpopulations showed low numbers of naïve and transitional B-cells in TTD1 patients, indicating abnormal B-cell differentiation in vivo ., Conclusion: In summary, our analyses confirmed the pathogenicity of novel ERCC2 mutations and show that ERCC2 deficiency is associated with antibody deficiency most likely due to altered B-cell differentiation resulting from impaired BCR-mediated B-cell activation and activation-induced gene transcription., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rossmanith, Sauerwein, Geier, Leiss-Piller, Stemberger, Sharapova, Gruber, Bergler, Verbsky, Csomos, Walter and Wolf.)
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- 2024
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12. Correction to: Clinical and Treatment History of Patients with Partial DiGeorge Syndrome and Autoimmune Cytopenia at Multiple Centers.
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Patel PK, Chinga ML, Yilmaz M, Joychan S, Ujhazi B, Ellison M, Gordon S, Nieves D, Csomos K, Eslin D, Afify ZA, Meznarich J, Bohnsack J, Walkovich K, Seidel MG, Sharapova S, Boyarchuk O, Latysheva E, Tuzankina I, Shaker AB, Ayala I, Sriaroon P, Westermann-Clark E, and Walter JE
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- 2024
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13. Clinical, immunological features, treatments, and outcomes of autoimmune hemolytic anemia in patients with RAG deficiency.
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Wang C, Sun B, Wu K, Farmer JR, Ujhazi B, Geier CB, Gordon S, Westermann-Clark E, Savic S, Secord E, Sargur R, Chen K, Jin JJ, Dutmer CM, Kanariou MG, Adeli M, Palma P, Bonfim C, Lycopoulou E, Wolska-Kusnierz B, Dbaibo G, Bleesing J, Moshous D, Neven B, Schuetz C, Geha RS, Notarangelo LD, Miano M, Buchbinder DK, Csomos K, Wang W, Wang JY, Wang X, and Walter JE
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- Humans, Anemia, Hemolytic, Autoimmune complications, Anemia, Hemolytic, Autoimmune therapy
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- 2024
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14. Clinical and Treatment History of Patients with Partial DiGeorge Syndrome and Autoimmune Cytopenia at Multiple Centers.
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Patel PK, Chinga ML, Yilmaz M, Joychan S, Ujhazi B, Ellison M, Gordon S, Nieves D, Csomos K, Eslin D, Afify ZA, Meznarich J, Bohnsack J, Walkovich K, Seidel MG, Sharapova S, Boyarchyk O, Latysheva E, Tuzankina I, Shaker AB, Ayala I, Sriaroon P, Westermann-Clark E, and Walter JE
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- Humans, Retrospective Studies, Antigens, CD19, Disease Progression, DiGeorge Syndrome diagnosis, DiGeorge Syndrome therapy, Cytopenia
- Abstract
Background: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation., Objectives: Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC., Methods: Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation., Results: Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19
hi CD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators., Conclusions: AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2024
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15. B cell abnormalities and autoantibody production in patients with partial RAG deficiency.
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Min Q, Csomos K, Li Y, Dong L, Hu Z, Meng X, Yu M, Walter JE, and Wang JY
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- Humans, Autoimmunity, Phenotype, Autoantibodies genetics, Homeodomain Proteins genetics, Severe Combined Immunodeficiency genetics
- Abstract
Mutations in the recombination activating gene 1 ( RAG1 ) and RAG2 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Min, Csomos, Li, Dong, Hu, Meng, Yu, Walter and Wang.)
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- 2023
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16. Separating the Wheat From the Chaff in Asthma and Bronchiectasis: The Saga Trajectory of a Patient With Adult-Onset RAG1 Deficiency.
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Chitty Lopez M, Yilmaz M, Diaz-Cabrera NM, Saco T, Ishmael L, Sotoudeh S, Bindernagel C, Ujhazi B, Gordon S, Potts DE, Danziger R, Bosticardo M, Kenney H, Illes P, Lee S, Harris M, Cuellar-Rodriguez J, Patel KN, Csomos K, Dimitrova D, Kanakry JA, Notarangelo LD, and Walter JE
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- Adult, Humans, Patients, Homeodomain Proteins, Asthma epidemiology, Bronchiectasis
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- 2023
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17. Lineage Reconstruction of In Vitro Identified Antigen-Specific Autoreactive B Cells from Adaptive Immune Receptor Repertoires.
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Blazso P, Csomos K, Tipton CM, Ujhazi B, and Walter JE
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- Humans, B-Lymphocytes, Autoimmunity, Antibodies, Autoimmune Diseases, Lupus Erythematosus, Systemic
- Abstract
The emergence, survival, growth and maintenance of autoreactive (AR) B-cell clones, the hallmark of humoral autoimmunity, leave their footprints in B-cell receptor repertoires. Collecting IgH sequences related to polyreactive (PR) ones from adaptive immune receptor repertoire (AIRR) datasets make the reconstruction and analysis of PR/AR B-cell lineages possible. We developed a computational approach, named ImmChainTracer, to extract members and to visualize clonal relationships of such B-cell lineages. Our approach was successfully applied on the IgH repertoires of patients suffering from monogenic hypomorphic RAG1 and 2 deficiency (pRD) or polygenic systemic lupus erythematosus (SLE) autoimmune diseases to identify relatives of AR IgH sequences and to track their fate in AIRRs. Signs of clonal expansion, affinity maturation and class-switching events in PR/AR and non-PR/AR B-cell lineages were revealed. An extension of our method towards B-cell expansion caused by any trigger (e.g., infection, vaccination or antibody development) may provide deeper insight into antigen specific B-lymphogenesis.
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- 2022
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18. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients.
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Geier CB, Ellison M, Cruz R, Pawar S, Leiss-Piller A, Zmajkovicova K, McNulty SM, Yilmaz M, Evans MO 2nd, Gordon S, Ujhazi B, Wiest I, Abolhassani H, Aghamohammadi A, Barmettler S, Bhar S, Bondarenko A, Bolyard AA, Buchbinder D, Cada M, Cavieres M, Connelly JA, Dale DC, Deordieva E, Dorsey MJ, Drysdale SB, Ehl S, Elfeky R, Fioredda F, Firkin F, Förster-Waldl E, Geng B, Goda V, Gonzalez-Granado L, Grunebaum E, Grzesk E, Henrickson SE, Hilfanova A, Hiwatari M, Imai C, Ip W, Jyonouchi S, Kanegane H, Kawahara Y, Khojah AM, Kim VH, Kojić M, Kołtan S, Krivan G, Langguth D, Lau YL, Leung D, Miano M, Mersyanova I, Mousallem T, Muskat M, Naoum FA, Noronha SA, Ouederni M, Ozono S, Richmond GW, Sakovich I, Salzer U, Schuetz C, Seeborg FO, Sharapova SO, Sockel K, Volokha A, von Bonin M, Warnatz K, Wegehaupt O, Weinberg GA, Wong KJ, Worth A, Yu H, Zharankova Y, Zhao X, Devlin L, Badarau A, Csomos K, Keszei M, Pereira J, Taveras AG, Beaussant-Cohen SL, Ong MS, Shcherbina A, and Walter JE
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- Humans, Receptors, CXCR4 genetics, Disease Progression, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes epidemiology, Immunologic Deficiency Syndromes genetics, Warts diagnosis, Warts epidemiology, Warts genetics, Agammaglobulinemia genetics, Neutropenia genetics, Lymphopenia complications
- Abstract
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts., (© 2022. The Author(s).)
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- 2022
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19. Dysregulated stem cell niches and altered lymphocyte recirculation cause B and T cell lymphopenia in WHIM syndrome.
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Zehentmeier S, Lim VY, Ma Y, Fossati J, Ito T, Jiang Y, Tumanov AV, Lee HJ, Dillinger L, Kim J, Csomos K, Walter JE, Choi J, and Pereira JP
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- Animals, B-Cell Activating Factor, Interleukin-7, Lymphotoxin beta Receptor, Mice, Primary Immunodeficiency Diseases, Stem Cell Niche, T-Lymphocytes, Warts, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes genetics, Lymphopenia
- Abstract
Gain-of-function (GOF) mutations in CXCR4 cause WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, characterized by infections, leukocyte retention in bone marrow (BM), and blood leukopenias. B lymphopenia is evident at early progenitor stages, yet why do CXCR4 GOF mutations that cause B (and T) lymphopenia remain obscure? Using a CXCR4 R334X GOF mouse model of WHIM syndrome, we showed that lymphopoiesis is reduced because of a dysregulated mesenchymal stem cell (MSC) transcriptome characterized by a switch from an adipogenic to an osteolineage-prone program with limited lymphopoietic activity. We identify lymphotoxin beta receptor (LTβR) as a critical pathway promoting interleukin-7 (IL-7) down-regulation in MSCs. Blocking LTβR or CXCR4 signaling restored IL-7 production and B cell development in WHIM mice. LTβR blocking also increased production of IL-7 and B cell activating factor (BAFF) in secondary lymphoid organs (SLOs), increasing B and T cell numbers in the periphery. These studies revealed that LTβR signaling in BM MSCs and SLO stromal cells limits the lymphocyte compartment size.
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- 2022
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20. Corrigendum: Case report: Initial treatment adjustments and complications in ovarian cancer patient with inborn error of immunity.
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Mammadova J, Redden A, Cruz R, Ujhazi B, Gordon S, Ellison M, Gatewood T, Duff C, Cannella A, Somboonwit C, Sriaroon C, Csomos K, Dasso JF, Harville T, Ismail-Khan R, and Walter JE
- Abstract
[This corrects the article DOI: 10.3389/fonc.2022.843741.]., (Copyright © 2022 Mammadova, Redden, Cruz, Ujhazi, Gordon, Ellison, Gatewood, Duff, Cannella, Somboonwit, Sriaroon, Csomos, Dasso, Harville, Ismail-Khan and Walter.)
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- 2022
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21. Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet + B cells.
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Csomos K, Ujhazi B, Blazso P, Herrera JL, Tipton CM, Kawai T, Gordon S, Ellison M, Wu K, Stowell M, Haynes L, Cruz R, Zakota B, Nguyen J, Altrich M, Geier CB, Sharapova S, Dasso JF, Leiding JW, Smith G, Al-Herz W, de Barros Dorna M, Fadugba O, Fronkova E, Kanderova V, Svaton M, Henrickson SE, Hernandez JD, Kuijpers T, Kandilarova SM, Naumova E, Milota T, Sediva A, Moshous D, Neven B, Saco T, Sargur R, Savic S, Sleasman J, Sunkersett G, Ward BR, Komatsu M, Pittaluga S, Kumanovics A, Butte MJ, Cancro MP, Pillai S, Meffre E, Notarangelo LD, and Walter JE
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- Cell Differentiation, Humans, Immune Tolerance, Lymphocyte Count, B-Lymphocytes, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Homeodomain Proteins genetics, Nuclear Proteins deficiency
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The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery., (© 2022. The Author(s).)
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- 2022
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22. Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene.
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Wang W, Min Q, Lai N, Csomos K, Wang Y, Liu L, Meng X, Sun J, Hou J, Ying W, Zhou Q, Sun B, Hui X, Ujhazi B, Gordon S, Buchbinder D, Schuetz C, Butte M, Walter JE, Wang X, and Wang JY
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- Class I Phosphatidylinositol 3-Kinases metabolism, Immunoglobulin M genetics, Mutation, Gain of Function Mutation, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism
- Abstract
Background: Activated phosphoinositide 3 kinase (PI3K) -delta syndrome (APDS) is an inborn error of immunity with variable clinical phenotype of immunodeficiency and immune dysregulation and caused by gain-of-function mutations in PIK3CD . The hallmark of immune phenotype is increased proportions of transitional B cells and plasmablasts (PB), progressive B cell loss, and elevated levels of serum IgM., Objective: To explore unique B cell subsets and the pathomechanisms driving B cell dysregulation beyond the transitional B cell stage in APDS., Methods: Clinical and immunological data was collected from 24 patients with APDS. In five cases, we performed an in-depth analysis of B cell phenotypes and cultured purified naïve B cells to evaluate their survival, activation, Ig gene class switch recombination (CSR), PB differentiation and antibody secretion. We also analyzed PB differentiation capacity of sorted CD27
- IgD- double-negative B (DNB) cells., Results: The patients had increased B cell sizes and higher proportions of IgM+ DNB cells than healthy controls (HC). Their naïve B cells exhibited increased death, impaired CSR but relatively normal PB differentiation. Upon stimulation, patient's DNB cells secreted a similar level of IgG but a higher level of IgM than DNB cells from HC. Targeted therapy of PI3K inhibition partially restored B cell phenotypes., Conclusions: The present study suggests additional mechanistic insight into B cell pathology of APDS: (1) decreased peripheral B cell numbers may be due to the increased death of naïve B cells; (2) larger B cell sizes and expanded DNB population suggest enhanced activation and differentiation of naïve B cells into DNB cells; (3) the impaired CSR yet normal PB differentiation can predominantly generate IgM-secreting cells, resulting in elevated IgM levels., Competing Interests: JEW is a consultant on APDS and leniolisib with Pharmin (Netherlands). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Min, Lai, Csomos, Wang, Liu, Meng, Sun, Hou, Ying, Zhou, Sun, Hui, Ujhazi, Gordon, Buchbinder, Schuetz, Butte, Walter, Wang and Wang.)- Published
- 2022
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23. Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma.
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Chitty-Lopez M, Westermann-Clark E, Dawson I, Ujhazi B, Csomos K, Dobbs K, Le K, Yamazaki Y, Sadighi Akha AA, Chellapandian D, Oshrine B, Notarangelo LD, Sunkersett G, Leiding JW, and Walter JE
- Subjects
- Asymptomatic Diseases, Genetic Predisposition to Disease, Humans, Infant, Newborn, Male, Phenotype, Predictive Value of Tests, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency immunology, Treatment Outcome, Genetic Variation, Hematopoietic Stem Cell Transplantation, Homeodomain Proteins genetics, Neonatal Screening, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency surgery
- Abstract
The T-cell receptor excision circle (TREC) assay detects T-cell lymphopenia (TCL) in newborns and is especially important to identify severe combined immunodeficiency (SCID). A spectrum of SCID variants and non-SCID conditions that present with TCL are being discovered with increasing frequency by newborn screening (NBS). Recombination-activating gene (RAG) deficiency is one the most common causes of classical and atypical SCID and other conditions with immune dysregulation. We present the case of an asymptomatic male with undetectable TRECs on NBS at 1 week of age. The asymptomatic newborn was found to have severe TCL, but normal B cell quantities and lymphocyte proliferation upon mitogen stimulation. Next generation sequencing revealed compound heterozygous hypomorphic RAG variants, one of which was novel. The moderately decreased recombinase activity of the RAG variants (16 and 40%) resulted in abnormal T and B-cell receptor repertoires, decreased fraction of CD3+ TCRVα7.2
+ T cells and an immune phenotype consistent with the RAG hypomorphic variants. The patient underwent successful treatment with hematopoietic stem cell transplantation (HSCT) at 5 months of age. This case illustrates how after identification of a novel RAG variant, in vitro studies are important to confirm the pathogenicity of the variant. This confirmation allows the clinician to expedite definitive treatment with HSCT in an asymptomatic phase, mitigating the risk of serious infectious and non-infectious complications., (Copyright © 2020 Chitty-Lopez, Westermann-Clark, Dawson, Ujhazi, Csomos, Dobbs, Le, Yamazaki, Sadighi Akha, Chellapandian, Oshrine, Notarangelo, Sunkersett, Leiding and Walter.)- Published
- 2020
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24. Arthritis in Two Patients With Partial Recombination Activating Gene Deficiency.
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Wu KY, Purswani P, Ujhazi B, Csomos K, Snezhina M, Elissaveta N, Stefanov S, Sharapova S, Ellison M, Milojevic D, Savic S, Sargur R, and Walter JE
- Abstract
Autoimmunity is becoming an increasingly recognized complication in patients with primary immunodeficiencies (PIDs), including a variety of combined immune deficiencies such as Recombination Activating Gene (RAG) defects. The approach to treating autoimmunity in PID patients is complex, requiring a balance between immunosuppression and susceptibility to infection. Inflammatory arthritis is a feature of immune dysregulation in many PIDs, and the optimal treatment may differ from first line therapies that usually consist of disease-modifying anti rheumatic drugs (DMARDs). An example of mechanism-based therapy of arthritis in PID uses blockade of IL-6 signaling with tocilizumab for patients with STAT 3 gain-of-function (GOF) mutation and augmented IL-6 pathway. Herein, we describe two PID cases with arthritis who were found to have defects in RAG. One patient with refractory inflammatory arthritis experienced remarkable improvement in symptoms with tocilizumab therapy. Arthritis can be a clinical feature of immune dysregulation in RAG deficiency, and tocilizumab therapy has been suggested to have utility in treatment of arthritis in RAG deficiency.
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- 2019
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25. Familial Immune Thrombocytopenia Associated With a Novel Variant in IKZF1 .
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Sriaroon P, Chang Y, Ujhazi B, Csomos K, Joshi HR, Zhou Q, Close DW, Walter JE, and Kumánovics A
- Abstract
We report a novel variant in IKZF1 associated with IKAROS haploinsufficiency in a patient with familial immune thrombocytopenia (ITP). IKAROS, encoded by the IKZF1 gene, is a hematopoietic zinc-finger transcription factor that can directly bind to DNA. We show that the identified IKZF1 variant (p.His195Arg) alters a completely conserved histidine residue required for the folding of the third zinc-finger of IKAROS protein, leading to a loss of characteristic immunofluorescence nuclear staining pattern. In our case, genetic testing was essential for the diagnosis of IKAROS haploinsufficiency, of which known presentations include infections, aberrant hematopoiesis, leukemia, and age-related decrease in humoral immunity. Our family study underscores that, after infections, ITP is the second most common clinical manifestation of IKAROS haploinsufficiency.
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- 2019
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26. Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency.
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Dorna MB, Barbosa PFA, Rangel-Santos A, Csomos K, Ujhazi B, Dasso JF, Thwaites D, Boyes J, Savic S, and Walter JE
- Abstract
Proteins expressed by recombination activating genes 1 and 2 (RAG1/2) are essential in the process of V(D)J recombination that leads to generation of the T and B cell repertoires. Clinical and immunological phenotypes of patients with RAG deficiencies correlate well to the degree of impaired RAG activity and this has been expanding to variants of combined immunodeficiency (CID) or even milder antibody deficiency syndromes. Pathogenic variants that severely impair recombinase activity of RAG1/2 determine a severe combined immunodeficiency (SCID) phenotype, whereas hypomorphic variants result in leaky (partial) SCID and other immunodeficiencies. We report a patient with novel pathogenic compound heterozygous RAG2 variants that result in a CID phenotype with two distinctive characteristics: late-onset progressive hypogammaglobulinemia and highly elevated B cell count. In addition, the patient had early onset of infections, T cell lymphopenia and expansion of lymphocytes after exposure to herpes family viruses. This case highlights the importance of considering pathogenic RAG variants among patients with preserved B cell count and CID phenotype.
- Published
- 2019
- Full Text
- View/download PDF
27. Two Unique Cases of X-linked SCID: A Diagnostic Challenge in the Era of Newborn Screening.
- Author
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Purswani P, Meehan CA, Kuehn HS, Chang Y, Dasso JF, Meyer AK, Ujhazi B, Csomos K, Lindsay D, Alberdi T, Joychan S, Trotter J, Duff C, Ellison M, Bleesing J, Kumanovics A, Comeau AM, Hale JE, Notarangelo LD, Torgersen TR, Ochs HD, Sriaroon P, Oshrine B, Petrovic A, Rosenzweig SD, Leiding JW, and Walter JE
- Abstract
In the era of newborn screening (NBS) for severe combined immunodeficiency (SCID) and the possibility of gene therapy (GT), it is important to link SCID phenotype to the underlying genetic disease. In western countries, X-linked interleukin 2 receptor gamma chain (IL2RG) and adenosine deaminase (ADA) deficiency SCID are two of the most common types of SCID and can be treated by GT. As a challenge, both IL2RG and ADA genes are highly polymorphic and a gene-based diagnosis may be difficult if the variant is of unknown significance or if it is located in non-coding areas of the genes that are not routinely evaluated with exon-based genetic testing (e.g., introns, promoters, and the 5'and 3' untranslated regions). Therefore, it is important to extend evaluation to non-coding areas of a SCID gene if the exon-based sequencing is inconclusive and there is strong suspicion that a variant in that gene is the cause for disease. Functional studies are often required in these cases to confirm a pathogenic variant. We present here two unique examples of X-linked SCID with variable immune phenotypes, where IL2R gamma chain expression was detected and no pathogenic variant was identified on initial genetic testing. Pathogenic IL2RG variants were subsequently confirmed by functional assay of gamma chain signaling and maternal X-inactivation studies. We propose that such tests can facilitate confirmation of suspected cases of X-linked SCID in newborns when initial genetic testing is inconclusive. Early identification of pathogenic IL2RG variants is especially important to ensure eligibility for gene therapy.
- Published
- 2019
- Full Text
- View/download PDF
28. Partial RAG deficiency in a patient with varicella infection, autoimmune cytopenia, and anticytokine antibodies.
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Goda V, Malik A, Kalmar T, Maroti Z, Patel B, Ujhazi B, Csomos K, Hale JE, Chen K, Bleesing J, Palma P, Cancrini C, Comeau AM, Krivan G, and Walter JE
- Subjects
- Adult, Antibodies, Viral blood, Autoantibodies blood, Cytokines immunology, Female, High-Throughput Nucleotide Sequencing, Humans, Stem Cell Transplantation, Chickenpox diagnosis, Herpesvirus 3, Human physiology, Homeodomain Proteins genetics, Mutation genetics, Purpura, Thrombocytopenic, Idiopathic diagnosis, Severe Combined Immunodeficiency diagnosis, T-Lymphocytes pathology
- Published
- 2018
- Full Text
- View/download PDF
29. Adult-Onset Myopathy in a Patient with Hypomorphic RAG2 Mutations and Combined Immune Deficiency.
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Henrickson SE, Walter JE, Quinn C, Kanakry JA, Bardakjian T, Dimitrova D, Ujhazi B, Csomos K, Bosticardo M, Dobbs K, Nasrallah M, Notarangelo LD, Holland SM, and Fadugba O
- Subjects
- Adult, Age of Onset, Biomarkers, Biopsy, Combined Modality Therapy, DNA Mutational Analysis, Humans, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes therapy, Male, Muscular Diseases diagnosis, Muscular Diseases therapy, Phenotype, Treatment Outcome, DNA-Binding Proteins genetics, Immunologic Deficiency Syndromes complications, Muscular Diseases complications, Muscular Diseases genetics, Mutation, Nuclear Proteins genetics
- Published
- 2018
- Full Text
- View/download PDF
30. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency.
- Author
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Lawless D, Geier CB, Farmer JR, Lango Allen H, Thwaites D, Atschekzei F, Brown M, Buchbinder D, Burns SO, Butte MJ, Csomos K, Deevi SVV, Egner W, Ehl S, Eibl MM, Fadugba O, Foldvari Z, Green DM, Henrickson SE, Holland SM, John T, Klemann C, Kuijpers TW, Moreira F, Piller A, Rayner-Matthews P, Romberg ND, Sargur R, Schmidt RE, Schröder C, Schuetz C, Sharapova SO, Smith KGC, Sogkas G, Speckmann C, Stirrups K, Thrasher AJ, Wolf HM, Notarangelo LD, Anwar R, Boyes J, Ujhazi B, Thaventhiran J, Walter JE, and Savic S
- Subjects
- Adult, DNA-Binding Proteins genetics, Humans, Immunologic Deficiency Syndromes physiopathology, Nuclear Proteins genetics, Prevalence, DNA-Binding Proteins deficiency, Homeodomain Proteins genetics, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes immunology, Nuclear Proteins deficiency
- Published
- 2018
- Full Text
- View/download PDF
31. Reduced numbers of circulating group 2 innate lymphoid cells in patients with common variable immunodeficiency.
- Author
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Geier CB, Kraupp S, Bra D, Eibl MM, Farmer JR, Csomos K, Walter JE, and Wolf HM
- Subjects
- Case-Control Studies, Female, Humans, Male, Middle Aged, Proto-Oncogene Proteins c-kit immunology, Retrospective Studies, Common Variable Immunodeficiency immunology, Lymphocyte Subsets immunology
- Abstract
Recent studies identified an emerging role of group 2 and 3 innate lymphoid cells (ILCs) as key players in the generation of T-dependent and T-independent antibody production. In this retrospective case-control study, CD117
+ ILCs (including the majority of ILC2 and ILC3) were reduced in patients with common variable immunodeficiency (CVID). The reduction in CD117+ ILCs was distinctive to CVID and could not be observed in patients with X-linked agammaglobulinemia. Patients with a more pronounced reduction in CD117+ ILC numbers showed significantly lower numbers of peripheral MZ-like B cells and an increased prevalence of chronic, non-infectious enteropathy. Subsequent phenotyping of ILC subsets in CVID revealed that the reduction in CD117+ ILC numbers is due to a reduction in ILC2 numbers. In vitro expansion of CVID ILC2 in response to IL-2, IL-7, IL-25 and IL-33 was impaired. Furthermore, upregulation of MHCII and IL-2RA in response to IL-2, IL-7, IL-25 and IL-33 was impaired in CVID ILC2. Thus, our results indicate a dysregulation of ILC subsets with a reduction in ILC2 numbers in CVID, however, further studies are needed to explore whether ILC abnormalities are a primary finding or secondary to disease complications encountered in CVID., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2017
- Full Text
- View/download PDF
32. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.
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Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, and Notarangelo LD
- Published
- 2016
- Full Text
- View/download PDF
33. Ligase-4 Deficiency Causes Distinctive Immune Abnormalities in Asymptomatic Individuals.
- Author
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Felgentreff K, Baxi SN, Lee YN, Dobbs K, Henderson LA, Csomos K, Tsitsikov EN, Armanios M, Walter JE, and Notarangelo LD
- Subjects
- Adolescent, Adult, Agammaglobulinemia genetics, Agammaglobulinemia immunology, Cell Line, Cells, Cultured, Child, Female, Fibroblasts radiation effects, Granulocytes radiation effects, Humans, Leukocytes, Mononuclear cytology, Lymphocyte Count, Lymphocyte Subsets immunology, Male, Mutation, Radiation, Ionizing, Young Adult, DNA Ligase ATP genetics, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes immunology
- Abstract
Purpose: DNA Ligase 4 (LIG4) is a key factor in the non-homologous end-joining (NHEJ) DNA double-strand break repair pathway needed for V(D)J recombination and the generation of the T cell receptor and immunoglobulin molecules. Defects in LIG4 result in a variable syndrome of growth retardation, pancytopenia, combined immunodeficiency, cellular radiosensitivity, and developmental delay., Methods: We diagnosed a patient with LIG4 syndrome by radiosensitivity testing on peripheral blood cells, and established that two of her four healthy siblings carried the same compound heterozygous LIG4 mutations. An extensive analysis of the immune phenotype, cellular radiosensitivity, telomere length, and T and B cell antigen receptor repertoire was performed in all siblings., Results: In the three genotypically affected individuals, variable severities of radiosensitivity, alterations of T and B cell counts with an increased percentage of memory cells, and hypogammaglobulinemia, were noticed. Analysis of T and B cell antigen receptor repertoires demonstrated increased usage of alternative microhomology-mediated end-joining (MHMEJ) repair, leading to diminished N nucleotide addition and shorter CDR3 length. However, overall repertoire diversity was preserved., Conclusions: We demonstrate that LIG4 syndrome presents with high clinical variability even within the same family, and that distinctive immunologic abnormalities may be observed also in yet asymptomatic individuals.
- Published
- 2016
- Full Text
- View/download PDF
34. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.
- Author
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Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, and Notarangelo LD
- Subjects
- Adolescent, Adult, Animals, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Antibody Specificity, Autoantibodies blood, Autoimmune Diseases genetics, Child, Child, Preschool, DEAD-box RNA Helicases immunology, DNA-Binding Proteins genetics, Disease Models, Animal, Female, Granulomatous Disease, Chronic genetics, Granulomatous Disease, Chronic therapy, Homeodomain Proteins genetics, Humans, Infant, Interferon-Induced Helicase, IFIH1, Male, Mice, Mice, Inbred Strains, Nuclear Proteins genetics, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency therapy, Toll-Like Receptors agonists, Toll-Like Receptors immunology, Virus Diseases immunology, Young Adult, Autoantibodies immunology, Autoantigens immunology, Autoimmune Diseases immunology, Cytokines immunology, DNA-Binding Proteins deficiency, Granulomatous Disease, Chronic immunology, Homeodomain Proteins immunology, Nuclear Proteins deficiency, Severe Combined Immunodeficiency immunology
- Abstract
Patients with mutations of the recombination-activating genes (RAG) present with diverse clinical phenotypes, including severe combined immune deficiency (SCID), autoimmunity, and inflammation. However, the incidence and extent of immune dysregulation in RAG-dependent immunodeficiency have not been studied in detail. Here, we have demonstrated that patients with hypomorphic RAG mutations, especially those with delayed-onset combined immune deficiency and granulomatous/autoimmune manifestations (CID-G/AI), produce a broad spectrum of autoantibodies. Neutralizing anti-IFN-α or anti-IFN-ω antibodies were present at detectable levels in patients with CID-G/AI who had a history of severe viral infections. As this autoantibody profile is not observed in a wide range of other primary immunodeficiencies, we hypothesized that recurrent or chronic viral infections may precipitate or aggravate immune dysregulation in RAG-deficient hosts. We repeatedly challenged Rag1S723C/S723C mice, which serve as a model of leaky SCID, with agonists of the virus-recognizing receptors TLR3/MDA5, TLR7/-8, and TLR9 and found that this treatment elicits autoantibody production. Altogether, our data demonstrate that immune dysregulation is an integral aspect of RAG-associated immunodeficiency and indicate that environmental triggers may modulate the phenotypic expression of autoimmune manifestations.
- Published
- 2015
- Full Text
- View/download PDF
35. Decline of FOXN1 gene expression in human thymus correlates with age: possible epigenetic regulation.
- Author
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Reis MD, Csomos K, Dias LP, Prodan Z, Szerafin T, Savino W, and Takacs L
- Abstract
Background: Thymic involution is thought to be an important factor of age related immunodeficiency. Understanding the molecular mechanisms of human thymic senescence may lead to the discovery of novel therapeutic approaches aimed at the reestablishment of central and peripheral T cell repertoire., Results: As an initial approach, here we report that the decline of human thymic FOXN1 transcription correlates with age, while other genes, DLL1, DLL4 and WNT4, essential for thymopoiesis, are constitutively transcribed. Using a human thymic epithelial cell line (hTEC), we show that FOXN1 expression is refractory to signals that induce FOXN1 transcription in primary 3D culture conditions and by stimulation of the canonical WNT signaling pathway. Blockage of FOXN1 induceability in the hTEC line may be mediated by an epigenetic mechanism, the CpG methylation of the FOXN1 gene., Conclusion: We showed a suppression of FOXN1 transcription both in cultured human thymic epithelial cells and in the aging thymus. We hypothesize that the underlying mechanism may be associated with changes of the DNA methylation state of the FOXN1 gene.
- Published
- 2015
- Full Text
- View/download PDF
36. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity.
- Author
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Mathieu AL, Verronese E, Rice GI, Fouyssac F, Bertrand Y, Picard C, Chansel M, Walter JE, Notarangelo LD, Butte MJ, Nadeau KC, Csomos K, Chen DJ, Chen K, Delgado A, Rigal C, Bardin C, Schuetz C, Moshous D, Reumaux H, Plenat F, Phan A, Zabot MT, Balme B, Viel S, Bienvenu J, Cochat P, van der Burg M, Caux C, Kemp EH, Rouvet I, Malcus C, Méritet JF, Lim A, Crow YJ, Fabien N, Ménétrier-Caux C, De Villartay JP, Walzer T, and Belot A
- Subjects
- Adolescent, Animals, Autoantibodies biosynthesis, Autoimmunity genetics, B-Lymphocytes immunology, B-Lymphocytes metabolism, B-Lymphocytes pathology, DNA End-Joining Repair immunology, DNA-Activated Protein Kinase deficiency, DNA-Activated Protein Kinase immunology, Female, Gene Expression Regulation, Granuloma immunology, Granuloma metabolism, Granuloma pathology, Humans, Immune Tolerance, Immunologic Deficiency Syndromes immunology, Immunologic Deficiency Syndromes metabolism, Immunologic Deficiency Syndromes pathology, Male, Mice, Nuclear Proteins deficiency, Nuclear Proteins immunology, Skin Neoplasms immunology, Skin Neoplasms metabolism, Skin Neoplasms pathology, Th1 Cells immunology, Th1 Cells metabolism, Th1 Cells pathology, Th2 Cells immunology, Th2 Cells metabolism, Th2 Cells pathology, Transcription Factors immunology, V(D)J Recombination immunology, Young Adult, AIRE Protein, DNA-Activated Protein Kinase genetics, Granuloma genetics, Immunologic Deficiency Syndromes genetics, Mutation, Nuclear Proteins genetics, Skin Neoplasms genetics, Transcription Factors genetics
- Abstract
Background: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance., Objective: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients., Methods: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency., Results: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro. The latter defect correlated in vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells., Conclusion: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
37. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders.
- Author
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Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, Nugent D, Coonrod EM, Durtschi JD, Augustine NH, Voelkerding KV, Csomos K, Rosen L, Browne S, Walter JE, Notarangelo LD, Hill HR, and Kumánovics A
- Subjects
- Agammaglobulinemia diagnosis, Agammaglobulinemia etiology, Biopsy, Child, Preschool, Common Variable Immunodeficiency complications, Common Variable Immunodeficiency diagnosis, DNA Mutational Analysis, Fatal Outcome, Female, Humans, Immunohistochemistry, Lung Diseases, Interstitial diagnosis, Lung Diseases, Interstitial etiology, Lymphopenia diagnosis, Lymphopenia etiology, Tomography, X-Ray Computed, Young Adult, Common Variable Immunodeficiency genetics, Homeodomain Proteins genetics, Mutation
- Abstract
Purpose: Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients., Methods: Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients., Results: Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection., Conclusion: Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.
- Published
- 2015
- Full Text
- View/download PDF
38. Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis.
- Author
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Walter JE, Lo MS, Kis-Toth K, Tirosh I, Frugoni F, Lee YN, Csomos K, Chen K, Pillai S, Dunham J, Tsokos GC, Luning Prak ET, and Notarangelo LD
- Subjects
- Adult, Female, Humans, Mutation, Missense, Arthritis genetics, DNA-Binding Proteins genetics, Lupus Erythematosus, Systemic genetics, Nuclear Proteins genetics
- Published
- 2015
- Full Text
- View/download PDF
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