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3. Endosome dysfunction leads to gain-of-function TLR7 and human lupus

Author

Mishra, H., Schlack-Leigers, C., Lim, E., Thieck, O., Magg, T., Raedler, J., Wolf, C., Klein, C., Ewers, H., Lee-Kirsch, M., Meierhofer, D., Hauck, F., and Majer, O.

Abstract

Hyperactive Toll-like receptor (TLR) 7 signaling has long been appreciated as a driver of autoimmune disease by breaking tolerance to self-nucleic acids in mouse models1–5. Recently, mutations in TLR7 or its associated regulator UNC93B16, 7, were identified as monogenic causes of human lupus; the unifying feature of these mutations being TLR7 gain-of-function. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes8, 9. Hence, its function depends on intricate transport mechanisms and membrane interactions within the endomembrane network. Whether perturbations of any of these endosome-related processes can give rise to TLR7 gain-of-function and facilitate self-reactivity has not been investigated. Here, we show that a dysregulated endosomal compartment leads to unrestricted TLR7 signaling and human lupus. The late endosomal BLOC-1-related protein complex (BORC) together with the small Arf1-like GTPase Arl8b controls TLR7 protein levels, and a direct interaction between Arl8b and Unc93b1 is required to regulate TLR7 turnover. We identified an amino acid insertion in UNC93B1 in a patient with childhood-onset lupus, which reduces the interaction with the BORC-Arl8b complex and leads to endosomal TLR7 accumulation. Therefore, a failure to control the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids in humans. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. As the cellular mechanisms restricting TLR7 signaling can be manifold, identifying and stratifying lupus patients based on a TLR7-driven pathogenesis could be a viable strategy towards a targeted therapy.

Published
2023

5. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome

Author

Albert, M.H., Slatter, M.A., Gennery, A.R., Gungor, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., Aleinikova, O.V., Balashov, D., Bernardo, M.E., Bodova, I., Bruno, B., Cavazzana, M., Chiesa, R., Fischer, A., Hauck, F., Ifversen, M., Kalwak, K., Klein, C., Kulagin, A., Kupesiz, A., Kuskonmaz, B., Lindemans, C.A., Locatelli, F., Lum, S.H., Maschan, A., Meisel, R., Moshous, D., Porta, F., Sauer, M.G., Sedlacek, P., Schulz, A., Suarez, F., Vallee, T.C., Winiarski, J.H., Zecca, M., Neven, B., Veys, P., Lankester, A.C., EBMT, European Soc Immunodeficiencies ES, and Stem CELL Transplant Primary Immun

Subjects
Transplantation Conditioning, Immunology, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Cell Biology, Hematology, Biochemistry, Tissue Donors, Wiskott-Aldrich Syndrome, Treatment Outcome, surgical procedures, operative, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, immune system diseases, Child, Preschool, Humans, Busulfan, Retrospective Studies
Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged

Published
2022

6. Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity

Author

Haimel, M., Pazmandi, J., Heredia, R.J., Dmytrus, J., Bal, S.K., Zoghi, S., Daele, P. van, Briggs, T.A., Wouters, C., Bader-Meunier, B., Aeschlimann, F.A., Caorsi, R., Eleftheriou, D., Hoppenreijs, E.P., Salzer, E., Bakhtiar, S., Derfalvi, B., Saettini, F., Kusters, M.A.A., Elfeky, R., Trück, J., Rivière, J.G., Burg, M. van der, Gattorno, M., Seidel, M.G., Burns, S., Warnatz, K., Hauck, F., Brogan, P., Gilmour, K.C., Schuetz, C., Simon, A., Bock, C., Hambleton, S., Vries, E de, Robinson, P.N., Gijn, M. van, Boztug, K., Haimel, M., Pazmandi, J., Heredia, R.J., Dmytrus, J., Bal, S.K., Zoghi, S., Daele, P. van, Briggs, T.A., Wouters, C., Bader-Meunier, B., Aeschlimann, F.A., Caorsi, R., Eleftheriou, D., Hoppenreijs, E.P., Salzer, E., Bakhtiar, S., Derfalvi, B., Saettini, F., Kusters, M.A.A., Elfeky, R., Trück, J., Rivière, J.G., Burg, M. van der, Gattorno, M., Seidel, M.G., Burns, S., Warnatz, K., Hauck, F., Brogan, P., Gilmour, K.C., Schuetz, C., Simon, A., Bock, C., Hambleton, S., Vries, E de, Robinson, P.N., Gijn, M. van, and Boztug, K.

Abstract

Contains fulltext : 248208.pdf (Publisher’s version ) (Open Access), BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. METHODS: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. RESULTS: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. CONCLUSIONS: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities.

Published
2022

7. Hematopoietic stem cell transplantation for Wiskott-Aldrich syndrome: an EBMT Inborn Errors Working Party analysis

Author

Albert, M. H., Slatter, M. A., Gennery, A. R., Gungor, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., Aleinikova, O. V., Balashov, D., Bernardo, M. E., Bodova, I., Bruno, B., Cavazzana, M., Chiesa, R., Fischer, A., Hauck, F., Ifversen, M., Kalwak, K., Klein, C., Kulagin, A., Kupesiz, A., Kuskonmaz, B., Lindemans, C. A., Locatelli, Franco, Lum, S. H., Maschan, A., Meisel, R., Moshous, D., Porta, F., Sauer, M. G., Sedlacek, P., Schulz, A., Suarez, F., Vallee, T. C., Winiarski, J. H., Zecca, M., Neven, B., Veys, P., Lankester, A. C., Locatelli F. (ORCID:0000-0002-7976-3654), Albert, M. H., Slatter, M. A., Gennery, A. R., Gungor, T., Bakunina, K., Markovitch, B., Hazelaar, S., Sirait, T., Courteille, V., Aiuti, A., Aleinikova, O. V., Balashov, D., Bernardo, M. E., Bodova, I., Bruno, B., Cavazzana, M., Chiesa, R., Fischer, A., Hauck, F., Ifversen, M., Kalwak, K., Klein, C., Kulagin, A., Kupesiz, A., Kuskonmaz, B., Lindemans, C. A., Locatelli, Franco, Lum, S. H., Maschan, A., Meisel, R., Moshous, D., Porta, F., Sauer, M. G., Sedlacek, P., Schulz, A., Suarez, F., Vallee, T. C., Winiarski, J. H., Zecca, M., Neven, B., Veys, P., Lankester, A. C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients affected by Wiskott-Aldrich syndrome (WAS). Reported HSCT outcomes have improved over time with respect to overall survival, but some studies have identified older age and HSCT from alternative donors as risk factors predicting poorer outcome. We analyzed 197 patients undergoing transplant at European Society for Blood and Marrow Transplantation centers between 2006 and 2017 who received conditioning as recommended by the Inborn Errors Working Party (IEWP): either busulfan (n = 103) or treosulfan (n = 94) combined with fludarabine ± thiotepa. After a median follow-up post-HSCT of 44.9 months, 176 patients were alive, resulting in a 3-year overall survival of 88.7% and chronic graft-versus-host disease (GVHD)-free survival (events include death, graft failure, and severe chronic GVHD) of 81.7%. Overall survival and chronic GVHD-free survival were not significantly affected by conditioning regimen (busulfan- vs treosulfan-based), donor type (matched sibling donor/matched family donor vs matched unrelated donor/mismatched unrelated donor vs mismatched family donor), or period of HSCT (2006-2013 vs 2014-2017). Patients aged <5 years at HSCT had a significantly better overall survival. The overall cumulative incidences of grade III to IV acute GVHD and extensive/moderate/severe chronic GVHD were 6.6% and 2.1%, respectively. Patients receiving treosulfan-based conditioning had a higher incidence of graft failure and mixed donor chimerism and more frequently underwent secondary procedures (second HSCT, unconditioned stem cell boost, donor lymphocyte infusion, or splenectomy). In summary, HSCT for WAS with conditioning regimens currently recommended by IEWP results in excellent survival and low rates of GVHD, regardless of donor or stem cell source, but age ≥5 years remains a risk factor for overall survival.

Published
2022

8. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Albert, M. H., Sirait, T., Eikema, D. -J., Bakunina, K., Wehr, C., Suarez, F., Fox, M. L., Mahlaoui, N., Gennery, A. R., Lankester, A. C., Beier, R., Bernardo, M. E., Bigley, V., Lindemans, C. A., Burns, S. O., Carpenter, B., Dybko, J., Gungor, T., Hauck, F., Lum, S. H., Balashov, D., Meisel, R., Moshous, D., Schulz, A., Speckmann, C., Slatter, M. A., Strahm, B., Uckan-Cetinkaya, D., Meyts, I., Vallee, T. C., Wynn, R., Neven, B., Morris, E. C., Aiuti, A., Maschan, A., Aljurf, M., Gedde-Dahl, T., Gurman, G., Bordon, V., Krivan, G., Locatelli, Franco, Porta, F., Valcarcel, D., Beguin, Y., Faraci, M., Kroger, N., Kulagin, A., Shaw, P. J., Veelken, J. H., Diaz de Heredia, C., Fagioli, F., Felber, M., Gruhn, B., Holter, W., Rossig, C., Sedlacek, P., Apperley, J., Ayas, M., Bodova, I., Choi, G., Cornelissen, J. J., Sirvent, A., Khan, A., Kupesiz, A., Lenhoff, S., Ozdogu, H., von der Weid, N., Rovira, M., Schots, R., Vinh, D. C., Locatelli F. (ORCID:0000-0002-7976-3654), Albert, M. H., Sirait, T., Eikema, D. -J., Bakunina, K., Wehr, C., Suarez, F., Fox, M. L., Mahlaoui, N., Gennery, A. R., Lankester, A. C., Beier, R., Bernardo, M. E., Bigley, V., Lindemans, C. A., Burns, S. O., Carpenter, B., Dybko, J., Gungor, T., Hauck, F., Lum, S. H., Balashov, D., Meisel, R., Moshous, D., Schulz, A., Speckmann, C., Slatter, M. A., Strahm, B., Uckan-Cetinkaya, D., Meyts, I., Vallee, T. C., Wynn, R., Neven, B., Morris, E. C., Aiuti, A., Maschan, A., Aljurf, M., Gedde-Dahl, T., Gurman, G., Bordon, V., Krivan, G., Locatelli, Franco, Porta, F., Valcarcel, D., Beguin, Y., Faraci, M., Kroger, N., Kulagin, A., Shaw, P. J., Veelken, J. H., Diaz de Heredia, C., Fagioli, F., Felber, M., Gruhn, B., Holter, W., Rossig, C., Sedlacek, P., Apperley, J., Ayas, M., Bodova, I., Choi, G., Cornelissen, J. J., Sirvent, A., Khan, A., Kupesiz, A., Lenhoff, S., Ozdogu, H., von der Weid, N., Rovira, M., Schots, R., Vinh, D. C., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.

Published
2022

11. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study

Author

Albert MH, Sirait T, Eikema DJ, Bakunina K, Wehr C, Suarez F, Fox ML, Mahlaoui N, Gennery AR, Lankester AJ, Beier R, Bernardo ME, Bigley V, Lindemans CA, OBurns S, Carpenter B, Dybko J, Gungor T, Hauck F, Lum SH, Balashov D, Meisel R, Moshous D, Schulz A, Speckmann C, Slatter MA, Strahm B, Uckan-Cetinkaya D, Meyts I, Vallee TC, Wynn R, Neven B, Morris EC, EBMT IEWP, ESID

Published
2022
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14. 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

16. 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

17. Hematopoietic cell transplantation in chronic granulomatous disease: a study of 712 children and adults

Author

Chiesa, R., Wang, J., Blok, H. -J., Hazelaar, S., Neven, B., Moshous, D., Schulz, A., Hoenig, M., Hauck, F., Seraihy, A. A., Gozdzik, J., Ljungman, P., Lindemans, C. A., Fernandes, J. F., Kalwak, K., Strahm, B., Schanz, U., Sedlacek, P., Sykora, K. -W., Aksoylar, S., Locatelli, Franco, Stepensky, P., Wynn, R., Lum, S. H., Zecca, M., Porta, F., Taskinen, M., Gibson, B., Matthes, S., Karakukcu, M., Hauri-Hohl, M., Veys, P., Gennery, A. R., Lucchini, G., Felber, M., Albert, M. H., Balashov, D., Lankester, A., Gungor, T., Slatter, M. A., Locatelli F. (ORCID:0000-0002-7976-3654), Chiesa, R., Wang, J., Blok, H. -J., Hazelaar, S., Neven, B., Moshous, D., Schulz, A., Hoenig, M., Hauck, F., Seraihy, A. A., Gozdzik, J., Ljungman, P., Lindemans, C. A., Fernandes, J. F., Kalwak, K., Strahm, B., Schanz, U., Sedlacek, P., Sykora, K. -W., Aksoylar, S., Locatelli, Franco, Stepensky, P., Wynn, R., Lum, S. H., Zecca, M., Porta, F., Taskinen, M., Gibson, B., Matthes, S., Karakukcu, M., Hauri-Hohl, M., Veys, P., Gennery, A. R., Lucchini, G., Felber, M., Albert, M. H., Balashov, D., Lankester, A., Gungor, T., Slatter, M. A., and Locatelli F. (ORCID:0000-0002-7976-3654)

Abstract

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged <18 years) and 77 adults. Median follow-up was 45 months. Median age at transplantation was 7 years (range, 0.1-48.6). Kaplan-Meier estimates of overall survival (OS) and event-free survival (EFS) at 3 years were 85.7% and 75.8%, respectively. In multivariate analysis, older age was associated with reduced survival and increased chronic graft-versus-host disease. Nevertheless, OS and EFS at 3 years for patients ‡18 years were 76% and 69%, respectively. Use of 1-antigen-mismatched donors was associated with reduced OS and EFS . No significant difference was found in OS, but a significantly reduced EFS was noted in the small group of patients who received a transplant from a donor with a >1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

Published
2020

21. Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency

Author

Aydin, S.E., Freeman, A.F., Al-Herz, W., Al-Mousa, H.A., Arnaout, R.K., Aydin, R.C., Barlogis, V., Belohradsky, B.H., Bonfim, C., Bredius, R.G., Chu, J.I., Ciocarlie, O.C., Dogu, F., Gaspar, H.B., Geha, R.S., Gennery, A.R., Hauck, F., Hawwari, A., Hickstein, D.D., Hoenig, M., Ikinciogullari, A., Klein, C., Kumar, A., Ifversen, M.R.S., Matthes, S., Metin, A., Neven, B., Pai, S.Y., Parikh, S.H., Picard, C., Renner, E.D., Sanal, O., Schulz, A.S., Schuster, F., Shah, N.N., Shereck, E.B., Slatter, M.A., Su, H.C., Montfrans, J. van, Woessmann, W., Ziegler, J.B., Albert, M.H., Inborn Errors Working Party Europe, and European Soc Primary Immunodefici

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, DOCK8 deficiency, medicine.medical_treatment, Graft vs Host Disease, Hematopoietic stem cell transplantation, Kaplan-Meier Estimate, Treosulfan, Article, Young Adult, Internal medicine, medicine, Journal Article, Immunology and Allergy, Guanine Nucleotide Exchange Factors, Humans, Child, Immunodeficiency, business.industry, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes, Infant, Retrospective cohort study, medicine.disease, Combined immunodeficiency, Regimen, Graft-versus-host disease, surgical procedures, operative, Child, Preschool, Failure to thrive, HSCT, Female, medicine.symptom, business, Busulfan, medicine.drug
Abstract

BACKGROUND: Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease.OBJECTIVE: To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables.METHODS: We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients.RESULTS: We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive.CONCLUSIONS: HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival. (C) 2018 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology

Published
2019

22. The AspectIX ORB Architecture

Author

Hauck, F., primary, Becker, U., additional, Geier, M., additional, Meier, E., additional, Rastofer, U., additional, and Steckermeier, M., additional

Published
1998
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28. 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

29. 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

45. A human immunodeficiency syndrome caused by mutations in CARMIL2

Author

Schober, T., primary, Magg, T., additional, Laschinger, M., additional, Rohlfs, M., additional, Linhares, N. D., additional, Puchalka, J., additional, Weisser, T., additional, Fehlner, K., additional, Mautner, J., additional, Walz, C., additional, Hussein, K., additional, Jaeger, G., additional, Kammer, B., additional, Schmid, I., additional, Bahia, M., additional, Pena, S. D., additional, Behrends, U., additional, Belohradsky, B. H., additional, Klein, C., additional, and Hauck, F., additional

Published
2017
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46. Neugeborenenscreening 2020

Author

Gramer, G., primary, Hauck, F., additional, Lobitz, S., additional, Sommerburg, O., additional, Speckmann, C., additional, and Hoffmann, G. F., additional

Published
2017
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