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Katja Weinacht, MD, PhD

Specialties

Hematology-Oncology

Work and Education

Professional Education

Technical University of Munich, Munich, Germany, 11/13/2002

Residency

Mass General Hospital for Children Pediatric Residency, Boston, MA, 06/30/2009

Fellowship

Boston Childrens Hospital Pediatric Hematology and Oncology Fellowship, Boston, MA, 06/30/2012

Board Certifications

Pediatric Hematology-Oncology, American Board of Pediatrics

Pediatrics, American Board of Pediatrics

Conditions Treated

DiGeorge Syndrome

Graft-Versus-Host Disease

Immune Dysregulation

Immune-Mediated Cytopenia

Primary Immunodeficiency

All Publications

Chronic Granulomatous Disease-Associated IBD Resolves and Does Not Adversely Impact Survival Following Allogeneic HCT. Journal of clinical immunology Marsh, R. A., Leiding, J. W., Logan, B. R., Griffith, L. M., Arnold, D. E., Haddad, E., Falcone, E. L., Yin, Z., Patel, K., Arbuckle, E., Bleesing, J. J., Sullivan, K. E., Heimall, J., Burroughs, L. M., Skoda-Smith, S., Chandrakasan, S., Yu, L. C., Oshrine, B. R., Cuvelier, G. D., Thakar, M. S., Chen, K., Teira, P., Shenoy, S., Phelan, R., Forbes, L. R., Chellapandian, D., Davila Saldana, B. J., Shah, A. J., Weinacht, K. G., Joshi, A., Boulad, F., Quigg, T. C., Dvorak, C. C., Grossman, D., Torgerson, T., Graham, P., Prasad, V., Knutsen, A., Chong, H., Miller, H., de la Morena, M. T., DeSantes, K., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Stenger, E., Pai, S., Routes, J. M., Puck, J. M., Kapoor, N., Pulsipher, M. A., Malech, H. L., Parikh, S., Kang, E. M., submitted on behalf of the Primary Immune Deficiency Treatment Consortium 2019

Abstract

INTRODUCTION: Inflammatory bowel disease (IBD) affects approximately 1/3 of patients with chronic granulomatous disease (CGD). Comprehensive investigation of the effect of allogeneic hematopoietic cell transplantation (HCT) on CGD IBD and the impact of IBD on transplant outcomes is lacking.METHODS: We collected data retrospectively from 145 patients with CGD who had received allogeneic HCT at 26 Primary Immune Deficiency Treatment Consortium (PIDTC) centers between January 1, 2005 and June 30, 2016.RESULTS: Forty-nine CGD patients with IBD and 96 patients without IBD underwent allogeneic HCT. Eighty-nine percent of patients with IBD and 93% of patients without IBD engrafted (p=0.476). Upper gastrointestinal acute GVHD occurred in 8.5% of patients with IBD and 3.5% of patients without IBD (p=0.246). Lower gastrointestinal acute GVHD occurred in 10.6% of patients with IBD and 11.8% of patients without IBD (p=0.845). The cumulative incidence of acute GVHD grades II-IV was 30% (CI 17-43%) in patients with IBD and 20% (CI 12-29%) in patients without IBD (p=0.09). Five-year overall survival was equivalent for patients with and without IBD: 80% [CI 66-89%] and 83% [CI 72-90%], respectively (p=0.689). All 33 surviving evaluable patients with a history of IBD experienced resolution of IBD by 2years following allogeneic HCT.CONCLUSIONS: In this cohort, allogeneic HCT was curative for CGD-associated IBD. IBD should not contraindicate HCT, as it does not lead to an increased risk of mortality. This study is registered at clinicaltrials.gov NCT02082353.

View details for DOI 10.1007/s10875-019-00659-8

View details for PubMedID 31376032

Severe autoinflammation in four patients with C-terminal variants in CDC42 successfully treated with IL-1beta inhibition. The Journal of allergy and clinical immunology Gernez, Y., de Jesus, A. A., Alsaleem, H., Macaubas, C., Roy, A., Lovell, D., Jagadeesh, K. A., Alehashemi, S., Erdman, L., Grimley, M., Talarico, S., Bacchetta, R., Lewis, D. B., Canna, S. W., Laxer, R. M., Mellins, E. D., Goldbach-Mansky, R., Weinacht, K. G. 2019

Abstract

Four patients with novel variants in the C-terminal domain of CDC42, severe autoinflammation, constitutive elevation of serum interleukin 18, and predisposition to macrophage activation syndrome respond to treatment with interleukin-1beta signaling inhibition.

View details for DOI 10.1016/j.jaci.2019.06.017

View details for PubMedID 31271789

Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Bucciol, G., Nicholas, S. K., Calvo, P., Cant, A., Edgar, J. M., Espanol, T., Ferrua, F., Galicchio, M., Gennery, A. R., Hadzic, N., Hanson, I., Kusminsky, G., Lange, A., Lanternier, F., Mahlaoui, N., Moshous, D., Nademi, Z., Neven, B., Oleastro, M., Porta, F., Quarello, P., Silva, M., Slatter, M. A., Soncini, E., Stefanowicz, M., Tandoi, F., Teisseyre, M., Torgerson, T. R., Veys, P., Weinacht, K. G., Wolska-Kusnierz, B., Pirenne, J., de la Morena, M., Meyts, I. 2019; 143 (5): 1952-+
Calm in the midst of cytokine storm: a collaborative approach to the diagnosis and treatment of hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Pediatric rheumatology online journal Halyabar, O., Chang, M. H., Schoettler, M. L., Schwartz, M. A., Baris, E. H., Benson, L. A., Biggs, C. M., Gorman, M., Lehmann, L., Lo, M. S., Nigrovic, P. A., Platt, C. D., Priebe, G. P., Rowe, J., Sundel, R. P., Surana, N. K., Weinacht, K. G., Mann, A., Yuen, J. C., Meleedy-Rey, P., Starmer, A., Banerjee, T., Dedeoglu, F., Degar, B. A., Hazen, M. M., Henderson, L. A. 2019; 17 (1): 7

Abstract

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) were historically thought to be distinct entities, often managed in isolation. In fact, these conditions are closely related. A collaborative approach, which incorporates expertise from subspecialties that previously treated HLH/MAS independently, is needed. We leveraged quality improvement (QI) techniques in the form of an Evidence-Based Guideline (EBG) to build consensus across disciplines on the diagnosis and treatment of HLH/MAS.METHODS: A multidisciplinary work group was convened that met monthly to develop the HLH/MAS EBG. Literature review and expert opinion were used to develop a management strategy for HLH/MAS. The EBG was implemented, and quality metrics were selected to monitor outcomes.RESULTS: An HLH/MAS clinical team was formed with representatives from subspecialties involved in the care of patients with HLH/MAS. Broad entry criteria for the HLH/MAS EBG were established and included fever and ferritin 500ng/mL. The rheumatology team was identified as the "gate-keeper," charged with overseeing the diagnostic evaluation recommended in the EBG. First-line medications were recommended based on the acuity of illness and risk of concurrent infection. Quality metrics to be tracked prospectively based on time to initiation of treatment and clinical response were selected.CONCLUSION: HLH/MAS are increasingly considered to be a spectrum of related conditions, and joint management across subspecialties could improve patient outcomes. Our experience in creating a multidisciplinary approach to HLH/MAS management can serve as a model for care at other institutions.

View details for DOI 10.1186/s12969-019-0309-6

View details for PubMedID 30764840

Epigenetic Immune Cell Quantification for Diagnosis and Monitoring of Patients with Primary Immune Deficiencies and Immune Regulatory Disorders Schulze, J., Werner, J., Schildknecht, K., Lakshmanan, U., Gruetzkau, A., Chu, J., Gernez, Y., Speckmann, C., Weinacht, K. G., Bertaina, A., Baron, U., Borte, S., Olek, S., Bacchetta, R. SPRINGER/PLENUM PUBLISHERS. 2019: S30
Novel CDC42 Mutation Causes Severe Autoinflammatory Syndrome Responsive to IL-1 Inhibition Gernez, Y., Kirbey, M., Balagas, J. M., Macaubas, C. I., Canna, S., Lewis, D. B., Mellins, E., Bacchetta, R., Weinacht, K. G. SPRINGER/PLENUM PUBLISHERS. 2019: S69
Artificial Thymic Organoids Represent a Reliable and Quick Tool to Study T Cell Differentiation in Human Bone Marrow Samples from Patients with Severe T Cell Immunodeficiency Bosticardo, M., Pala, F., Calzoni, E., Gardner, C., Dobbs, K., De Ravin, S., Hartog, N., Markert, M., Weinacht, K. G., Malech, H. L., Seet, C., Montel-Hagen, A., Crooks, G. M., Notarangelo, L. D. SPRINGER/PLENUM PUBLISHERS. 2019: S51S52
Combined liver and hematopoietic stem cell transplantation in X-linked hyper IgM syndrome. The Journal of allergy and clinical immunology Bucciol, G., Nicholas, S. K., Calvo, P. L., Cant, A., Edgar, J. D., Espanol, T., Ferrua, F., Galicchio, M., Gennery, A. R., Hadzic, N., Hanson, I. C., Kusminsky, G., Lange, A., Lanternier, F., Mahlaoui, N., Moshous, D., Nademi, Z., Neven, B., Oleastro, M., Porta, F., Quarello, P., Silva, M., Slatter, M. A., Soncini, E., Stefanowicz, M., Tandoi, F., Teisseyre, M., Torgerson, T. R., Veys, P., Weinacht, K. G., Wolska-Kusnierz, B., Pirenne, J., de la Morena, M. T., Meyts, I. 2019

Abstract

Liver disease in X-linked hyper IgM syndrome (XHIGM) is an important predictor of mortality. In case liver transplantation (LT) is required, a survival benefit is observed when LT is combined with HSCT.

View details for PubMedID 30682461

Engineering Regenerative Thymic Tissues to Restore Long-Term T Cell Lymphopoiesis Gai, H., Gras-Pena, R., Verma, Y., Fateh, V., Ikeda, K., Dejene, B., Min, D., Wang, J., Swigut, T., Weinberg, K. I., Hollander, G. A., Heilshorn, S., Roncarolo, M., Sebastiano, V., Weinacht, K. G. AMER SOC HEMATOLOGY. 2018
An Engineered Cell-Traceable Model of Reticular Dysgenesis in Human Hematopoietic Stem Cells Linking Metabolism and Differentiation Wang, W., Awani, A., Reich, L., Nakauchi, Y., Thomas, D., Dever, D. P., Porteus, M., Weinacht, K. G. AMER SOC HEMATOLOGY. 2018
Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. The Journal of allergy and clinical immunology Forbes, L. R., Vogel, T. P., Cooper, M. A., Castro-Wagner, J., Schussler, E., Weinacht, K. G., Plant, A. S., Su, H. C., Allenspach, E. J., Slatter, M., Abinun, M., Lilic, D., Cunningham-Rundles, C., Eckstein, O., Olbrich, P., Guillerman, R. P., Patel, N. C., Demirdag, Y. Y., Zerbe, C., Freeman, A. F., Holland, S. M., Szabolcs, P., Gennery, A., Torgerson, T. R., Milner, J. D., Leiding, J. W. 2018

View details for PubMedID 30092289

Recent outcome of hematopoietic cell transplantation for Wiskott-Aldrich syndrome is excellent in all donor types: A Primary Immune Deficiency Treatment Consortium (PIDTC) Study Pai, S., Brazauskas, R., Bleesing, J., Dvorak, C. C., Kletzel, M., Petrovic, A., Prockop, S. E., Quinones, R., Goldman, F. D., Quigg, T. C., Hanson, I. C., Stenger, E., Thakar, M. S., Saldana, B., Bednarski, J. J., Smith, A. R., Parikh, S. H., Leiding, J. W., Miller, H. K., Shereck, E., Chong, H. J., DeSantes, K., Cuvelier, G. E., Chen, K., Weinacht, K. G., Abu-Arja, R. F., Kapoor, N., Moore, T. B., Gillio, A. P., Joshi, A. Y., Barnum, J. L., Chandrakasan, S., Haddad, E., Keller, M., Rozmus, J., Sullivan, K., Griffith, L. M., Ochs, H., Notarangelo, L. D., Puck, J., Kohn, D. B., Cowan, M. J., Rawlings, D., Burroughs, L. SPRINGER/PLENUM PUBLISHERS. 2018: 399400
Resolution of CGD Related Colitis after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Chronic Granulomatous Disease-Early Results From the 6903 Study of the Primary Immune Deficiency Treatment Consortium (PIDTC) Leiding, J. W., Logan, B. R., Yin, Z., Arbuckle, E., Bleesing, J. J., Sullivan, K. E., Heimall, J., Burroughs, L., Skoda-Smith, S., Chandrakasan, S., Yu, L. C., Oshrine, B. R., Cuvelier, G. E., Thakar, M., Chen, K., Shenoy, S., Saldana, B., Weinacht, K. G., Joshi, A., Boulad, F., Quigg, T. C., Dvorak, C. C., Knutsen, A., Chong, H., Miller, H. K., De la Morena, M., DeSantes, K., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Pai, S., Stenger, E., Puck, J., Kapoor, N., Pulsipher, M. A., Haddad, E., Griffith, L. M., Shearer, W., Malech, H. L., Parikh, S., Marsh, R. A., Kang, E. M. ELSEVIER SCIENCE INC. 2018: S53S54
Human Ipsc-Derived Thymic Epithelial Progenitor Cells as Stem Cell-Based Therapyto Restore Thymic Function in Hematopoietic Stem Cell Transplant Recipients Gai, H., Sebastiano, V., Weinacht, K. G. ELSEVIER SCIENCE INC. 2018: S364
Ruxolitinib reverses Dysregulated T Helper Cell Responses and controls Autoimmunity caused by a Novel STAT1 Gain of Function Mutation Journal of Allergy and Clinical Immunology Weinacht, K. G., Charbonnier, L. M., Alroqi, F., Plant, A., Qiao, Q., Wu, H., Ma, C., Torgerson, T. R., Rosenweig, S. D., Flesier, T. A., Notarangelo, L. D., Hanson, I. C., Forbes, L., Chatila, T. A. 2017
Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress JOURNAL OF EXPERIMENTAL MEDICINE Rissone, A., Weinacht, K. G., La Marca, G., Bishop, K., Giocaliere, E., Jagadeesh, J., Felgentreff, K., Dobbs, K., Al-Herz, W., Jones, M., Chandrasekharappa, S., Kirby, M., Wincovitch, S., Simon, K. L., Itan, Y., Devine, A., Schlaeger, T., Schambach, A., Sood, R., Notarangelo, L. D., Candotti, F. 2015; 212 (8): 1185-1202

Abstract

Adenylate kinases (AKs) are phosphotransferases that regulate the cellular adenine nucleotide composition and play a critical role in the energy homeostasis of all tissues. The AK2 isoenzyme is expressed in the mitochondrial intermembrane space and is mutated in reticular dysgenesis (RD), a rare form of severe combined immunodeficiency (SCID) in humans. RD is characterized by a maturation arrest in the myeloid and lymphoid lineages, leading to early onset, recurrent, and overwhelming infections. To gain insight into the pathophysiology of RD, we studied the effects of AK2 deficiency using the zebrafish model and induced pluripotent stem cells (iPSCs) derived from fibroblasts of an RD patient. In zebrafish, Ak2 deficiency affected hematopoietic stem and progenitor cell (HSPC) development with increased oxidative stress and apoptosis. AK2-deficient iPSCs recapitulated the characteristic myeloid maturation arrest at the promyelocyte stage and demonstrated an increased AMP/ADP ratio, indicative of an energy-depleted adenine nucleotide profile. Antioxidant treatment rescued the hematopoietic phenotypes in vivo in ak2 mutant zebrafish and restored differentiation of AK2-deficient iPSCs into mature granulocytes. Our results link hematopoietic cell fate in AK2 deficiency to cellular energy depletion and increased oxidative stress. This points to the potential use of antioxidants as a supportive therapeutic modality for patients with RD.

View details for DOI 10.1084/jem.20141286

View details for Web of Science ID 000360379400004

View details for PubMedID 26150473

Diagnosis of immunodeficiency caused by a purine nucleoside phosphorylase defect by using tandem mass spectrometry on dried blood spots JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY La Marca, G., Canessa, C., Giocaliere, E., Romano, F., Malvagia, S., Funghini, S., Moriondo, M., Valleriani, C., Lippi, F., Ombrone, D., Della Bona, M. L., Speckmann, C., Borte, S., Brodszki, N., Gennery, A. R., Weinacht, K., Celmeli, F., Pagel, J., de Martino, M., Guerrini, R., Wittkowski, H., Santisteban, I., Bali, P., Ikinciogullari, A., Hershfield, M., Notarangelo, L. D., Resti, M., Azzari, C. 2014; 134 (1): 155-?

Abstract

Purine nucleoside phosphorylase (PNP) deficiency is a rare form of autosomal recessive combined primary immunodeficiency caused by a enzyme defect leading to the accumulation of inosine, 2'-deoxy-inosine (dIno), guanosine, and 2'-deoxy-guanosine (dGuo) in all cells, especially lymphocytes. Treatments are available and curative for PNP deficiency, but their efficacy depends on the early approach. PNP-combined immunodeficiency complies with the criteria for inclusion in a newborn screening program.This study evaluate whether mass spectrometry can identify metabolite abnormalities in dried blood spots (DBSs) from affected patients, with the final goal of individuating the disease at birth during routine newborn screening.DBS samples from 9 patients with genetically confirmed PNP-combined immunodeficiency, 10,000 DBS samples from healthy newborns, and 240 DBSs from healthy donors of different age ranges were examined. Inosine, dIno, guanosine, and dGuo were tested by using tandem mass spectrometry (TMS). T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) levels were evaluated by using quantitative RT-PCR only for the 2 patients (patients 8 and 9) whose neonatal DBSs were available.Mean levels of guanosine, inosine, dGuo, and dIno were 4.4, 133.3, 3.6, and 3.8 mol/L, respectively, in affected patients. No indeterminate or false-positive results were found. In patient 8 TREC levels were borderline and KREC levels were abnormal; in patient 9 TRECs were undetectable, whereas KREC levels were normal.TMS is a valid method for diagnosis of PNP deficiency on DBSs of affected patients at a negligible cost. TMS identifies newborns with PNP deficiency, whereas TREC or KREC measurement alone can fail.

View details for DOI 10.1016/j.jaci.2014.01.040

View details for Web of Science ID 000338930300020

View details for PubMedID 24767876

Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Felgentreff, K., Du, L., Weinacht, K. G., Dobbs, K., Bartish, M., Giliani, S., Schlaeger, T., DeVine, A., Schambach, A., Woodbine, L. J., Davies, G., Baxi, S. N., van der Burg, M., Bleesing, J., Gennery, A., Manis, J., Pan-Hammarstrom, Q., Notarangelo, L. D. 2014; 111 (24): 8889-8894

Abstract

Nonhomologous end-joining (NHEJ) is a key pathway for efficient repair of DNA double-strand breaks (DSBs) and V(D)J recombination. NHEJ defects in humans cause immunodeficiency and increased cellular sensitivity to ionizing irradiation (IR) and are variably associated with growth retardation, microcephaly, and neurodevelopmental delay. Repair of DNA DSBs is important for reprogramming of somatic cells into induced pluripotent stem cells (iPSCs). To compare the specific contribution of DNA ligase 4 (LIG4), Artemis, and DNA-protein kinase catalytic subunit (PKcs) in this process and to gain insights into phenotypic variability associated with these disorders, we reprogrammed patient-derived fibroblast cell lines with NHEJ defects. Deficiencies of LIG4 and of DNA-PK catalytic activity, but not Artemis deficiency, were associated with markedly reduced reprogramming efficiency, which could be partially rescued by genetic complementation. Moreover, we identified increased genomic instability in LIG4-deficient iPSCs. Cell cycle synchronization revealed a severe defect of DNA repair and a G0/G1 cell cycle arrest, particularly in LIG4- and DNA-PK catalytically deficient iPSCs. Impaired myeloid differentiation was observed in LIG4-, but not Artemis- or DNA-PK-mutated iPSCs. These results indicate a critical importance of the NHEJ pathway for somatic cell reprogramming, with a major role for LIG4 and DNA-PKcs and a minor, if any, for Artemis.

View details for DOI 10.1073/pnas.1323649111

View details for Web of Science ID 000337300100048

View details for PubMedID 24889605

Primary Immune Deficiency Treatment Consortium (PIDTC) report. journal of allergy and clinical immunology Griffith, L. M., Cowan, M. J., Notarangelo, L. D., Kohn, D. B., Puck, J. M., Pai, S., Ballard, B., Bauer, S. C., Bleesing, J. J., Boyle, M., Brower, A., Buckley, R. H., van der Burg, M., Burroughs, L. M., Candotti, F., Cant, A. J., Chatila, T., Cunningham-Rundles, C., Dinauer, M. C., Dvorak, C. C., Filipovich, A. H., Fleisher, T. A., Bobby Gaspar, H., Gungor, T., Haddad, E., Hovermale, E., Huang, F., Hurley, A., Hurley, M., Iyengar, S., Kang, E. M., Logan, B. R., Long-Boyle, J. R., Malech, H. L., McGhee, S. A., Modell, F., Modell, V., Ochs, H. D., O'Reilly, R. J., Parkman, R., Rawlings, D. J., Routes, J. M., Shearer, W. T., Small, T. N., Smith, H., Sullivan, K. E., Szabolcs, P., Thrasher, A., Torgerson, T. R., Veys, P., Weinberg, K., Zuniga-Pflucker, J. C. 2014; 133 (2): 335-347 e11

Abstract

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2PIDTC workshops, and consideration of future consortium objectives.

View details for DOI 10.1016/j.jaci.2013.07.052

View details for PubMedID 24139498

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. journal of allergy and clinical immunology Chen, R., Giliani, S., Lanzi, G., Mias, G. I., Lonardi, S., Dobbs, K., Manis, J., Im, H., Gallagher, J. E., Phanstiel, D. H., Euskirchen, G., Lacroute, P., Bettinger, K., Moratto, D., Weinacht, K., Montin, D., Gallo, E., Mangili, G., Porta, F., Notarangelo, L. D., Pedretti, S., Al-Herz, W., Alfahdli, W., Comeau, A. M., Traister, R. S., Pai, S., Carella, G., Facchetti, F., Nadeau, K. C., Snyder, M., Notarangelo, L. D. 2013; 132 (3): 656-664 e17

Abstract

Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families.We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA.Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA.We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.

View details for DOI 10.1016/j.jaci.2013.06.013

View details for PubMedID 23830146

Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Chen, R., Giliani, S., Lanzi, G., Mias, G. I., Lonardi, S., Dobbs, K., Manis, J., Im, H., Gallagher, J. E., Phanstiel, D. H., Euskirchen, G., Lacroute, P., Bettinger, K., Moratto, D., Weinacht, K., Montin, D., Gallo, E., Mangili, G., Porta, F., Notarangelo, L. D., Pedretti, S., Al-Herz, W., Alfahdli, W., Comeau, A. M., Traister, R. S., Pai, S., Carella, G., Facchetti, F., Nadeau, K. C., Snyder, M., Notarangelo, L. D. 2013; 132 (3): 656-?

Abstract

Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects.We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families.We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA.Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA.We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.

View details for DOI 10.1016/j.jaci.2013.06.013

View details for Web of Science ID 000323612000018

View details for PubMedID 23830146

First reported case of Omenn syndrome in a patient with reticular dysgenesis JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY Henderson, L. A., Frugoni, F., Hopkins, G., Al-Herz, W., Weinacht, K., Comeau, A. M., Bonilla, F. A., Notarangelo, L. D., Pai, S. 2013; 131 (4): 1227-1230

View details for DOI 10.1016/j.jaci.2012.07.045

View details for Web of Science ID 000317187200034

View details for PubMedID 23014587

The role of induced pluripotent stem cells in research and therapy of primary immunodeficiencies. Current opinion in immunology Weinacht, K. G., Brauer, P. M., Felgentreff, K., Devine, A., Gennery, A. R., Giliani, S., Al-Herz, W., Schambach, A., Ziga-Pflcker, J. C., Notarangelo, L. D. 2012; 24 (5): 617-624

Abstract

The advent of reprogramming technology has greatly advanced the field of stem cell biology and nurtured our hope to create patient specific renewable stem cell sources. While the number of reports of disease specific induced pluripotent stem cells is continuously rising, the field becomes increasingly more aware that induced pluripotent stem cells are not as similar to embryonic stem cells as initially assumed. Our state of the art understanding of human induced pluripotent stem cells, their capacity, their limitations and their promise as it pertains to the study and treatment of primary immunodeficiencies, is the content of this review.

View details for DOI 10.1016/j.coi.2012.07.001

View details for PubMedID 22841347

Trans locus inhibitors limit concomitant polysaccharide synthesis in the human gut symbiont Bacteroides fragilis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chatzidaki-Livanis, M., Weinacht, K. G., Comstock, L. E. 2010; 107 (26): 11976-11980

Abstract

Bacteroides is an abundant genus of bacteria of the human intestinal microbiota. Bacteroides species synthesize a large number of capsular polysaccharides (PS), a biological property not shared with closely related oral species, suggesting importance for intestinal survival. Bacteroides fragilis, for example, synthesizes eight capsular polysaccharides per strain, each of which phase varies via inversion of the promoters located upstream of seven of the eight polysaccharide biosynthesis operons. In a single cell, many of these polysaccharide loci promoters can be simultaneously oriented on for transcription of the downstream biosynthesis operons. Here, we demonstrate that despite the promoter orientations, concomitant transcription of multiple polysaccharide loci within a cell is inhibited. The proteins encoded by the second gene of each of these eight loci, collectively designated the UpxZ proteins, inhibit the synthesis of heterologous polysaccharides. These unique proteins interfere with the ability of UpxY proteins encoded by other polysaccharide loci to function in transcriptional antitermination of their respective operon. The eight UpxZs have different inhibitory spectra, thus establishing a hierarchical regulatory network for polysaccharide synthesis. Limitation of concurrent polysaccharide synthesis strongly suggests that these bacteria evolved this property as an evasion-type mechanism to avoid killing by polysaccharide-targeting factors in the ecosystem.

View details for DOI 10.1073/pnas.1005039107

View details for Web of Science ID 000279332300058

View details for PubMedID 20547868

Tyrosine site-specific recombinases mediate DNA inversions affecting the expression of outer surface proteins of Bacteroides fragilis MOLECULAR MICROBIOLOGY Weinacht, K. G., Roche, H., Krinos, C. M., Coyne, M. J., Parkhill, J., Comstock, L. E. 2004; 53 (5): 1319-1330

Abstract

The chromosome of Bacteroides fragilis has been shown to undergo 13 distinct DNA inversions affecting the expression of capsular polysaccharides and mediated by a serine site-specific recombinase designated Mpi. In this study, we demonstrate that members of the tyrosine site-specific recombinase family, conserved in B. fragilis, mediate additional DNA inversions of the B. fragilis genome. These DNA invertases flip promoter regions in their immediate downstream region. The genetic organization of the genes regulated by these invertible promoter regions suggests that they are operons and many of the products are predicted to be outer membrane proteins. Phenotypic analysis of a deletion mutant of one of these DNA invertases, tsr15 (aapI), which resulted in the promoter region for the downstream genes being locked ON, confirmed the synthesis of multiple surface proteins by this operon. In addition, this deletion mutant demonstrated an autoaggregative phenotype and showed significantly greater adherence than wild-type organisms in a biofilm assay, suggesting a possible functional role for these phase-variable outer surface proteins. This study demonstrates that DNA inversion is a universal mechanism used by this commensal microorganism to phase vary expression of its surface molecules and involves at least three conserved DNA invertases from two evolutionarily distinct families.

View details for DOI 10.1111/j.1365-2958.2004.04219.x

View details for Web of Science ID 000223495100004

View details for PubMedID 15387812

Mpi recombinase globally modulates the surface architecture of a human commensal bacterium PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Coyne, M. J., Weinacht, K. G., Krinos, C. M., Comstock, L. E. 2003; 100 (18): 10446-10451

Abstract

The mammalian gut represents a complex and diverse ecosystem, consisting of unique interactions between the host and microbial residents. Bacterial surfaces serve as an interface that promotes and responds to this dynamic exchange, a process essential to the biology of both symbionts. The human intestinal microorganism, Bacteroides fragilis, is able to extensively modulate its surface. Analysis of the B. fragilis genomic sequence, together with genetic conservation analyses, cross-species cloning experiments, and mutational studies, revealed that this organism utilizes an endogenous DNA inversion factor to globally modulate the expression of its surface structures. This DNA invertase is necessary for the inversion of at least 13 regions located throughout the genome, including the promoter regions for seven of the capsular polysaccharide biosynthesis loci, an accessory polysaccharide biosynthesis locus, and five other regions containing consensus promoter sequences. Bacterial DNA invertases of the serine site-specific recombinase family are typically encoded by imported elements such as phage and plasmids, and act locally on a single region of the imported element. In contrast, the conservation and unique global regulatory nature of the process in B. fragilis suggest an evolutionarily ancient mechanism for surface adaptation to the changing intestinal milieu during commensalism.

View details for DOI 10.1073/pnas.1832655100

View details for Web of Science ID 000185119300057

View details for PubMedID 12915735

Extensive surface diversity of a commensal microorganism by multiple DNA inversions NATURE Krinos, C. M., Coyne, M. J., Weinacht, K. G., Tzianabos, A. O., Kasper, D. L., Comstock, L. E. 2001; 414 (6863): 555-558

Abstract

The dynamic interactions between a host and its intestinal microflora that lead to commensalism are unclear. Bacteria that colonize the intestinal tract do so despite the development of a specific immune response by the host. The mechanisms used by commensal organisms to circumvent this immune response have yet to be established. Here we demonstrate that the human colonic microorganism, Bacteroides fragilis, is able to modulate its surface antigenicity by producing at least eight distinct capsular polysaccharides-a number greater than any previously reported for a bacterium-and is able to regulate their expression in an on-off manner by the reversible inversion of DNA segments containing the promoters for their expression. This means of generating surface diversity allows the organism to exhibit a wide array of distinct surface polysaccharide combinations, and may have broad implications for how the predominant human colonic microorganisms, the Bacteroides species, maintain an ecological niche in the intestinal tract.

View details for Web of Science ID 000172405900050

View details for PubMedID 11734857

[Drug hypersensitivity]. Terapevticheskii? arkhiv TAREEV, E. M., VINOGRADOVA, O. M., Semenkova, E. N., SOLOV'EVA, A. P. 1975; 47 (4): 5-12

View details for PubMedID 238301