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Related Research Units

Pathology Research

Research Overview

The Manis lab focuses on the development of the immune system. One area of work focuses on the basic mechanisms that control programmed DNA breaks in B cells of the immune system.  Errors in the repair of programmed immune system breaks lead to immunodeficiency and can lead to cancers including lymphoma.  The laboratory has expertise in generating gene-targeted mouse embryonic stem cells and mice to study immune system defects.  Another area of focus is in developing mouse models for human primary immunodeficiency syndromes.  Presently, a mouse model of Job's Syndrome, replicating autosomal-dominant Hyper IgE syndrome due to defective Stat 3 is being examined to understand lineage specific contributions to the disease.

 

Publications

  1. A progranulin variant causing childhood interstitial lung disease responsive to anti-TNF-a biologic therapy. Med. 2025 Feb 25; 100607. View Abstract
  2. Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. Cell Stem Cell. 2025 Feb 06; 32(2):191-208.e11. View Abstract
  3. UM171 enhances fitness and engraftment of gene-modified hematopoietic stem cells from patients with sickle cell disease. Blood Adv. 2024 Nov 26; 8(22):5885-5895. View Abstract
  4. Age-associated clonal B cells drive B cell lymphoma in mice. Nat Aging. 2024 Oct; 4(10):1403-1417. View Abstract
  5. Antibody-mediated antigen loss switches augmented immunity to antibody-mediated immunosuppression. Blood. 2023 09 21; 142(12):1082-1098. View Abstract
  6. Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells. bioRxiv. 2023 May 27. View Abstract
  7. Humanized V(D)J-rearranging and TdT-expressing mouse vaccine models with physiological HIV-1 broadly neutralizing antibody precursors. Proc Natl Acad Sci U S A. 2023 01 03; 120(1):e2217883120. View Abstract
  8. Development of a double shmiR lentivirus effectively targeting both BCL11A and ZNF410 for enhanced induction of fetal hemoglobin to treat ß-hemoglobinopathies. Mol Ther. 2022 08 03; 30(8):2693-2708. View Abstract
  9. Author Correction: DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2022 May; 23(5):815. View Abstract
  10. Form follows function for freeze-dried platelets. Am J Hematol. 2022 03 01; 97(3):253-255. View Abstract
  11. Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion. Sci Transl Med. 2021 07 28; 13(604). View Abstract
  12. Parameters affecting successful stem cell collections for genetic therapies in sickle cell disease. Transfus Apher Sci. 2021 Feb; 60(1):103059. View Abstract
  13. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N Engl J Med. 2021 01 21; 384(3):205-215. View Abstract
  14. Preclinical Evaluation of a Novel Lentiviral Vector Driving Lineage-Specific BCL11A Knockdown for Sickle Cell Gene Therapy. Mol Ther Methods Clin Dev. 2020 Jun 12; 17:589-600. View Abstract
  15. Therapeutic base editing of human hematopoietic stem cells. Nat Med. 2020 04; 26(4):535-541. View Abstract
  16. Serine/threonine phosphatase PP2A is essential for optimal B cell function. JCI Insight. 2020 03 12; 5(5). View Abstract
  17. Highly efficient therapeutic gene editing of human hematopoietic stem cells. Nat Med. 2019 May; 25(5):776-783. View Abstract
  18. Proteinase 3 Limits the Number of Hematopoietic Stem and Progenitor Cells in Murine Bone Marrow. Stem Cell Reports. 2018 11 13; 11(5):1092-1105. View Abstract
  19. Successful hematopoietic stem cell mobilization and apheresis collection using plerixafor alone in sickle cell patients. Blood Adv. 2018 10 09; 2(19):2505-2512. View Abstract
  20. Hypomorphic Rag1 mutations alter the preimmune repertoire at early stages of lymphoid development. Blood. 2018 07 19; 132(3):281-292. View Abstract
  21. Evaluation of the Role of stat3 in Antibody and TH17-Mediated Responses to Pneumococcal Immunization and Infection by Use of a Mouse Model of Autosomal Dominant Hyper-IgE Syndrome. Infect Immun. 2018 05; 86(5). View Abstract
  22. Corrigendum: Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content. Front Immunol. 2017; 8:1244. View Abstract
  23. DOCK8 and STAT3 dependent inhibition of IgE isotype switching by TLR9 ligation in human B cells. Clin Immunol. 2017 10; 183:263-265. View Abstract
  24. Natural Killer Cells from Patients with Recombinase-Activating Gene and Non-Homologous End Joining Gene Defects Comprise a Higher Frequency of CD56bright NKG2A+++ Cells, and Yet Display Increased Degranulation and Higher Perforin Content. Front Immunol. 2017; 8:798. View Abstract
  25. EXTL3 mutations cause skeletal dysplasia, immune deficiency, and developmental delay. J Exp Med. 2017 03 06; 214(3):623-637. View Abstract
  26. Correction: Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells. PLoS Genet. 2016 Dec; 12(12):e1006509. View Abstract
  27. Complex Breakpoints and Template Switching Associated with Non-canonical Termination of Homologous Recombination in Mammalian Cells. PLoS Genet. 2016 Nov; 12(11):e1006410. View Abstract
  28. Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. J Clin Invest. 2016 11 01; 126(11):4219-4236. View Abstract
  29. Heterozygosity for transmembrane activator and calcium modulator ligand interactor A144E causes haploinsufficiency and pneumococcal susceptibility in mice. J Allergy Clin Immunol. 2017 Apr; 139(4):1293-1301.e4. View Abstract
  30. Platelet refractoriness: it's not the B-all and end-all. Blood. 2016 Apr 07; 127(14):1740-1. View Abstract
  31. Rapid generation of novel models of RAG1 deficiency by CRISPR/Cas9-induced mutagenesis in murine zygotes. Oncotarget. 2016 Mar 15; 7(11):12962-74. View Abstract
  32. A novel mutation in the POLE2 gene causing combined immunodeficiency. J Allergy Clin Immunol. 2016 Feb; 137(2):635-638.e1. View Abstract
  33. Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching. Nature. 2015 Sep 03; 525(7567):134-139. View Abstract
  34. Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. J Allergy Clin Immunol. 2015 Jul; 136(1):140-150.e7. View Abstract
  35. Defective lymphoid organogenesis underlies the immune deficiency caused by a heterozygous S32I mutation in I?Ba. J Exp Med. 2015 Feb 09; 212(2):185-202. View Abstract
  36. Differential role of nonhomologous end joining factors in the generation, DNA damage response, and myeloid differentiation of human induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2014 Jun 17; 111(24):8889-94. View Abstract
  37. Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med. 2014 May 05; 211(5):929-42. View Abstract
  38. TRIF signaling is essential for TLR4-driven IgE class switching. J Immunol. 2014 Mar 15; 192(6):2651-8. View Abstract
  39. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol. 2013 Sep; 132(3):656-664.e17. View Abstract
  40. Focal adhesion kinase regulates the localization and retention of pro-B cells in bone marrow microenvironments. J Immunol. 2013 Feb 01; 190(3):1094-102. View Abstract
  41. BAL1 and its partner E3 ligase, BBAP, link Poly(ADP-ribose) activation, ubiquitylation, and double-strand DNA repair independent of ATM, MDC1, and RNF8. Mol Cell Biol. 2013 Feb; 33(4):845-57. View Abstract
  42. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nat Immunol. 2012 May 13; 13(6):612-20. View Abstract
  43. B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice. Blood. 2012 Mar 22; 119(12):2819-28. View Abstract
  44. Immature B cells preferentially switch to IgE with increased direct Sµ to Se recombination. J Exp Med. 2011 Dec 19; 208(13):2733-46. View Abstract
  45. Signatures of murine B-cell development implicate Yy1 as a regulator of the germinal center-specific program. Proc Natl Acad Sci U S A. 2011 Feb 15; 108(7):2873-8. View Abstract
  46. Analysis of mice lacking DNaseI hypersensitive sites at the 5' end of the IgH locus. PLoS One. 2010 Nov 15; 5(11):e13992. View Abstract
  47. AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling. Mol Cell. 2010 Sep 24; 39(6):873-85. View Abstract
  48. Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4. J Exp Med. 2010 Feb 15; 207(2):417-27. View Abstract
  49. Downstream class switching leads to IgE antibody production by B lymphocytes lacking IgM switch regions. Proc Natl Acad Sci U S A. 2010 Feb 16; 107(7):3040-5. View Abstract
  50. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol Cell. 2009 Oct 09; 36(1):110-20. View Abstract
  51. Integrity of the AID serine-38 phosphorylation site is critical for class switch recombination and somatic hypermutation in mice. Proc Natl Acad Sci U S A. 2009 Feb 24; 106(8):2717-22. View Abstract
  52. Oncogenic transformation in the absence of Xrcc4 targets peripheral B cells that have undergone editing and switching. J Exp Med. 2008 Dec 22; 205(13):3079-90. View Abstract
  53. Fixing DNA breaks during class switch recombination. J Exp Med. 2008 Mar 17; 205(3):509-13. View Abstract
  54. Knock out, knock in, knock down--genetically manipulated mice and the Nobel Prize. N Engl J Med. 2007 Dec 13; 357(24):2426-9. View Abstract
  55. S-S synapsis during class switch recombination is promoted by distantly located transcriptional elements and activation-induced deaminase. Immunity. 2007 Nov; 27(5):711-22. View Abstract
  56. SOCS3 protein developmentally regulates the chemokine receptor CXCR4-FAK signaling pathway during B lymphopoiesis. Immunity. 2007 Nov; 27(5):811-23. View Abstract
  57. B-cell receptor cross-linking delays activation-induced cytidine deaminase induction and inhibits class-switch recombination to IgE. J Allergy Clin Immunol. 2008 Jan; 121(1):191-196.e2. View Abstract
  58. IgH class switching and translocations use a robust non-classical end-joining pathway. Nature. 2007 Sep 27; 449(7161):478-82. View Abstract
  59. Integrative analysis reveals 53BP1 copy loss and decreased expression in a subset of human diffuse large B-cell lymphomas. Oncogene. 2008 Jan 10; 27(3):318-22. View Abstract
  60. Evolution of the immunoglobulin heavy chain class switch recombination mechanism. Adv Immunol. 2007; 94:157-214. View Abstract
  61. Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations. DNA Repair (Amst). 2006 Sep 08; 5(9-10):1030-41. View Abstract
  62. 53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis. Proc Natl Acad Sci U S A. 2006 Feb 28; 103(9):3310-5. View Abstract
  63. MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals. Mol Cell. 2006 Jan 20; 21(2):187-200. View Abstract
  64. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell. 2006 Jan 20; 21(2):201-14. View Abstract
  65. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature. 2005 Nov 24; 438(7067):508-11. View Abstract
  66. Artemis-independent functions of DNA-dependent protein kinase in Ig heavy chain class switch recombination and development. Proc Natl Acad Sci U S A. 2005 Feb 15; 102(7):2471-5. View Abstract
  67. p63 and p73 are not required for the development and p53-dependent apoptosis of T cells. Cancer Cell. 2004 Jul; 6(1):85-9. View Abstract
  68. 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nat Immunol. 2004 May; 5(5):481-7. View Abstract
  69. Artemis and p53 cooperate to suppress oncogenic N-myc amplification in progenitor B cells. Proc Natl Acad Sci U S A. 2004 Feb 24; 101(8):2410-5. View Abstract
  70. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci U S A. 2003 Sep 16; 100(19):10794-9. View Abstract
  71. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell. 2003 Aug 08; 114(3):359-70. View Abstract
  72. Novel antibody switching defects in human patients. J Clin Invest. 2003 Jul; 112(1):19-22. View Abstract
  73. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J Exp Med. 2003 May 05; 197(9):1213-9. View Abstract
  74. Elucidation of a downstream boundary of the 3' IgH regulatory region. Mol Immunol. 2003 Jan; 39(12):753-60. View Abstract
  75. Leaky Scid phenotype associated with defective V(D)J coding end processing in Artemis-deficient mice. Mol Cell. 2002 Dec; 10(6):1379-90. View Abstract
  76. Internal IgH class switch region deletions are position-independent and enhanced by AID expression. Proc Natl Acad Sci U S A. 2002 Jul 23; 99(15):9984-9. View Abstract
  77. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell. 2002 Jun 28; 109(7):811-21. View Abstract
  78. The function of AID in somatic mutation and class switch recombination: upstream or downstream of DNA breaks. J Exp Med. 2002 May 06; 195(9):F37-41. View Abstract
  79. IgH class switch recombination to IgG1 in DNA-PKcs-deficient B cells. Immunity. 2002 Apr; 16(4):607-17. View Abstract
  80. Mechanism and control of class-switch recombination. Trends Immunol. 2002 Jan; 23(1):31-9. View Abstract
  81. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001 Jul 19; 412(6844):300-7. View Abstract
  82. DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway. Mol Cell. 2000 Jun; 5(6):993-1002. View Abstract
  83. Interplay of p53 and DNA-repair protein XRCC4 in tumorigenesis, genomic stability and development. Nature. 2000 Apr 20; 404(6780):897-900. View Abstract
  84. The interplay between nonhomologous end-joining and cell cycle checkpoint factors in development, genomic stability, and tumorigenesis. Cold Spring Harb Symp Quant Biol. 2000; 65:395-403. View Abstract
  85. Precursors of Hodgkin's disease and B-cell lymphomas. N Engl J Med. 1999 Apr 22; 340(16):1280-2. View Abstract
  86. Position-dependent inhibition of class-switch recombination by PGK-neor cassettes inserted into the immunoglobulin heavy chain constant region locus. Proc Natl Acad Sci U S A. 1999 Mar 16; 96(6):3000-5. View Abstract
  87. Nonhomologous end-joining proteins are required for V(D)J recombination, normal growth, and neurogenesis. Cold Spring Harb Symp Quant Biol. 1999; 64:169-81. View Abstract
  88. Class switching in B cells lacking 3' immunoglobulin heavy chain enhancers. J Exp Med. 1998 Oct 19; 188(8):1421-31. View Abstract
  89. Ku70 is required for late B cell development and immunoglobulin heavy chain class switching. J Exp Med. 1998 Jun 15; 187(12):2081-9. View Abstract
  90. Ig heavy chain class switching in Rag-deficient mice. Int Immunol. 1998 Mar; 10(3):325-32. View Abstract
  91. Growth retardation and leaky SCID phenotype of Ku70-deficient mice. Immunity. 1997 Nov; 7(5):653-65. View Abstract
  92. Agammaglobulinemia and insights into B-cell differentiation. N Engl J Med. 1996 Nov 14; 335(20):1523-5. View Abstract
  93. Active transport of iron by intestine: selective genetic defect in the mouse. Nature. 1970 Jul 25; 227(5256):385-6. View Abstract
  94. Actinomycin D and the regulation of apoferritin synthesis in rat liver. Nature. 1966 Apr 30; 210(5035):538-9. View Abstract
  95. Active transport of iron by intestine: effect of erythropoiesis stimulated by phenylhydrazine. Nature. 1966 Mar 26; 209(5030):1356. View Abstract

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