Clinical Focus

  • Pediatric Hematology-Oncology

Administrative Appointments

  • Attending Physician, Pediatric SCTRM Stanford School of Medicine (2016 - Present)
  • Assistant Professor, Pediatrics Stanford School of Medicine (2012 - 2016)

Honors & Awards

  • Mentored Clinical Scientist Research Career Development Award (K08), NIAID (2016-21)
  • Research Fellowship Award, Charles King Trust (2013-15)
  • Amy-Potter Research Fellowship Award, Boston Children’s Hospital, Harvard Medical School (2013-14)
  • Research Fellowship Award, Primary Immunodeficiency Treatment Consortium (2013-14)
  • Amy-Potter Research Fellowship Award, Boston Children’s Hospital, Harvard Medical School (2012-13)
  • Dan Heller Teaching Award, Harvard Medical School (2009)

Boards, Advisory Committees, Professional Organizations

  • Member, American Society of Pediatric Hematology/Oncology (ASPHO) (2009 - Present)
  • Member, Children’s Oncology Group (COG) (2009 - Present)
  • Associate Member, American Society of Hematology (ASH) (2009 - Present)
  • Member, Primary Immunodeficiency Treatment Consortium (PIDTC) (2012 - Present)
  • Member, International Society of Stem Cell Research (ISSCR) (2014 - Present)

Professional Education

  • Fellowship:Boston Childrens Hospital Pediatric Hematology and Oncology Fellowship (2012) MA
  • Residency:Mass General Hospital for Children Pediatric Residency (2009) MA
  • Board Certification, American Board of Pediatric Hematology-Oncology, 2013
  • Board Certification, American Board of Pediatrics, 2009
  • Research Fellowship, Pediatric Immunology, Laboratory Dr. Luigi D. Notarangelo, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 2010-2012
  • Clinical Fellowship, Pediatric Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 2009-2012
  • Residency, Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 2006-2009
  • Postdoctoral Fellow, Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 2005-2006
  • PhD (Medicine), Technische Universitaet Muenchen, School of Medicine, Munich, Germany, 2004
  • MD, Technische Universitaet Muenchen, School of Medicine, Munich, Germany, 2002


  • Comstock LE, Coyne MJ, Weinacht KG, Kasper DL, Tzianabos AO. "United States Patent 10/388,390 Method of Overexpression of Zwitterionic Polysaccharides", Brigham and Women’s Hospital, Mar 13, 2003

Research & Scholarship

Current Research and Scholarly Interests

I am a pediatric hematologist-oncologist with special interest in the niche of diseases that intersect immune dysfunction, primary immunodeficiency and bone marrow failure. My clinical practice focuses on pediatric patients requiring a hematopoietic stem cell transplantation, patients with DiGeorge Syndrome and patients with genetic immune diseases presenting with autoimmunity. As a physician-scientist, I strive to advance our insights into the mechanisms leading to immunodeficiency, autoimmunity and tolerance on a molecular level and to translate our research into novel targeted therapies patients.

My work is a natural extension of my clinical training in pediatric hematology-oncology combined with my scientific background in immunology and microbiology. After completing my clinical training at Boston Children’s Hospital/Dana-Farber Cancer Institute, I joined the laboratory of Luigi D. Notarangelo in the division of immunology, Boston Children’s Hospital/Harvard Stem Cell Institute, where I have acquired skills in the field of reprogramming, tissue engineering and gene correction. In my laboratory, we now use iPSC-based disease models to study how defects in mitochondrial metabolism and oxidative stress affect hematopoietic stem and progenitor cell development and cell death with the goal of identifying therapeutic targets. A separate focus of my laboratory is devoted to understanding the thymic developmental defects in DiGeorge syndrome.

Clinical Trials

  • Natural History Study of SCID Disorders Recruiting

    This study is a prospective evaluation of children with Severe Combined Immune Deficiency (SCID) who are treated under a variety of protocols used by participating institutions. In order to determine the patient, recipient and transplant-related variables that are most important in determining outcome, study investigators will uniformly collect pre-, post- and peri-transplant (or other treatment) information on all children enrolled into this study. Children will be divided into three strata: - Stratum A: Typical SCID with virtual absence of autologous T cells and poor T cell function - Stratum B: Atypical SCID (leaky SCID, Omenn syndrome and reticular dysgenesis with limited T cell diversity or number and reduced function), and - Stratum C: ADA deficient SCID and XSCID patients receiving alternative therapy including PEG-ADA ERT or gene therapy. Each Group/Cohort Stratum will be analyzed separately.

    View full details

  • Patients Treated for Chronic Granulomatous Disease (CGD) Since 1995 Recruiting

    Chronic granulomatous disease (CGD) is an inherited immune system abnormality in which bone marrow transplantation (BMT) has been shown to be curative. However the risks of transplantation are high and not all patients with CGD may need to undergo this high risk procedure. This study will determine the long term medical condition and daily functioning of participants with CGD after a transplant and if possible, compare these results to participants who do not undergo a transplant.

    View full details

  • Patients Treated for SCID (1968-Present) Recruiting

    People with Primary Immune Deficiency (PID) may develop severe, life-threatening infections as a result of inherited defects in the genes that normally instruct blood-forming cells to develop and to fight infections. PID diseases include Severe Combined Immune Deficiency (SCID), leaky SCID, Omenn syndrome (OS), and Reticular Dysgenesis (RD). PIDs may be treated by transplantation of bone marrow stem cells from a healthy person or, in some cases, by enzyme replacement or by gene therapy. Patients with SCID were among the first to receive bone marrow stem cell (also called hematopoietic cells) transplantation (HCT) more than 40 years ago, and HCT is the standard treatment today for this group of diseases. Since PID diseases are rare, there are not enough patients at any single center to determine the full range of causes, natural history, or best methods of treatment. For this research study many PID centers across North America have organized into the Primary Immune Deficiency Treatment Consortium (PIDTC) to pool their experience and study PIDs together. Researchers will collect information on your general health, psychological and developmental health, and the current status of your immune system to help better define future approaches to PID treatments.

    View full details

  • Patients Treated for Wiskott-Aldrich Syndrome (WAS) Since 1990 Not Recruiting

    Wiskott - Aldrich syndrome (WAS) is a rare serious medical condition that causes problems both with the immune system and with easy bruising and bleeding. The immune abnormalities cause patients with WAS to be very susceptible to infections. Depending on the specific type of primary immune deficiency diseases, there are effective treatments, including antibiotics, cellular therapy and gene therapy, but studies of large numbers of patients are needed to determine the full range of causes, natural history, or the best methods of treatment for long term success. This multicenter study combines retrospective, prospective and cross-sectional analyses of the transplant experiences for patients with WAS who have already received HCT since 1990, or who will undergo Hematopoietic cell transplant (HCT) during the study period. The retrospective and prospective portions of the study will address the impact of a number of pre and post-transplant factors on post-transplant disease correction and ultimate benefit from HCT and the cross-sectional portion of the study will assess the benefit of HCT 2 years post-HCT in consenting surviving patients.

    Stanford is currently not accepting patients for this trial. For more information, please contact Matthew Porteus, MD, 650-725-6520.

    View full details


Stanford Advisees


All Publications

  • 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


    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

  • 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


    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 DOI 10.1016/j.jaci.2018.12.1013

    View details for PubMedID 30682461

  • 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
  • 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
  • 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 DOI 10.1016/j.jaci.2018.07.020

    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: 399–400
  • 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: S53–S54
  • 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


    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-?


    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 μmol/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


    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


    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 2 PIDTC 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-?


    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., Zúñiga-Pflücker, J. C., Notarangelo, L. D. 2012; 24 (5): 617-624


    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


    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


    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


    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


    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