Katja Weinacht, MD, PhD

  • Katja G Weinacht



Work and Education

Professional Education

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


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


Boston Childrens Hospital Hematology 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

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 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


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

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., Ziga-Pflcker, 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