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1. High-dimensional profiling reveals Tc17 cell enrichment in active Crohn's disease and identifies a potentially targetable signature.

Author

Globig, A-M, Hipp, AV, Otto-Mora, P, Heeg, M, Mayer, LS, Ehl, S, Schwacha, H, Bewtra, M, Tomov, V, Thimme, R, Hasselblatt, P, and Bengsch, B

Subjects
CD8-Positive T-Lymphocytes, Humans, Crohn Disease, Interleukin-17, Lymphocyte Count, Th17 Cells, Prevention, Crohn's Disease, Biodefense, Vaccine Related, Digestive Diseases, Clinical Research, Inflammatory Bowel Disease, Autoimmune Disease, 2.1 Biological and endogenous factors, Aetiology, Oral and gastrointestinal, Inflammatory and immune system, Good Health and Well Being
Abstract

The immune-pathology in Crohn's disease is linked to dysregulated CD4+ T cell responses biased towards pathogenic TH17 cells. However, the role of CD8+ T cells able to produce IL-17 (Tc17 cells) remains unclear. Here we characterize the peripheral blood and intestinal tissue of Crohn's disease patients (n = 61) with flow and mass cytometry and reveal a strong increase of Tc17 cells in active disease, mainly due to induction of conventional T cells. Mass cytometry shows that Tc17 cells express a distinct immune signature (CD6high, CD39, CD69, PD-1, CD27low) which was validated in an independent patient cohort. This signature stratifies patients into groups with distinct flare-free survival associated with differential CD6 expression. Targeting of CD6 in vitro reduces IL-17, IFN-γ and TNF production. These results identify a distinct Tc17 cell population in Crohn's disease with proinflammatory features linked to disease activity. The Tc17 signature informs clinical outcomes and may guide personalized treatment decisions.

Published
2022

3. Leukämien und Lymphome

Author

Schrappe, M., Möricke, A., Attarbaschi, A., von Stackelberg, A., Creutzig, U., Reinhardt, D., Suttorp, M., Rensing-Ehl, A., Ehl, S., Burkhardt, B., Klapper, W., Wößmann, W., Körholz, D., Mauz-Körholz, C., Niemeyer, C., Niemeyer, Charlotte, editor, and Eggert, Angelika, editor

Published
2018
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5. Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

Author

Geier, CB, Ellison, M, Cruz, R, Pawar, S, Leiss-Piller, A, Zmajkovicova, K, McNulty, SM, Yilmaz, M, Evans, MO, 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, Forster-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-D, Kojic, M, Koltan, S, Krivan, G, Langguth, D, Lau, Y-L, 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, K-J, Worth, A, Yu, H, Zharankova, Y, Zhao, X, Devlin, L, Badarau, A, Csomos, K, Keszei, M, Pereira, J, Taveras, AG, Beaussant-Cohen, SL, Ong, M-S, Shcherbina, A, Walter, JE, Geier, CB, Ellison, M, Cruz, R, Pawar, S, Leiss-Piller, A, Zmajkovicova, K, McNulty, SM, Yilmaz, M, Evans, MO, 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, Forster-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-D, Kojic, M, Koltan, S, Krivan, G, Langguth, D, Lau, Y-L, 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, K-J, Worth, A, Yu, H, Zharankova, Y, Zhao, X, Devlin, L, Badarau, A, Csomos, K, Keszei, M, Pereira, J, Taveras, AG, Beaussant-Cohen, SL, Ong, M-S, Shcherbina, A, and Walter, JE

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.

Published
2022

8. NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation and hyperinflammation Running title: NCKAP1L deficiency: NCKAP1L deficiency

Author

Castro, C. (Carla) N. (Noemi), Rosenzwajg, M. (Michelle), Carapito, R. (Raphaël), Shahrooei, M. (Mohammad), Konantz, M. (Martina), Khan, A. (Amjad), Miao, Z. (Zhichao), Gross, M. (Miriam), Tranchant, T. (Thibaud), Radosavljevic, M. (Mirjana), Paul, N. (Nicodème), Stemmelen, T. (Tristan), Pitoiset, F. (Fabien), Hirschler, A. (Aurélie), Nespola, B. (Benoit), Molitor, A. (Anne), Rolli, V. (Veronique), Pichot, A. (Angelique), Faletti, L. (Laura) E. (Eva), Rinaldi, B. (Bruno), Friant, S. (Sylvie), Mednikov, M. (Mark), Karauzum, H. (Hatice), Javad Aman, M. (M), Carapito, C. (Christine), Lengerke, C. (Claudia), Ziaee, V. (Vahid), Eyaid, W. (Wafaa), Ehl, S. (Stephan), Alroqi, F. (Fayhan), Parvaneh, N. (Nima), and Bahram, S. (Seiamak)

Subjects
hal-03024718, Aucun
Abstract

The Nck-associated protein 1-like (NCKAP1L) gene, alternatively called hematopoietic protein 1 (HEM-1), encodes a hematopoietic lineage-specific regulator of the actin cytoskeleton. Nckap1l-deficient mice have anomalies in lymphocyte development, phagocytosis, and neutrophil migration. Here we report, for the first time, NCKAP1L deficiency cases in humans. In two unrelated patients of Middle Eastern origin, recessive mutations in NCKAP1L abolishing protein expression led to immunodeficiency, lymphoproliferation, and hyperinflammation with features of hemophagocytic lymphohistiocytosis. Immunophenotyping showed an inverted CD4/CD8 ratio with a major shift of both CD4+ and CD8+ cells toward memory compartments, in line with combined RNA-seq/proteomics analyses revealing a T cell exhaustion signature. Consistent with the core function of NCKAP1L in the reorganization of the actin cytoskeleton, patients' T cells displayed impaired early activation, immune synapse morphology, and leading edge formation. Moreover, knockdown of nckap1l in zebrafish led to defects in neutrophil migration. Hence, NCKAP1L mutations lead to broad immune dysregulation in humans, which could be classified within actinopathies.

Published
2020

9. Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis

Author

Felber, M., Steward, C.G., Kentouche, K., Fasth, A., Wynn, R.F., Zeilhofer, U., Haunerdinger, V., Volkmer, B., Prader, S., Gruhn, B., Ehl, S., Lehmberg, K., Muller, D., Gennery, A.R., Albert, M.H., Hauck, F., Rao, K., Veys, P., Hassan, M., Lankester, A.C., Schmid, J.P., Hauri-Hohl, M.M., Gungor, T., Inborn Errors Working Party IEWP E, European Soc Immunodeficiencies ES, and University of Zurich

Subjects
medicine.medical_specialty, Hemophagocytic lymphohistiocytosis, business.industry, medicine.medical_treatment, 2720 Hematology, 610 Medicine & health, Hematology, Hematopoietic stem cell transplantation, Defibrotide, medicine.disease, Gastroenterology, Fludarabine, medicine.anatomical_structure, 10036 Medical Clinic, Cord blood, Internal medicine, 540 Chemistry, Medicine, Alemtuzumab, Bone marrow, business, Busulfan, 10038 Institute of Clinical Chemistry, medicine.drug
Abstract

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation–approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti–T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

Published
2020

10. Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Author

Zielen, S., Duecker, R.P., Woelke, S., Donath, H., Bakhtiar, S., Buecker, A., Kreyenberg, H., Huenecke, S., Bader, P., Mahlaoui, N., Ehl, S., El-Helou, S.M., Pietrucha, B., Plebani, A., Flier, M. van der, Aerde, K.J. van, Kilic, S.S., Reda, S.M., Kostyuchenko, L., McDermott, E., Galal, N., Pignata, C., Pérez, J.L.S., Laws, H.J., Niehues, T., Kutukculer, N., Seidel, M.G., Marques, L., Ciznar, P., Edgar, J.D.M., Soler-Palacín, P., Bernuth, H. von, Krueger, R., Meyts, I., Baumann, U., Kanariou, M., Grimbacher, B., Hauck, F., Graf, D., Granado, L.I.G., Prader, S., Reisli, I., Slatter, M., Rodríguez-Gallego, C., Arkwright, P.D., Bethune, C., Deripapa, E., Sharapova, S.O., Lehmberg, K., Davies, E.G., Schuetz, C., Kindle, G., Schubert, R., Zielen, S., Duecker, R.P., Woelke, S., Donath, H., Bakhtiar, S., Buecker, A., Kreyenberg, H., Huenecke, S., Bader, P., Mahlaoui, N., Ehl, S., El-Helou, S.M., Pietrucha, B., Plebani, A., Flier, M. van der, Aerde, K.J. van, Kilic, S.S., Reda, S.M., Kostyuchenko, L., McDermott, E., Galal, N., Pignata, C., Pérez, J.L.S., Laws, H.J., Niehues, T., Kutukculer, N., Seidel, M.G., Marques, L., Ciznar, P., Edgar, J.D.M., Soler-Palacín, P., Bernuth, H. von, Krueger, R., Meyts, I., Baumann, U., Kanariou, M., Grimbacher, B., Hauck, F., Graf, D., Granado, L.I.G., Prader, S., Reisli, I., Slatter, M., Rodríguez-Gallego, C., Arkwright, P.D., Bethune, C., Deripapa, E., Sharapova, S.O., Lehmberg, K., Davies, E.G., Schuetz, C., Kindle, G., and Schubert, R.

Abstract

Item does not contain fulltext, Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).

Published
2021

11. Mutations haplo-insuffisantes du gène SOCS1 : une nouvelle cause d’auto-immunité à début précoce traitée par une thérapie ciblée

Author

Hadjadj, J., primary, Carla, C., additional, Tusseau, M., additional, Stolzenberg, M.C., additional, Aladjidi, N., additional, Lega, J.C., additional, Jean-François, V., additional, Picard, C., additional, Walzer, T., additional, Ehl, S., additional, Fischer, A., additional, Neven, B., additional, Belot, A., additional, and Rieux-Laucat, F., additional

Published
2020
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12. THU0053 CONTRIBUTION OF DEFECTIVE NON-APOPTOTIC FAS SIGNALING TO IMMUNE DYSREGULATION IN AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS)

Author

Staniek, J., primary, Kalina, T., additional, Andrieux, G., additional, Boerries, M., additional, Janowska, I., additional, Fuentes, M., additional, Bakardjieva, M., additional, Raabe, J., additional, Neumann, J., additional, Stuchly, J., additional, Benes, V., additional, Garcia, R., additional, Garcia, J., additional, Diez, P., additional, Catala, A., additional, Neven, B., additional, Neth, O., additional, Olbrich, P., additional, Voll, R., additional, Alsina, L., additional, Allende, L., additional, Gonzales-Granado, L., additional, Thiel, J., additional, Venhoff, N., additional, Lorenzetti, R., additional, Unger, S., additional, Seidl, M., additional, Mielenz, D., additional, Schneider, P., additional, Ehl, S., additional, Rensing-Ehl, A., additional, Smulski, C., additional, and Rizzi, M., additional

Published
2020
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13. Phylogeographic analyses point to long-term survival on the spot in micro-endemic Lycian salamanders

Author

Veith, M. Göçmen, B. Sotiropoulos, K. Eleftherakos, K. Lötters, S. Godmann, O. Karış, M. Oğuz, A. Ehl, S.

Abstract

Lycian salamanders (genus Lyciasalamandra) constitute an exceptional case of micro-endemism of an amphibian species on the Asian Minor mainland. These viviparous salamanders are confined to karstic limestone formations along the southern Anatolian coast and some islands. We here study the genetic differentiation within and among 118 populations of all seven Lyciasalamandra species across the entire genus’ distribution. Based on circa 900 base pairs of fragments of the mitochondrial 16SrDNA and ATPase genes, we analysed the spatial haplotype distribution as well as the genetic structure and demographic history of populations. We used 253 geo-referenced populations and CHELSA climate data to infer species distribution models which we projected on climatic conditions of the Last Glacial Maximum (LGM). Within all but one species, distinct phyloclades were identified, which only in parts matched current taxonomy. Most haplotypes (78%) were private to single populations. Sometimes population genetic parameters showed contradicting results, although in several cases they indicated recent population expansion of phyloclades. Climatic suitability of localities currently inhabited by salamanders was significantly lower during the LGM compared to recent climate. All data indicated a strong degree of isolation among Lyciasalamandra populations, even within phyloclades. Given the sometimes high degree of haplotype differentiation between adjacent populations, they must have survived periods of deteriorated climates during the Quaternary on the spot. However, the alternative explanation of male biased dispersal combined with a pronounced female philopatry can only be excluded if independent nuclear data confirm this result. © 2020 Veith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Published
2020

14. Two new populations of Lyciasalamandra flavimembris substantially extend the genus' distribution range in Anatolia

Author

Oğuz M.A., Göçmen B., Kariş M., Ehl S., and Veith M.

Subjects
Morphology, Genetics, Anatolia, Distribution, Lyciasalamandra
Abstract

We report on two new populations of Lyciasalamandra flavimembris from Bodrum/Muğla, based on fieldwork in March 2018. We studied the new populations morphologically and genetically (16SrDNA). According to these records, the known distribution range of the genus is extended about 40 km to the West. Morphologically and genetically, specimens from these two populations show similarities to both subspecies described so far. © Biharean Biologist, Oradea, Romania, 2020, We would like to thank Mr. Yakup ?a?maz (Ankara) and Ak?n Demir (Mu?la) for their assistance and thank Mr. Sabahattin O?UZ and Mrs. Asiye O?UZ (Mu?la) for their accommodation support during our fieldwork.

Published
2020

15. Das Ende einer Odyssee

Author

Hudowenz, O, Klemm, P, Müller-Ladner, U, Tarner, I, Lange, U, Ehl, S, Warnatz, K, Hudowenz, O, Klemm, P, Müller-Ladner, U, Tarner, I, Lange, U, Ehl, S, and Warnatz, K

Published
2020

16. Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Author

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

Subjects
Adult, DNA-Binding Proteins, Homeodomain Proteins, Immunologic Deficiency Syndromes, Prevalence, Humans, Nuclear Proteins
Published
2018
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17. Disease evolution and response to rapamycin in Activated Phosphoinositide 3-Kinase delta syndrome: the european society for immunodeficiencies-Activated Phosphoinositide 3-Kinase d syndrome registry

Author

Maccari, M.E., Abolhassani, H., Aghamohammadi, A., Aiuti, A., Aleinikova, O., Bangs, C., Baris, S., Barzaghi, F., Baxendale, H., Buckland, M., Burns, S.O., Cancrini, C., Cant, A., Cathebras, P., Cavazzana, M., Chandra, A., Conti, F., Coulter, T., Devlin, L.A., Edgar, J.D.M., Faust, S., Fischer, A., Prat, M.G., Hammarstrom, L., Heeg, M., Jolles, S., Karakoc-Aydiner, E., Kindle, G., Kiykim, A., Kumararatne, D., Grimbacher, B., Longhurst, H., Mahlaoui, N., Milota, T., Moreira, F., Moshous, D., Mukhina, A., Neth, O., Neven, B., Nieters, A., Olbrich, P., Ozen, A., Schmid, J.P., Picard, C., Prader, S., Rae, W., Reichenbach, J., Rusch, S., Savic, S., Scarselli, A., Scheible, R., Sediva, A., Sharapova, S.O., Shcherbina, A., Slatter, M., Soler-Palacin, P., Stanislas, A., Suarez, F., Tucci, F., Uhlmann, A., van Montfrans, J., Warnatz, K., Williams, A.P., Wood, P., Kracker, S., Condliffe, A.M., and Ehl, S.

Abstract

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal\ud dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary\ud immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical\ud and immunological manifestations, questions about long-term disease evolution and\ud response to therapy remain. The prospective European Society for Immunodeficiencies\ud (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors,\ud and evaluate treatment responses. So far, 77 patients have been recruited (51\ud APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early\ud occurrence of recurrent respiratory infections followed by chronic lymphoproliferation,\ud gastrointestinal manifestations, and cytopenias. Although most manifestations occur by\ud age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was\ud observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2\ud patients. By age 20, half of the patients had received at least one immunosuppressant,\ud but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response\ud to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9,\ud and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial,\ud 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and\ud cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative\ud manifestations should be a key target for novel therapies. This report from\ud the ESID-APDS registry provides comprehensive baseline documentation for a growing\ud cohort that will be followed prospectively to establish prognostic factors and identify\ud patients for treatment studies.

Published
2018

18. Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Author

Barzaghi, F., Hernandez, L.C.A., Neven, B., Ricci, S., Kucuk, Z.Y., Bleesing, J.J., Nademi, Z., Slatter, M.A., Ulloa, E.R., Shcherbina, A., Roppelt, A., Worth, A., Silva, J., Aiuti, A., Murguia-Favela, L., Speckmann, C., Carneiro-Sampaio, M., Fernandes, J.F., Baris, S., Ozen, A., Karakoc-Aydiner, E., Kiykim, A., Schulz, A., Steinmann, S., Notarangelo, L.D., Gambineri, E., Lionetti, P., Shearer, W.T., Forbes, L.R., Martinez, C., Moshous, D., Blanche, S., Fisher, A., Ruemmele, F.M., Tissandier, C., Ouachee-Chardin, M., Rieux-Laucat, F., Cavazzana, M., Qasim, W., Lucarelli, B., Albert, M.H., Kobayashi, I., Alonso, L., Heredia, C.D. de, Kanegane, H., Lawitschka, A., Seo, J.J., Gonzalez-Vicent, M., Diaz, M.A., Goyal, R.K., Sauer, M.G., Yesilipek, A., Kim, M., Yilmaz-Demirdag, Y., Bhatia, M., Khlevner, J., Padilla, E.J.R., Martino, S., Montin, D., Neth, O., Molinos-Quintana, A., Valverde-Fernandez, J., Broides, A., Pinsk, V., Ballauf, A., Haerynck, F., Bordon, V., Dhooge, C., Garcia-Lloret, M.L., Bredius, R.G., Kawak, K., Haddad, E., Seidel, M.G., Duckers, G., Pai, S.Y., Dvorak, C.C., Ehl, S., Locatelli, F., Goldman, F., Gennery, A.R., Cowan, M.J., Roncarolo, M.G., Bacchetta, R., PIDTC, IEWP, European Soc Blood Marrow, Barzaghi, Federica, Hernandez, Laura Cristina Amaya, Neven, Benedicte, Ricci, Silvia, Kucuk, Zeynep Yesim, Bleesing, Jack J., Nademi, Zohreh, Slatter, Mary Anne, Ulloa, Erlinda Rose, Shcherbina, Anna, Roppelt, Anna, Worth, Austen, Silva, Juliana, Aiuti, Alessandro, Murguia-Favela, Luis, Speckmann, Carsten, Carneiro-Sampaio, Magda, Fernandes, Juliana Folloni, Baris, Safa, Ozen, Ahmet, Karakoc-Aydiner, Elif, Kiykim, Ayca, Schulz, Ansgar, Steinmann, Sandra, Notarangelo, Lucia Dora, Gambineri, Eleonora, Lionetti, Paolo, Shearer, William Thomas, Forbes, Lisa R., Martinez, Caridad, Moshous, Despina, Blanche, Stephane, Fisher, Alain, Ruemmele, Frank M., Tissandier, Come, Ouachee-Chardin, Marie, Rieux-Laucat, Frederic, Cavazzana, Marina, Qasim, Waseem, Lucarelli, Barbarella, Albert, Michael H., Kobayashi, Ichiro, Alonso, Laura, De Heredia, Cristina Diaz, Kanegane, Hirokazu, Lawitschka, Anita, Seo, Jong Jin, Gonzalez-Vicent, Marta, Diaz, Miguel Angel, Goyal, Rakesh Kumar, Sauer, Martin G., Yesilipek, Akif, Kim, Minsoo, Yilmaz-Demirdag, Yesim, Bhatia, Monica, Khlevner, Julie, Padilla, Erick J. Richmond, Martino, Silvana, Montin, Davide, Neth, Olaf, Molinos-Quintana, Agueda, Valverde-Fernandez, Justo, Broides, Arnon, Pinsk, Vered, Ballauf, Antje, Haerynck, Filomeen, Bordon, Victoria, Dhooge, Catharina, Garcia-Lloret, Maria Laura, Bredius, Robbert G., Kalwak, Krzysztof, Haddad, Elie, Seidel, Markus Gerhard, Duckers, Gregor, Pai, Sung-Yun, Dvorak, Christopher C., Ehl, Stephan, Locatelli, Franco, Goldman, Frederick, Gennery, Andrew Richard, Cowan, Mort J., Roncarolo, Maria-Grazia, Bacchetta, Rosa, Amaya Hernandez, Laura Cristina, Murguia-Favela, Lui, Shearer, William Thoma, Rieux-Laucat, Frédéric, Diaz De Heredia, Cristina, Richmond Padilla, Erick J., and Kałwak, Krzysztof

Subjects
0301 basic medicine, Male, Allergy, medicine.medical_treatment, Medizin, Disease, Hematopoietic stem cell transplantation, SIROLIMUS, Regenerative Medicine, primary immune deficiency, Medicine and Health Sciences, IPEX, Immunology and Allergy, 2.1 Biological and endogenous factors, Enteropathy, Aetiology, POLYENDOCRINOPATHY, Child, Pediatric, CÉLULAS-TRONCO, immunosuppression, Hematopoietic Stem Cell Transplantation, Genetic Diseases, X-Linked, Immunosuppression, Forkhead Transcription Factors, X-LINKED SYNDROME, Allografts, Survival Rate, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Immune System Diseases, Genetic Diseases, Child, Preschool, hematopoietic stem cell transplantation, Female, hematopoietic stem, neonatal diabetes, FOXP3, Primary Immune Deficiency, Treg cells, enteropathy, genetic autoimmunity, rapamycin, Type 1, Diarrhea, Adult, medicine.medical_specialty, Adolescent, Immunology, Neonatal onset, Article, Disease-Free Survival, 03 medical and health sciences, Neonatal diabete, Clinical Research, Internal medicine, IMMUNODYSREGULATION, medicine, Primary Immune Deficiency Treatment Consortium (PIDTC) and the Inborn Errors Working Party (IEWP) of the European Society for Blood and Marrow Transplantation, Diabetes Mellitus, Genetics, Humans, REGULATORY T-CELLS, cell transplantation, Preschool, Retrospective Studies, Immunosuppression Therapy, Transplantation, IMMUNE DYSREGULATION, business.industry, MUTATIONS, Infant, Retrospective cohort study, STEM-CELL TRANSPLANTATION, IPEX syndrome, X-Linked, medicine.disease, Stem Cell Research, BONE-MARROW-TRANSPLANTATION, Treg cell, FOXP3 MUTATIONS, Diabetes Mellitus, Type 1, 030104 developmental biology, ENGRAFTMENT, Mutation, business, Follow-Up Studies
Abstract

Background Immunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. Objective This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. Methods Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. Results We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. Conclusions Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen., GRAPHICAL ABSTRACT

Published
2018

19. Refining the dermatological spectrum in primary immunodeficiency: mucosa‐associated lymphoid tissue lymphoma translocation protein 1 deficiency mimicking Netherton/Omenn syndromes

Author

Wiegmann, H., primary, Reunert, J., additional, Metze, D., additional, Marquardt, T., additional, Engel, T., additional, Kunde, V., additional, Ehl, S., additional, Foell, D., additional, Heuvel, I., additional, Oji, V., additional, and Wittkowski, H., additional

Published
2019
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20. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity

Author

Seidel, M.G., Kindle, G., Gathmann, B., Quinti, I., Buckland, M., Montfrans, J. van, Scheible, R., Rusch, S., Gasteiger, L.M., Grimbacher, B., Veerdonk, F.L. van de, Weemaes, C.M.R., Mahlaoui, N., Ehl, S., Seidel, M.G., Kindle, G., Gathmann, B., Quinti, I., Buckland, M., Montfrans, J. van, Scheible, R., Rusch, S., Gasteiger, L.M., Grimbacher, B., Veerdonk, F.L. van de, Weemaes, C.M.R., Mahlaoui, N., and Ehl, S.

Abstract

Item does not contain fulltext, Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on more than 25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies, or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remain without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with an external review. They were implemented for novel entries and verification of existing data sets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

Published
2019

21. The burden of common variable immunodeficiency disorders: A retrospective analysis of the European Society for Immunodeficiency (ESID) registry data

Author

Odnoletkova, I, Kindle, G, Quinti, I, Grimbacher, B, Knerr, V, Gathmann, B, Ehl, S, Mahlaoui, N, Van Wilder, P, Bogaerts, K, de Vries, E, Farrugia, A, Krishnarajah, S, Mendivil, J, Prior, M, Rübesam, T, Runken, M, in collaboration with the Plasma Protein Therapeutics Association (PPTA) Taskforce, Tranzo, Scientific center for care and wellbeing, and Huisarts & Ziekenhuis

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, Génétique clinique, Primary immunodeficiency, Primary antibody deficiency, Common variable immunodeficiency, Burden of disease DALY, Health economics, Diagnostic delay, Population, lcsh:Medicine, Pharmacologie, 03 medical and health sciences, Life Expectancy, Cost of Illness, medicine, Burden of disease, common variable immunodeficiency, DALY, diagnostic delay, health economics, primary antibody deficiency, primary immunodeficiency, genetics (clinical), pharmacology (medical), Humans, Pharmacology (medical), Registries, Risk factor, education, Genetics (clinical), Disease burden, Retrospective Studies, education.field_of_study, business.industry, Research, lcsh:R, General Medicine, Sciences bio-médicales et agricoles, medicine.disease, Comorbidity, Europe, 030104 developmental biology, Years of potential life lost, Cohort, business
Abstract

BACKGROUND: Common variable immunodeficiency disorders (CVID) are a group of rare innate disorders characterized by specific antibody deficiency and increased rates of infections, comorbidities and mortality. The burden of CVID in Europe has not been previously estimated. We performed a retrospective analysis of the European Society for Immunodeficiencies (ESID) registry data on the subset of patients classified by their immunologist as CVID and treated between 2004 and 2014. The registered deaths and comorbidities were used to calculate the annual average age-standardized rates of Years of Life Lost to premature death (YLL), Years Lost to Disability (YLD) and Disability Adjusted Life Years (DALY=YLL + YLD). These outcomes were expressed as a rate per 105 of the CVID cohort (the individual disease burden), and of the general population (the societal disease burden). RESULTS: Data of 2700 patients from 23 countries were analysed. Annual comorbidity rates: bronchiectasis, 21.9%; autoimmunity, 23.2%; digestive disorders, 15.6%; solid cancers, 5.5%; lymphoma, 3.8%, exceeded the prevalence in the general population by a factor of 34.0, 7.6, 8.1, 2.4 and 32.6, respectively. The comorbidities of CVID caused 8722 (6069; 12,363) YLD/105 in this cohort, whereas 44% of disability burden was attributable to infections and bronchiectasis. The total individual burden of CVID was 36,785 (33,078, 41,380) DALY/105. With estimated CVID prevalence of ~ 1/ 25,000, the societal burden of CVID ensued 1.5 (1.3, 1.7) DALY/105 of the general population. In exploratory analysis, increased mortality was associated with solid tumor, HR (95% CI): 2.69 (1.10; 6.57) p = 0.030, lymphoma: 5.48 (2.36; 12.71) p, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2018

22. Infektionsanfälligkeit bei Immundefizienz

Author

Speckmann, C, Ehl, S, Liese, J, Trück, Johannes, University of Zurich, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, and Simon, Arne

Subjects
10036 Medical Clinic, 610 Medicine & health
Published
2018

24. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects

Author

Schwab, C., Gabrysch, A., Olbrich, P., Patino, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J.A., Sansom, D.M., Lucena, J.M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, Desiree, Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z.Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P.D., Cant, A., Lorenz, H.M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K.E., Moutschen, M., Litzman, J., Freiberger, T., Veerdonk, F.L. van de, Recher, M., Albert, M.H., Hauck, F., Seneviratne, S., Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Duckers, G., Niehues, T., Fronkova, E., Kanderova, V., Platt, C.D., Chou, J., Chatila, T.A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deya-Martinez, A., Hambleton, S., Kanegane, H., Tasken, K., Neth, O., Grimbacher, B., Schwab, C., Gabrysch, A., Olbrich, P., Patino, V., Warnatz, K., Wolff, D., Hoshino, A., Kobayashi, M., Imai, K., Takagi, M., Dybedal, I., Haddock, J.A., Sansom, D.M., Lucena, J.M., Seidl, M., Schmitt-Graeff, A., Reiser, V., Emmerich, F., Frede, N., Bulashevska, A., Salzer, U., Schubert, Desiree, Hayakawa, S., Okada, S., Kanariou, M., Kucuk, Z.Y., Chapdelaine, H., Petruzelkova, L., Sumnik, Z., Sediva, A., Slatter, M., Arkwright, P.D., Cant, A., Lorenz, H.M., Giese, T., Lougaris, V., Plebani, A., Price, C., Sullivan, K.E., Moutschen, M., Litzman, J., Freiberger, T., Veerdonk, F.L. van de, Recher, M., Albert, M.H., Hauck, F., Seneviratne, S., Schmid, J., Kolios, A., Unglik, G., Klemann, C., Speckmann, C., Ehl, S., Leichtner, A., Blumberg, R., Franke, A., Snapper, S., Zeissig, S., Cunningham-Rundles, C., Giulino-Roth, L., Elemento, O., Duckers, G., Niehues, T., Fronkova, E., Kanderova, V., Platt, C.D., Chou, J., Chatila, T.A., Geha, R., McDermott, E., Bunn, S., Kurzai, M., Schulz, A., Alsina, L., Casals, F., Deya-Martinez, A., Hambleton, S., Kanegane, H., Tasken, K., Neth, O., and Grimbacher, B.

Abstract

Item does not contain fulltext, BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

Published
2018

25. Infektionsanfälligkeit bei Immundefizienz

Author

DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, Simon, Arne, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, ( ), Berner, R ( Reinhard ), Bialek, R ( Ralf ), Forster, J ( Johannes ), Härtel, C ( Christoph ), Heininger, U ( Ulrich ), Huppertz, H ( Hans-Iko ), Liese, J G ( Johannes G ), Nadal, D ( David ), Simon, A ( Arne ), Speckmann, C, Ehl, S, Liese, J, Trück, Johannes; https://orcid.org/0000-0002-0418-7381, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, Berner, Reinhard, Bialek, Ralf, Forster, Johannes, Härtel, Christoph, Heininger, Ulrich, Huppertz, Hans-Iko, Liese, Johannes G, Nadal, David, Simon, Arne, DGPI - Deutsche Gesellschaft für Pädiatrische Infektiologie, ( ), Berner, R ( Reinhard ), Bialek, R ( Ralf ), Forster, J ( Johannes ), Härtel, C ( Christoph ), Heininger, U ( Ulrich ), Huppertz, H ( Hans-Iko ), Liese, J G ( Johannes G ), Nadal, D ( David ), Simon, A ( Arne ), Speckmann, C, Ehl, S, Liese, J, and Trück, Johannes; https://orcid.org/0000-0002-0418-7381

Published
2018

26. Fieber unbekannter Ursache, hämatologische, dermatologische und neurologische Symptome bei zwei Patienten: ADA2 Defizienz (DADA2)

Author

Dückers, G, Klemann, C, Eisert, S, Lara, E, Utz, N, Siepermann, K, Ehl, S, Schneider, D, Niemeyer, C, and Niehues, T

Subjects
ddc: 610, FUO, Autoinflammation, ADA2 Defekt, Fieber unklarer Ursache, 610 Medical sciences, Medicine
Abstract

Einleitung: Patient 1, ein 15 Jahre alter Junge, nicht konsanguiner deutscher Eltern präsentiert sich mit einer spontanen intrazerebralen Blutung im Frontalhirn. Im Verlauf entwickelt der Junge therapierefraktäres, „spiking“ Fieber, eine Livedo reticularis, Panzytopenie und einen[zum vollständigen Text gelangen Sie über die oben angegebene URL], 44. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 30. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 26. Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)

Published
2016
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29. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Author

Coulter, T, Chandra, A, Bacon, C, Babar, J, Curtis, J, Screaton, N, Goodlad, J, Farmer, G, Steele, C, Leahy, T, Doffinger, R, Baxendale, H, Bernatoniene, J, Edgar, J, Longhurst, H, Ehl, S, C Grimbacher B, S, Sediva A Milota, Tfs, Williams, A, Hayman, G, Kucuk, Z, Hague, R, French, P, Brooker, R, Forsyth, P, Herriot, R, Cancrini, C, Palma, P, Ariganello, P, Conlon, N, Feighery, C, Gavin, P, Jones, A, Imai, K, Ibrahim, M, Markelj, G, Abinun, M, Rieux-Laucat, F, Latour, S, I Fischer A Touzot F, P, Casanova, J, Durandy, A, Burns, S, Savic, S, Kumararatne, D, Moshous, D, Kracker, S, Vanhaesebroeck, B, K Picard C, O, Nejentsev, S, and Condliffe AM Cant AJ

Subjects
Settore MED/38
Published
2016

30. Refining the dermatological spectrum in primary immunodeficiency: mucosa‐associated lymphoid tissue lymphoma translocation protein 1 deficiency mimicking Netherton/Omenn syndromes.

Author

Wiegmann, H., Reunert, J., Metze, D., Marquardt, T., Engel, T., Kunde, V., Ehl, S., Foell, D., Heuvel, I., Oji, V., and Wittkowski, H.

Subjects
FAILURE to thrive syndrome, MUCOSA-associated lymphoid tissue lymphoma, PROTEIN deficiency, NF-kappa B, SYNDROMES
Abstract

Summary: The proteinase mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1), which forms part of the caspase recruitment domain‐containing protein 11–B‐cell lymphoma 10–MALT1 signalosome complex, plays a direct role in nuclear factor kappa B activation. Here, we describe the case of a female infant with severe immune dysregulation leading to recurrent systemic infections, failure to thrive and severe crises of ichthyosiform erythroderma with high levels of serum IgE. Hence, initial symptoms indicated Netherton syndrome or Omenn syndrome. Surprisingly, sequence analyses of SPINK5 and RAG1/RAG2, respectively, excluded these diseases. During the hospital stay the patient's health deteriorated, despite intensive care therapy, and she died. In order to delineate the diagnosis, whole‐exome sequencing was performed. Two compound heterozygous mutations in MALT1 were found and verified by Sanger sequencing (exon 2 c.245T>C, exon 2 c.310dup), which led to a MALT1 deficiency at the protein level. Based on these results, an immunological analysis was performed, as was immunofluorescence staining of key skin proteins, to confirm a diagnosis of MALT1 deficiency. This case report provides a closer description of the clinical and histological skin phenotype of MALT1 deficiency, and we conclude that MALT1 deficiency must be considered a possible differential diagnosis of Netherton and Omenn syndromes. What's already known about this topic? Mucosa‐associated lymphoid tissue lymphoma translocation protein 1 (MALT1) deficiency is a combined immunodeficiency.MALT1 is part of the caspase recruitment domain‐containing protein 11–B‐cell lymphoma 10–MALT1 signalosome complex, which is essential for nuclear factor kappa B activation.Current publications describe a phenotype of recurrent systemic infections; only in a few cases has an inflammatory involvement of the integument been described. What does this study add? A closer description of the cutaneous phenotype of MALT1 deficiency in a patient with two novel MALT1 mutations.Immune mapping of follicular epidermis shows lympho‐epithelial Kazal‐type‐related inhibitor is reduced in MALT1 deficiency and absent on interfollicular staining.Clinically, MALT1 deficiency mimics Netherton syndrome and Omenn syndrome, and should be considered a differential diagnosis [ABSTRACT FROM AUTHOR]

Published
2020
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31. The German PID-net registry

Author

El-Helou, S. M., Biegner, A. K., Bode, S., Ehl, S., Heeg, M., Ritterbusch, H., Rusch, S., Schmitt, R., Warnatz, K., Baerlecken, N. T., Baumann, U., Beider, R., Ernst, D., Gerschmann, S., Klemann, C., Mielke, G., Schmidt, R. E., Schuermann, G., Viemann, D., Albert, M., Eichinger, A., Eisl, E., Hauck, F., Klein, C., Sollinger, F., von Bernuth, H., Hanitsch, L., Krueger, R., Scheibenbogen, C., Avila, A., Borte, M., Borte, S., Fasshauer, M., Hauenherm, A., Kellner, N., Mueller, H., Uelzen, A., Bader, P., Bakhtiar, S., Hess, U., Lee, J. Y., Schubert, R., Voss, S., Zielen, S., Bienemann, K., Lankisch, P., Laws, H. J., Neubert, J., Dueckers, G., Lamers, B., Langemeyer, V., Niehues, T., Hoenig, M., Schulz, A., Schwarz, K., Steinmann, S., Graf, D., Haase, G., Liese, J. G., Morbach, H., Schwaneck, E., Tony, H. P., Foell, D., Hellige, A., Masjosthusmann, K., Mohr, M., Wittkowski, H., Fischer, J. C., Hedrich, C. M., Roesen-Wolff, A., Roesler, J., Behrends, U., Rieber, N., Schauer, U., Boesecke, C., Dilloo, D., Engelhardt, A., Huelsmann, B., Rockstroh, J., Scholtes, C., Schoenberger, S., Wasmuth, J. C., Handgretinger, R., Henes, J., Holzer, U., Kanz, L., Ankermann, T., von Bismarck, P., Schreiber, S., Zeuner, R., Huppertz, H. I., Kaiser-Labusch, P., Greil, J., Jakoby, D., Kulozik, A. E., Graf, N., Heine, S., Garwer, B., Kobbe, R., Lehmberg, K., Mueller, I., Herrmann, F., Horneff, G., Klein, A., Peitz, J., Schmidt, N., Apel, K., Bielack, S., Gross-Wieltsch, U., Deutz, P., Lassay, L., Kamitz, D., Stienen, A., Tenbrock, K., Wagner, N., Classen, C. F., Weiss, M., Bernbeck, B., Brummel, B., Lara-Villacanas, E., Muenstermann, E., Schneider, D., Tietsch, N., Westkemper, M., Naumann-Bartsch, N., Metzler, M., Sobik, B., Kuehnle, I., Kullmann, S., Kramm, C., Girschick, H., Elbe, S., Specker, C., Vinnemeier-Laubenthal, L., Haenicke, H., Schulz, C., Schweigerer, L., Mueller, T. G., Kindle, G., Grimbacher, B., El-Helou, S. M., Biegner, A. K., Bode, S., Ehl, S., Heeg, M., Ritterbusch, H., Rusch, S., Schmitt, R., Warnatz, K., Baerlecken, N. T., Baumann, U., Beider, R., Ernst, D., Gerschmann, S., Klemann, C., Mielke, G., Schmidt, R. E., Schuermann, G., Viemann, D., Albert, M., Eichinger, A., Eisl, E., Hauck, F., Klein, C., Sollinger, F., von Bernuth, H., Hanitsch, L., Krueger, R., Scheibenbogen, C., Avila, A., Borte, M., Borte, S., Fasshauer, M., Hauenherm, A., Kellner, N., Mueller, H., Uelzen, A., Bader, P., Bakhtiar, S., Hess, U., Lee, J. Y., Schubert, R., Voss, S., Zielen, S., Bienemann, K., Lankisch, P., Laws, H. J., Neubert, J., Dueckers, G., Lamers, B., Langemeyer, V., Niehues, T., Hoenig, M., Schulz, A., Schwarz, K., Steinmann, S., Graf, D., Haase, G., Liese, J. G., Morbach, H., Schwaneck, E., Tony, H. P., Foell, D., Hellige, A., Masjosthusmann, K., Mohr, M., Wittkowski, H., Fischer, J. C., Hedrich, C. M., Roesen-Wolff, A., Roesler, J., Behrends, U., Rieber, N., Schauer, U., Boesecke, C., Dilloo, D., Engelhardt, A., Huelsmann, B., Rockstroh, J., Scholtes, C., Schoenberger, S., Wasmuth, J. C., Handgretinger, R., Henes, J., Holzer, U., Kanz, L., Ankermann, T., von Bismarck, P., Schreiber, S., Zeuner, R., Huppertz, H. I., Kaiser-Labusch, P., Greil, J., Jakoby, D., Kulozik, A. E., Graf, N., Heine, S., Garwer, B., Kobbe, R., Lehmberg, K., Mueller, I., Herrmann, F., Horneff, G., Klein, A., Peitz, J., Schmidt, N., Apel, K., Bielack, S., Gross-Wieltsch, U., Deutz, P., Lassay, L., Kamitz, D., Stienen, A., Tenbrock, K., Wagner, N., Classen, C. F., Weiss, M., Bernbeck, B., Brummel, B., Lara-Villacanas, E., Muenstermann, E., Schneider, D., Tietsch, N., Westkemper, M., Naumann-Bartsch, N., Metzler, M., Sobik, B., Kuehnle, I., Kullmann, S., Kramm, C., Girschick, H., Elbe, S., Specker, C., Vinnemeier-Laubenthal, L., Haenicke, H., Schulz, C., Schweigerer, L., Mueller, T. G., Kindle, G., and Grimbacher, B.

Published
2017

32. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study

Author

Coulter, TI, Chandra, A, Bacon, CM, Babar, J, Curtis, J, Screaton, N, Goodlad, JR, Farmer, G, Steele, CL, Leahy, TR, Doffinger, R, Baxendale, H, Bernatoniene, J, Edgar, JD, Longhurst, HJ, Ehl, S, Speckmann, C, Grimbacher, B, Sediva, A, Milota, T, Faust, SN, Williams, AP, Hayman, G, Kucuk, ZY, Hague, R, French, P, Brooker, R, Forsyth, P, Herriot, R, Cancrini, C, Palma, P, Ariganello, P, Conlon, N, Feighery, C, Gavin, PJ, Jones, A, Imai, K, Ibrahim, MA, Markelj, G, Abinun, M, Rieux-Laucat, F, Latour, S, Pellier, I, Fischer, A, Touzot, F, Casanova, JL, Durandy, A, Burns, SO, Savic, S, Kumararatne, DS, Moshous, D, Kracker, S, Vanhaesebroeck, B, Okkenhaug, K, Picard, C, Nejentsev, S, Condliffe, AM, Cant, AJ, Chandra, Anita [0000-0002-9061-879X], Okkenhaug, Klaus [0000-0002-9432-4051], Nezhentsev, Sergey [0000-0002-7528-4461], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Adolescent, bronchiectasis, Class I Phosphatidylinositol 3-Kinases, International Cooperation, Immunology, PPV, Pneumococcal polysaccharide vaccine, HSCT, Hematopoietic stem cell transplantation, Cohort Studies, Mice, Young Adult, APDS, Activated phosphoinositide-3 kinase δ syndrome, phosphoinositide 3-kinase inhibitor, Immune Deficiencies, Infection, and Systemic Immune Disorders, Recurrence, PI3K, Phosphoinositide 3-kinase, Surveys and Questionnaires, BALF, Bronchoalveolar lavage fluid, Activated phosphoinositide 3-kinase δ syndrome, Animals, Humans, Immunology and Allergy, Enzyme Inhibitors, CMV, Cytomegalovirus, Child, HSV, Herpes simplex virus, Respiratory Tract Infections, CNS, Central nervous system, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes, Immunoglobulins, Intravenous, Infant, GOF, Gain of function, Herpesviridae Infections, Antibiotic Prophylaxis, Middle Aged, PIK3CD gene, Survival Analysis, Lymphoproliferative Disorders, Child, Preschool, Mutation, CT, Computed tomography, p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency, Female, immunodeficiency, phosphoinositide 3-kinase δ, OR, Odds ratio
Abstract

Background: Activated PI3-Kinase Delta Syndrome (APDS) is a recently described combined immunodeficiency resulting from gain-of-function mutations in PIK3CD, the gene encoding the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ).\ud Objective: To review the clinical, immunological, histopathological and radiological features of APDS in a large genetically-defined international cohort.\ud Methods: Clinical questionnaire, and review of medical notes, radiology histopathology and laboratory investigations of 53 APDS patients.\ud Results: Recurrent sino-pulmonary infections (96%) and non-neoplastic lymphoproliferation (75%) were common, often from childhood. Other significant complications included herpesvirus infections (49%), autoinflammatory disease (34%), and lymphoma (13%). Unexpectedly, neurodevelopmental delay occurred in 19% of the cohort, suggesting a role for PI3Kδ in the central nervous system (CNS); consistent with this PI3Kδ is broadly expressed in the developing murine CNS. Thoracic imaging revealed high rates of mosaic attenuation (90%) and bronchiectasis (60% in cohort); the incidence of bronchiectasis was greater than in common variable immunodeficiency (CVID). Elevated IgM (78%), IgG deficiency (43%) and CD4 lymphopenia (84%) were significant immunological features. No immunological marker reliably predicted clinical severity, which ranged from asymptomatic to death in early childhood. The majority of patients received immunoglobulin replacement and antibiotic prophylaxis, and five patients underwent haematopoietic stem cell transplant (HSCT). Five patients died from complications of APDS.\ud Conclusion: APDS is a combined immunodeficiency with multiple clinical manifestations, many with incomplete penetrance and others with variable expressivity. The severity of complications in some patients supports consideration of HSCT for severe childhood disease. Clinical trials of selective PI3Kδ inhibitors offer new prospects for APDS treatment.

Published
2017
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34. S100A12 as diagnostic tool in the differential diagnosis of sJIA associated MAS vs. hereditary or acquired HLH

Author

Reumatologie onderzoek 2, Child Health, CTI Vastert, Infection & Immunity, Reumatologie patientenzorg, Immuno/reuma onderzoek 1 (Vastert), Holzinger, D., Fall, N., Grom, A., de Jager, W., Vastert, S., Strippoli, R., Bracaglia, C., Sundberg, E., Horne, A., Ehl, S., De Benedetti, F., Beutel, K., Foell, D., Reumatologie onderzoek 2, Child Health, CTI Vastert, Infection & Immunity, Reumatologie patientenzorg, Immuno/reuma onderzoek 1 (Vastert), Holzinger, D., Fall, N., Grom, A., de Jager, W., Vastert, S., Strippoli, R., Bracaglia, C., Sundberg, E., Horne, A., Ehl, S., De Benedetti, F., Beutel, K., and Foell, D.

Published
2015

39. Autorenverzeichnis

Author

Graul-Neumann, L., Horn, D., Hübner, C., Huppke, P., König, R., Majewski, F., Meinecke, P., Pankau, R., Rosenbaum, T., Schnabel, D., Schuelke, M., Spranger, J., Theile, U., Tinschert, S., Wilichowski, E., Wollmann, H.A., Zenker, M., Bartmann, P., Bassler, D., Bührer, C., Flemmer, A.W., Forster, J., Franz, A., Gonser, M., Gortner, L., Groneck, P., Hentschel, R., Herting, E., Hoyme, U.B., Hummler, H., Jandeck, C., Jorch, G., Korinthenberg, R., Liese, J., Maier, R.F., Martius, J., Merkenschlager, A., Poets, C.F., Pohlandt, F., Roll, C., Roos, R., Roth, B., Schneider, K.T.M., Speer, Ch., Stopfkuchen, H., Teichmann, A., Thomas, W., Vetter, K., von der Wense, A., Zielen, S., Assmann, B., Hoffmann, G.F., Kölker, S., Lindner, M., Mönch, E., Santer, R., Spiekerkötter, U., Zschocke, J., Bauer, K., Böhles, H.-J., Sinclair, Jack, Jauch, K.W., Jochum, F., Kauth, Thomas, Koletzko, B., Krawinkel, M., Krohn, K., Mihatsch, Walter, Moß, A., Mühlebach, S., Verwied-Jorky, S., Wabitsch, M., Zimmer, K.-P., Albers, N., L'Allemand, D., Binder, G., Brämswig, J.H., Dörr, H.G., Grüters-Kieslich, A., Hauffa, B.P., Heger, S., Hiort, O., Holl, R., Holterhus, P.M., Köhler, B., Korsch, Eckhard, Kratzsch, J., Krude, H., Mohnike, K., Neu, A., Pfäffle, R., Richter-Unruh, A., Riepe, F.G., Simic-Schleicher, G., Schönau, E., Sinnecker, G., Sippell, W., Willgerodt, H., Wölfle, J., Wudy, S.A., Aygören-Pürsün, E., Bas, M., Baumann, U., Biedermann, T., Blume, J., Buchholz, B., Dückers, G., Dunsch, D., Edelhäuser, M., Ehl, S., Feiterna-Sperling, C., Funk, M., Hartmann, K., Königs, C., Kreuz, W., Krudewig, J., Laws, H.-J., Linde, R., Martinez-Saguer, I., Maurer, M., Nadal, David, Niehues, T., Notheis, G., Ott, H., Schulze, I., Wedi, B., Wintergerst, U., Bürk, G., Foeldvari, I., Frosch, M., Girschick, H., Gerhold, K., Guellac, N., Haas, J.P., Häfner, R., Häuser, W., Heiligenhaus, A., Hospach, T., Horneff, G., Huppertz, H.-I., Illhardt, A., Jansson, A.F., Kallinich, T., Michels, H., Mönkemöller, K., Neudorf, U., Richter, M., Schnöbel-Müller, E., Thon, A., Zernikow, B., Behnisch, W., Cario, H., Dickerhoff, R., Eber, S., Führer, M., Kohne, E., Kulozik, A.E., Kunz, J., Muckenthaler, M., Eberl, W., Gaedicke, G., Muntean, W., Streif, W., Beck, J.D., Berthold, F., Bielack, S., Calaminus, G., Claviez, A., Creutzig, U., Dirksen, U., Dworzak, M., Göbel, U., Graf, N., Grießmeier, B., Henze, G., Hero, B., Jürgens, H., Kaiser, U., Klingebiel, T., Koscielniak, E., Kramm, C., Langer, T., Lawrenz, B., Lehrnbecher, T., Leiss, U., Mentzel, H.-J., Minkov, M., Peitz, J., Placzek, R., Reinhardt, D., Reiter, A., Rutkowski, S., Schmittenbecher, P., Schneider, D.T., Schreiber-Gollwitzer, B.M., Schrappe, M., Schroten, H., Schröder, H.M., Schuster, V., von Schweinitz, D., Sörensen, N., Tallen, G., Timmermann, B., Warmuth-Metz, M., Weckesser, M., Wessel, L., Wirth, T., Wolff, J.E.A., Wößmann, W., Zehnhoff-Dinnesen, A. am, Apitz, C., Arnold, R., Baumgartner, H., Bennink, G., Bertram, H., Blankenburg, M., Bönner, G., von der Breek, J., Breuer, J., Buchhorn, R., Bürsch, J., Cesnjevar, R., Dähnert, I., Deisenhofer, I., Diller, G.-P., Doenst, T., Dubowy, K.-O., Eicken, A., Ewert, P., Fink, C., Franke, J., Gebauer, R., Gorenflo, M., Grabitz, Haas, N.A., Häusler, H.-J., Hager, A., Hebebrand, J., Henschel, W., Hirt, M., Hoeper, M.M., Hörer, J., Hofbeck, M., Horke, A., Hraska, V., Hulpke-Wette, M., šek, J. Janou, Jux, C., Kändler, L., Kandolf, R., Kaulitz, R., Kienast, W., Klaassen, S., Knirsch, W., Kramer, H.H., Kreuder, J.G., Kriebel, T., Läer, S., Laser, K.T., Lê, T.-P., Lewin, M.A.G., Lindinger, A., Mackenzie, C.R., Mebus, S., van der Mei, S.H., Miera, O., Ovroutski, S., Paul, T., Photiadis, J., Pozza, R. Dalla, Rickers, C., Rosendahl, W., Ruschewski, W., Sachweh, J.S., Schäfers, H.-J., Scheewe, J., Schirmer, K.-R., Schlensak, C., Schlez, M., Schmaltz, A.A., Schmitt, K., Schneider, H., Schneider, M.B., Schranz, D., Schreiber, C., Schulze-Neick, I., Sieverding, L.F.J., Singer, H., Stieh, J., Sreeram, N., Thies, W.-R., Thul, J., Trauzeddel, R., Tschöpe, C., Uebing, A., Ulmer, H.E., Vogel, M., Vogt, M., Weil, J., Wessel, A., Will, J.C., Wühl, E., Ballmann, M., Barben, J., Bauer, C.P., Bend, J., Berdel, D., Blankenstein, O., Bremer, W., Brunsmann, F., Buchholz, T., Bufe, A., Derichs, N., Eber, E., Friedrichs, F., Frischer, T., Gembruch, U., Gieler, U., Götz, M., Haas, W.H., Hamelmann, E., Hammer, J., Hellermann, M., Jacobeit, J., Jung, A., Keim, V., Kitz, R., Kleinheinz, A., Koletzko, S., Kopp, I., Kopp, M., Lau, S., Lauener, R., Loff, Magdorf, K., Muche-Borowski, C., Müller, F.-M., Müsken, H., Naehrlich, L., Nicolai, T., Nüßlein, Th., Paditz, E., Palm, Frau B., Paul, K., Pfeiffer-Auler, S., Pfeiffer-Kascha, Frau D., Posselt, H.-G., Przybilla, B., Räwer, H.-C., Ratjen, F., Reese, I., Riedler, J., Rietschel, E., Rose, M., Rossi, R., Ruëff, F., Schäfer, T., Schmidt, S., Schmitt-Grohé, S., Schulze, J., Schuster, A., Seidenberg, J., Sitter, H., Smaczny, C., Spindler, T., Staab, D., Stern, M., Strassburg, C.P., Strömer, K., Stuhrmann-Spangenberg, M., Szczepanski, R., Tacke, A., Tiedgen, M., Urschitz, M.S., Vagts, J., Vogelberg, C., Wahn, U., Walker, A., Werfel, T., Wildhaber, J.H., Zach, M., Zimmermann, Th., Ballauff, A., Bannert, N., Böhn, I., Buderus, S., Bufler, P., Burdelski, M., Gerner, P., Grosse, K.-P., Henker, J., Henneke, P., Huber, W., Lang, T., Lentze, M.J., Melter, M., Müller, T., Pfister, E.-D., Rodeck, B., Schmidt-Choudhury, A., Skopnik, H., Wirth, S., Witt, H., Bachmann, H., Dötsch, J., Ehrich, J.H., Fuchshuber, Arno, Hoppe, B., Hoyer, P.F., Kemper, M.J., Michalk, D., Müller, D., Müller-Wiefel, D.E., Pohl, M., Tönshoff, B., Zerres, K., Bast, T., Baumeister, F.A.M., Berner, R., Bode, H., Christen, H.J., Collmann, H., Ebinger, F., Eiffert, H., Evers, S., Gold, R., Groß, S., Hanefeld, F., Heinen, F., Holthausen, H., Hübner, A., Jacobi, G., Karch, D., Kauschke, C., Kerkhoff, G., Kiese-Himmel, C., Klepper, J., Kohlschütter, A., Korn-Merker, E., Krägeloh-Mann, I., Kropp, P., Kurlemann, G., de Langen-Müller, U., Lenard, H.G., Michael, Th., von Moers, A., Felderhoff-Müser, U., Nau, R., Neubauer, B.A., Neuhäuser, G., Neumann, K., Noterdaeme, M., Pothmann, R., Rating, D., Reitter, B., Rickels, E., Ritz, A.M., Rosenkötter, H., Schmitt, B., Stephani, U., Stöver, B., Tibussek, D., Trollmann, R., Trommer, G., Tuxhorn, I., Wohlrab, G., Boergen, K.P., Brosch, S., Delb, W., Frank, R., Herrmann, B., von Hofacker, N., de Camargo, O. Kraus, Kries, R.v., Michaelis, R., Papousek, M., Schlack, H.G., Schriever, J., Skrodzki, K., Straßburg, H.-M., Thyen, U., Becker, K., Fels, T., Fitze, G., Grasshoff-Derr, S., Göbel, P., Illing, P., Lieber, J., Schmidt, A., Wessel, L.M., Berthold, L.D., Hahn, G., Hirsch, W., Moritz, J.D., Schröder, C., Schumacher, R., Stegmann, J., Steinborn, M., Tietze, R., Wunsch, R., Deppe, W., Hermann, T., Kiosz, D., Leidig, E., Mayer, H., Oepen, J., Stachow, R., Ahrens, F., Frey, G., Huttegger, I., Preil, M.-L., Schmittenbecher, P.P., Traupe, H., Eberhardt, O., Hasler, C., Krauspe, R., Meenen, N.M., Meurer, A., Rödl, R., Stücker, R., and Zilkens, C.

Published
2015
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41. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

Author

Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.

Subjects
0301 basic medicine, Male, Pediatrics, syndromic, Sex Factor, Disease, registry, medicine.disease_cause, Cohort Studies, 0302 clinical medicine, Primary Immunodeficiency Disease, inborn error of immunity, Immunology and Allergy, warning signs, Age Factor, Registries, Family history, presenting symptom, Child, Primary immunodeficiency, Granuloma, autoimmune, immune dysregulation, inflammatory, Adult, Autoimmune Diseases, Female, Humans, Infections, Lymphoproliferative Disorders, Middle Aged, Primary Immunodeficiency Diseases, Sex Factors, Age Factors, 10177 Dermatology Clinic, Infections/epidemiology, 3. Good health, Settore MED/02, Warning signs, Lymphoproliferative Disorder, 2723 Immunology and Allergy, Infection, Human, medicine.medical_specialty, Immunology, 610 Medicine & health, Malignancy, primary immunodeficiency, Autoimmune Disease, 03 medical and health sciences, Immunity, Autoimmune Diseases/epidemiology, medicine, 2403 Immunology, business.industry, warning sign, Common variable immunodeficiency, Granuloma/epidemiology, Immune dysregulation, medicine.disease, Primary Immunodeficiency Diseases/epidemiology, 030104 developmental biology, Lymphoproliferative Disorders/epidemiology, Cohort Studie, business, 030215 immunology
Abstract

BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Published
2021

42. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome

Author

Klaus Warnatz, Kohsuke Imai, Bénédicte Neven, Mette Holm, Ulrich Duffner, B Carpenter, Musa Karakukcu, Hassan Abolhassani, Robert Wynn, Neena Kapoor, Jennifer A. Kanakry, Marina Garcia-Prat, Mariacristina Menconi, Anna Mukhina, Pere Soler-Palacín, Takahiro Tomoda, Claudia Wehr, Diana K. Bayer, Eleonora Gambineri, Gulbu Uzel, Austen Worth, Arunkumar Modi, Mary Slatter, Tania Nicole Masmas, Dimana Dimitrova, Carsten Speckmann, J.J. Bleesing, Shankara Paneesha, Kanchan Rao, Sylwia Kołtan, Carmem Bonfim, Jasmeen Dara, Colin G. Steward, Winnie Ip, Emma C. Morris, Asghar Aghamohammadi, Andrew R. Gennery, Gašper Markelj, Luigi D. Notarangelo, Stephen M. Hughes, Sujal Ghosh, Tsubasa Okano, Ansgar Schulz, Arjan C. Lankester, Stephen Jolles, Ebru Yilmaz, Alexandra Laberko, Maria Elena Maccari, Stephan Ehl, Christopher C. Dvorak, Despina Moshous, Hyoung Jin Kang, Carolina Prando, Zohreh Nademi, Institut Català de la Salut, [Dimitrova D] Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. [Nademi Z] Children’s Bone Marrow Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom. The Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom. [Maccari ME, Ehl S] Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [Uzel G] Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. [Tomoda T] Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. [Garcia-Prat M, Soler-Palacín P] Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Graft Rejection, Male, 0301 basic medicine, Oncology, Allergy, lymphoproliferation, mTOR inhibitor, Kaplan-Meier Estimate, Regenerative Medicine, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, hemic and lymphatic diseases, Immunology and Allergy, Cumulative incidence, Child, Otros calificadores::/terapia [Otros calificadores], Immunodeficiency, Cancer, Primary immunodeficiency, Hematopoietic Stem Cell Transplantation, MTOR Inhibitors, Hematology, Middle Aged, Síndromes de deficiència immunitària - Tractament, enfermedades del sistema inmune::síndromes de inmunodeficiencia [ENFERMEDADES], Treatment Outcome, surgical procedures, operative, Child, Preschool, Immune System Diseases::Immunologic Deficiency Syndromes [DISEASES], Female, terapéutica::terapia biológica::tratamientos basados en células y tejidos::trasplante de células::trasplante de células madre::trasplante de células madre hematopoyéticas [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Homologous, Adult, medicine.medical_specialty, activated phosphoinositide 3-kinase delta syndrome, Adolescent, Class I Phosphatidylinositol 3-Kinases, Primary Immunodeficiency Diseases, graft failure, Immunology, serotherapy, Activated PI3K-delta syndrome, Context (language use), Article, Young Adult, 03 medical and health sciences, Rare Diseases, Internal medicine, medicine, Transplantation, Homologous, Humans, Preschool, Retrospective Studies, Aged, Transplantation, allogeneic hematopoietic cell transplantation, Cèl·lules mare hematopoètiques - Trasplantació, business.industry, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Retrospective cohort study, Other subheadings::/therapy [Other subheadings], Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, 030104 developmental biology, Graft-versus-host disease, allogeneic hemato-poietic cell transplantation, Avaluació de resultats (Assistència sanitària), Therapeutics::Biological Therapy::Cell- and Tissue-Based Therapy::Cell Transplantation::Stem Cell Transplantation::Hematopoietic Stem Cell Transplantation [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], business, 030215 immunology
Abstract

Immunodeficiència primària; Limfoproliferació; Inhibidor de mTOR Inmunodeficiencia primaria; Linfoproliferación; Inhibidor de mTOR Primary immunodeficiency; Lymphoproliferation; MTOR inhibitor Background Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). Objectives This study sought to characterize HCT outcomes in APDS. Methods Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. Results Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure–free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. Conclusions Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time. This research was funded in part from the Intramural Program of the National Cancer Institute, National Institutes of Health. The funding source had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the article for publication.

Published
2022
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43. Comparative efficacy of leniolisib (CDZ173) versus standard of care on rates of respiratory tract infection and serum immunoglobulin M (IgM) levels among individuals with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS): An externally-controlled study.

Author

Whalen J, Chandra A, Kracker S, Ehl S, Seidel MG, Gulas I, Dron L, Velummailum R, Nagamuthu C, Liu S, Tutein Nolthenius J, and Maccari ME

Abstract

Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error of immunity (IEI), in a 12-week randomised controlled trial. However, longer-term comparative data versus standard of care are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 (NCT02859727) and the European Society for Immunodeficiencies (ESID) registry. The endpoints were chosen following feasibility assessment considering comparability and availability of data from both sources. Baseline characteristics between groups were balanced through inverse probability of treatment weighting. The leniolisib-treated group included 37 participants, with 62 and 49 participants in the control group for the respiratory tract infections and serum IgM analyses, respectively. Significant reductions in the annual rate of respiratory tract infections (rate ratio: 0.34; 95% confidence interval [CI]: 0.19, 0.59) and serum IgM levels (treatment effect: -1.09 g/L; 95% CI: -1.78, -0.39, p=0.002) were observed in leniolisib-treated individuals versus standard of care. The results were consistent across all sensitivity analyses, regardless of censoring, baseline infection rate definition, missing data handling, or covariate selection. These novel data provide an extended comparison of leniolisib treatment versus standard of care, highlighting the potential for leniolisib to deliver long-term benefits by restoring immune system function and reducing infection rate, potentially reducing complications and treatment burden., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Published
2024
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44. The Microbiome Modifies Manifestations of Hemophagocytic Lymphohistiocytosis in Perforin-Deficient Mice.

Author

Mann J, Runge S, Schell C, Gräwe K, Thoulass G, Lao J, Ammann S, Grün S, König C, Berger SA, Hild B, Aichele P, Rosshart SP, and Ehl S

Abstract

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome caused by inborn errors of cytotoxicity. Patients with biallelic PRF1 null mutations (encoding perforin) usually develop excessive immune cell activation, hypercytokinemia, and life-threatening immunopathology in the first 6 months of life, often without an apparent infectious trigger. In contrast, perforin-deficient (PKO) mice only develop HLH after systemic infection with lymphocytic choriomeningitis virus (LCMV). We hypothesized that restricted microbe-immune cell interactions due to specific pathogen-free (SPF) housing might explain the need for this specific viral trigger in PKO mice. To investigate the influence of a "wild" microbiome in PKO mice, we fostered PKO newborns with Wildling microbiota ('PKO-Wildlings') and monitored them for signs of HLH. PKO-Wildlings survived long-term without spontaneous disease. Also, systemic infection with vaccinia virus did not reach the threshold of immune activation required to trigger HLH in PKO-Wildlings. Interestingly, after infection with LCMV, PKO-Wildlings developed an altered HLH pattern. This included lower IFN-γ serum levels along with improved IFN-γ-driven anemia, but more elevated levels of IL-17 and increased liver inflammation compared with PKO-SPF mice. Thus, wild microbiota alone is not sufficient to trigger HLH in PKO mice, but host-microbe interactions shape inflammatory cytokine patterns, thereby influencing manifestations of HLH immunopathology., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Published
2024
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45. A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

Author

Molitor A, Lederle A, Radosavljevic M, Sapuru V, Zavorka Thomas ME, Yang J, Shirin M, Collin-Bund V, Jerabkova-Roda K, Miao Z, Bernard A, Rolli V, Grenot P, Castro CN, Rosenzwajg M, Lewis EG, Person R, Esperón-Moldes US, Kaare M, Nokelainen PT, Batzir NA, Hoffer GZ, Paul N, Stemmelen T, Naegely L, Hanauer A, Bibi-Triki S, Grün S, Jung S, Busnelli I, Tripolszki K, Al-Ali R, Ordonez N, Bauer P, Song E, Zajo K, Partida-Sanchez S, Robledo-Avila F, Kumanovics A, Louzoun Y, Hirschler A, Pichot A, Toker O, Mejía CAM, Parvaneh N, Knapp E, Hersh JH, Kenney H, Delmonte OM, Notarangelo LD, Goetz JG, Kahwash SB, Carapito C, Bajwa RPS, Thomas C, Ehl S, Isidor B, Carapito R, Abraham RS, Hite RK, Marcus N, Bertoli-Avella A, and Bahram S

Subjects
Humans, Male, Female, Calcium metabolism, Child, Mutation, Jurkat Cells, Child, Preschool, Genes, Dominant, Pedigree, Phenotype, Inositol 1,4,5-Trisphosphate Receptors genetics, Inositol 1,4,5-Trisphosphate Receptors metabolism
Abstract

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 ( ITPR1 ), 2 ( ITPR2 ), and 3 ( ITPR3 ) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4 + lymphopenia, a quasi-absence of naïve CD4 + and CD8 + cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg 2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

Published
2024
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47. Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.

Author

Chiang SCC, Covill LE, Tesi B, Campbell TM, Schlums H, Nejati-Zendegani J, Mördrup K, Wood S, Theorell J, Sekine T, Al-Herz W, Akar HH, Belen FB, Chan MY, Devecioglu O, Aksu T, Ifversen M, Malinowska I, Sabel M, Unal E, Unal S, Introne WJ, Krzewski K, Gilmour KC, Ehl S, Ljunggren HG, Nordenskjöld M, Horne A, Henter JI, Meeths M, and Bryceson YT

Subjects
Humans, Adolescent, Child, Adult, Female, K562 Cells, Male, Child, Preschool, Middle Aged, Infant, Young Adult, Aged, Sensitivity and Specificity, Prospective Studies, Receptors, Antigen, T-Cell metabolism, Receptors, Antigen, T-Cell genetics, Exocytosis, T-Lymphocytes, Cytotoxic immunology, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic genetics, Lymphohistiocytosis, Hemophagocytic pathology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism
Abstract

Abstract: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK)-cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Assessment of Fc receptor-triggered NK-cell and T-cell receptor (TCR)-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH than routine K562 cell-based assays, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis after K562 target cell stimulation displayed a higher interindividual variability, in part explained by differences in NK-cell differentiation or large functional reductions after shipment. We thus recommend combined analysis of TCR-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Published
2024
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48. Immune profiling and functional analysis of NK and T cells in ataxia telangiectasia.

Author

Graafen L, Heinze A, Albinger N, Salzmann-Manrique E, Ganß F, Hünecke S, Cappel C, Wölke S, Donath H, Trischler J, Theilen TM, Heller C, Königs C, Ehl S, Bader P, Klingebiel T, Klusmann JH, Zielen S, Schubert R, and Ullrich E

Subjects
Humans, Male, Female, Child, Adolescent, Adult, Retrospective Studies, Child, Preschool, Young Adult, T-Lymphocytes immunology, T-Lymphocytes metabolism, Immunophenotyping, Ataxia Telangiectasia immunology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism
Abstract

Ataxia telangiectasia (AT) is a rare autosomal-recessive disorder characterized by profound neurodegeneration, combined immunodeficiency, and an increased risk for malignant diseases. Treatment options for AT are limited, and the long-term survival prognosis for patients remains grim, primarily due to the emergence of chronic respiratory pathologies, malignancies, and neurological complications. Understanding the dysregulation of the immune system in AT is fundamental for the development of novel treatment strategies. In this context, we performed a retrospective longitudinal immunemonitoring of lymphocyte subset distribution in a cohort of AT patients ( n = 65). Furthermore, we performed FACS analyses of peripheral blood mononuclear cells from a subgroup of 12 AT patients to examine NK and T cells for the expression of activating and functional markers. We observed reduced levels of peripheral blood CD3 + CD8 + cytotoxic T cells, CD3 + CD4 + T helper cells, and CD19 + B cells, whereas the amount of CD3 -- CD56 + NK cells and CD3 + CD56 + NKT-like cells was similar compared with age-matched controls. Notably, there was no association between the age-dependent kinetic of T-, B-, or NK-cell counts and the occurrence of malignancy in AT patients. Additionally, our results indicate an altered NK- and T-cell response to cytokine stimulation in AT with increased levels of TRAIL, FasL, and CD16 expression in NK cells, as well as an elevated activation level of T cells in AT with notably higher expression levels of IFN-γ, CD107a, TRAIL, and FasL. Together, these findings imply function alterations in AT lymphocytes, specifically in T and NK cells, shedding light on potential pathways for innovative therapies., Competing Interests: EU has no COIs directly related to this manuscript. EU has a sponsored research project with Gilead, BMS, and CRIION. 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 © 2024 Graafen, Heinze, Albinger, Salzmann-Manrique, Ganß, Hünecke, Cappel, Wölke, Donath, Trischler, Theilen, Heller, Königs, Ehl, Bader, Klingebiel, Klusmann, Zielen, Schubert and Ullrich.)

Published
2024
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49. Correction: Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.

Author

Kögl T, Chang HF, Staniek J, Chiang SCC, Thoulass G, Lao J, Weißert K, Dettmer-Monaco V, Geiger K, Manna PT, Beziat V, Momenilandi M, Tu SM, Keppler SJ, Pattu V, Wolf P, Kupferschmid L, Tholen S, Covill LE, Ebert K, Straub T, Groß M, Gather R, Engel H, Salzer U, Schell C, Maier S, Lehmberg K, Cornu TI, Pircher H, Shahrooei M, Parvaneh N, Elling R, Rizzi M, Bryceson YT, Ehl S, Aichele P, and Ammann S

Published
2024
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50. Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.

Author

Kögl T, Chang HF, Staniek J, Chiang SCC, Thoulass G, Lao J, Weißert K, Dettmer-Monaco V, Geiger K, Manna PT, Beziat V, Momenilandi M, Tu SM, Keppler SJ, Pattu V, Wolf P, Kupferschmid L, Tholen S, Covill LE, Ebert K, Straub T, Groß M, Gather R, Engel H, Salzer U, Schell C, Maier S, Lehmberg K, Cornu TI, Pircher H, Shahrooei M, Parvaneh N, Elling R, Rizzi M, Bryceson YT, Ehl S, Aichele P, and Ammann S

Subjects
Animals, Mice, Humans, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic genetics, Lymphohistiocytosis, Hemophagocytic metabolism, Mice, Knockout, Mice, Inbred C57BL, Female, Male, Germinal Center immunology, Germinal Center metabolism, Immunity, Humoral, Exocytosis, Qa-SNARE Proteins metabolism, Qa-SNARE Proteins genetics, B-Lymphocytes immunology, B-Lymphocytes metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism
Abstract

SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses., (© 2024 Kögl et al.)

Published
2024
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