Genetic Analysis of Immune Disorders

The purposes of this study are to 1) identify the genes responsible for certain immune disorders, 2) learn about the medical problems they cause, and 3) learn how to predict who is likely to develop these disorders and what the risk is of passing them on to children.

Natural History Study of GATA2 Deficiency and Related Disorders

The purpose of this study is to improve understanding of GATA2 deficiency so there can be better diagnostic tests and treatments in the future.

Juan C. Gea-Banacloche, M.D.

Section or Unit Name
Infectious Diseases Consult Service
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Program Description

Provide direct clinical care to patients requiring management of infectious diseases in the Clinical Center as an attending on the general ID and transplant ID consult service.

Work closely with the transplant ID service to strengthen teaching and develop the educational experience of ID fellows rotating on the service and the transplant ID fellow.

Work closely with the transplant ID service to develop the new NIH transplant ID fellowship.

Provide infectious disease expertise in the management of pre- and post-transplant clinical care.

Provides ID consultation/support to DCR special projects as requested.

Selected Publications

Gea-Banacloche JC. Infectious complications of chimeric antigen receptor (CAR) T-cell therapies. Semin Hematol. 2023 Jan;60(1):52-58.

Gea-Banacloche J, Komanduri KV, Carpenter P, Paczesny S, Sarantopoulos S, Young JA, El Kassar N, Le RQ, Schultz KR, Griffith LM, Savani BN, Wingard JR. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report. Biol Blood Marrow Transplant. 2017 Jun;23(6):870-881.

Gea-Banacloche JC. Rituximab-associated infections. Semin Hematol. 2010 Apr;47(2):187-98.

Gea-Banacloche J, Masur H, Arns da Cunha C, Chiller T, Kirchhoff LV, Shaw P, Tomblyn M, Cordonnier C; Center for International Blood and Marrow Transplant Research; National Marrow Donor Program; European Blood and Marrow Transplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Disease Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Diseases Canada; Centers for Disease Control and Prevention. Regionally limited or rare infections: prevention after hematopoietic cell transplantation. Bone Marrow Transplant. 2009 Oct;44(8):489-94.

Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004 Mar;32(3):858-73.

Gea-Banacloche JC, Clifford Lane H. Immune reconstitution in HIV infection. AIDS. 1999;13 Suppl A:S25-38.

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Major Areas of Research
  • Immune reconstitution after allogeneic Hematopoietic Stem Cell Transplantation
  • Infections in transplant recipients

Steven Holland, M.D.

Education:

M.D., 1983, The Johns Hopkins University School of Medicine

Steven M. Holland, M.D.

Jennifer M. Cuellar-Rodriguez, M.D.

Specialty(s): Infectious Disease, Internal Medicine
Provides direct clinical care to patients at NIH Clinical Center

Education:

M.D., 1999, Universidad Autónoma de Guadalajara, Mexico

Jennifer M. Cuellar-Rodriguez, M.D.

Michael P. O'Connell, Ph.D.

Education:

Ph.D., Cell and Molecular Biology (Developmental Origins of Health and Disease), 2006
M.Sc., Biochemical Pharmacology, 2003
B.Sc., Sport and Health Sciences, minor in Psychology, 2001

Michael O'Connell, Ph.D.

Jennifer M. Cuellar-Rodriguez, M.D.

Staff Clinician
Director, Transplant Infectious Diseases Consult Service

Major Areas of Research

  • Infections in immunocompromised host
  • Transplant for primary immunodeficiencies

Program Description

The Transplant Infectious Diseases Consult Service is composed of experienced transplant infectious diseases physicians. In collaboration with the Blood and Immune Deficiency Cellular Therapy Program (BID-CTP), a clinical initiative that spans across four institutes within NIH, and with the Experimental Transplantation and Immunology Branch (ETIB), the consult service provides direct patient care, educational support and develops institutional guidelines for the prevention and management of infections for patients undergoing hematopoietic stem cell transplant, gene or cellular therapies at the NIH clinical center.

Biography

Dr. Cuellar Rodriguez received her medical degree from the Universidad Autónoma de Guadalajara (Guadalajara, Mexico) in 1999 and her Diploma in Tropical Medicine and Hygiene from the London School of Hygiene and Tropical Medicine (London, UK) in 2003. She completed an Internal Medicine residency and Infectious Diseases fellowship at the at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) in Mexico City, followed by a Clinical Fellowship in Transplant Infectious Diseases at the Cleveland Clinic in Cleveland, OH. In 2009, she joined NIAID as a clinical fellow (visiting program) where she completed an advanced infectious diseases fellowship (academic/research track) in infections in immunocompromised host. She was later promoted to staff clinician in 2011. In 2014, Dr. Cuellar Rodriguez returned to the INCMNSZ to serve as head of the Transplant Infectious Diseases Section, within the Department of Infectious Disease, where she remained until 2019. She then returned to NIAID in the Division of Intramural Research and is now the director of the Transplant Infectious Diseases Consult Service.

Research Group

Juan Gea-Banacloche, M.D., Staff Clinician
Mark Parta, M.D., MPHTM, Physician III

Section or Unit Name
Transplant Infectious Diseases Consult Service
First Name
Jennifer
Last Name
Cuellar-Rodriguez
Middle Name
M.
Suffix
M.D.
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Program Description

The Transplant Infectious Diseases Consult Service is composed of experienced transplant infectious diseases physicians. In collaboration with the Blood and Immune Deficiency Cellular Therapy Program (BID-CTP), a clinical initiative that spans across four institutes within NIH, and with the Experimental Transplantation and Immunology Branch (ETIB), the consult service provides direct patient care, educational support and develops institutional guidelines for the prevention and management of infections for patients undergoing hematopoietic stem cell transplant, gene or cellular therapies at the NIH clinical center.

Clinical Studies
  • Survey of Pneumocystis Infections in NIH patients, Principal Investigator
  • A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects with VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) Syndrome, Associate Investigator
  • A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Patients with Primary Immunodeficiency Diseases, Associate Investigator
  • Detection and Characterization of Host Defense Defects, Associate Investigator
  • Allogeneic Hematopoietic Stem Cell Transplant for Patients with Mutations in GATA2 or the MonoMAC syndrome, Associate Investigator
  • Screening Protocol for Detection and Characterization of Infections and Infection Susceptibility, Associate Investigator
  • Natural History Study of the Complications Associated with Allogeneic Hematopoietic Stem Cell Transplantations, Associate Investigator
Additional Information

Research Group

  • Juan Gea-Banacloche, M.D., Staff Clinician
  • Mark Parta, M.D., MPHTM, Physician III

Training Program

Infectious Diseases Fellowship Program

Major Areas of Research
  • Infections in immunocompromised host
  • Transplant for primary immunodeficiencies

Steven Holland, M.D.

Director, Division of Intramural Research
Chief, Immunopathogenesis Section

Major Areas of Research

  • Immune defects of phagocytes: GATA2 deficiency (MonoMAC), nontuberculous mycobacterial infections, chronic granulomatous disease, hyper IgE (Job’s) syndrome, leukocyte adhesion deficiency
  • Cytokines and their receptors in the pathogenesis and therapy of infections
  • Susceptibility to disseminated mycobacterial infections, such as GATA2, autoantibodies to interferon gamma and defects in the interferon gamma/IL-12 pathway
  • Mechanisms of mycobacterial pathogenesis
  • Mechanisms of bacterial pathogenesis (e.g., Burkholderia)
  • Mechanisms of Coccidioides immitis pathogenesis
  • Mechanisms of airway dysfunction leading to mycobacterial and fungal infection

Program Description

The Immunopathogenesis Section therapeutic and research programs take a fully integrated approach to infectious disease, incorporating the molecular genetics of the host and the pathogen as well as mechanisms of pathogenesis that allow the development and study of novel therapeutics. The integrated bench-to-bedside model is intrinsic to the Immunopathogenesis Section approach and is reflected in the close involvement of trainees (both M.D. and Ph.D.) in laboratory work and in the clinical appreciation of disease, which together add new insights into mechanisms of action and avenues of therapy. New protocols in Coccidioides infections and pathogenesis of mycobacterial infections are in progress.

Biography

Dr. Holland received his M.D. from the Johns Hopkins University School of Medicine in 1983, where he stayed as a resident in internal medicine, assistant chief of service in medicine, and fellow in infectious diseases. He came to the National Institutes of Health in 1989 as a National Research Council fellow in the Laboratory of Molecular Microbiology, working on transcriptional regulation of HIV. In 1991, Dr. Holland joined the Laboratory of Host Defenses, shifting his research to the host side, with a focus on phagocyte defects and their associated infections. His work centered on the pathogenesis and management of chronic granulomatous disease, as well as other congenital immune defects affecting phagocytes, including those predisposing to mycobacterial diseases. He was chief of LCID from 2004 to 2016 and was selected as DIR director in 2016.

Research Group

Li Ding, M.D.
Emilia Falcone, M.D.
Yu Han, Ph.D.
Alexandra F. Freeman, M.D.
Amy P. Hsu, B.A.
Beatriz Marciano, M.D.
Masashi Matsuyama, M.D., Ph.D.
Katelyn McCann, B.S.
Lindsey Rosen, B.S.
Gulbu Uzel, M.D.
Elizabeth P. Sampiao, M.D., Ph.D.
Christa S. Zerbe, M.D.
Ofer Zimmerman, M.D.

Selected Publications

Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Long Priel D, Riva D, Mendez L, Uzel G, Freeman AF, Olivier KN, Anderson VL, Currens R, Mackley V, Kang A, Al-Adeli M, Mace E, Orange JS, Kang E, Lockett SJ, Chen, Steinbach PJ, Hsu AP, Zarember KA, Malech HL, Gallin JI, Holland SM. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood. 2016 Aug 24. Epub ahead of print.

Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee  J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014 Sept 10;345(6204):1623-7.

Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, Arthur DC, Gu W, Gould CM, Brewer CC, Cowen EW, Freeman AF, Olivier KN, Uzel G, Zelazny AM, Daub JR, Spalding CD, Claypool RJ, Giri NK, Alter BP, Mace EM, Orange JS, Cuellar-Rodriguez J, Hickstein DD, Holland SM. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014 Feb 6;123(6):809-21.

Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, Chandrasekaran P, Rosen LB, Carvalho DS, Ding L, Vinh DC, Browne SK, Datta S, Milner JD, Kuhns DB, Long Priel DA, Sadat MA, Shiloh M, De Marco B, Alvares M, Gillman JW, Ramarathnam V, de la Morena M, Bezrodnik L, Moreira I, Uzel G, Johnson D, Spalding C, Zerbe CS, Wiley H, Greenberg DE, Hoover SE, Rosenzweig SD, Galgiani JN, Holland SM. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013 Jun;131(6):1624-34.

Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, Kirk JL, Jutivorakool K, Zaman R, Ding L, Hsu AP, Patel SY, Olivier KN, Lulitanond V, Mootsikapun P, Anunnatsiri S, Angkasekwinai N, Sathapatayavongs B, Hsueh PR, Shieh CC, Brown MR, Thongnoppakhun W, Claypool R, Sampaio EP, Thepthai C, Waywa D, Dacombe C, Reizes Y, Zelazny AM, Saleeb P, Rosen LB, Mo A, Iadarola M, Holland SM. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med.2012 Aug 23;367(8):725-34.

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Section or Unit Name
Immunopathogenesis Section
First Name
Steven
Last Name
Holland
Suffix
M.D.
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This Researcher/Clinician’s Person Page
Program Description

The Immunopathogenesis Section therapeutic and research programs take a fully integrated approach to infectious disease, incorporating the molecular genetics of the host and the pathogen as well as mechanisms of pathogenesis that allow the development and study of novel therapeutics. The integrated bench-to-bedside model is intrinsic to the Immunopathogenesis Section approach and is reflected in the close involvement of trainees (both M.D. and Ph.D.) in laboratory work and in the clinical appreciation of disease, which together add new insights into mechanisms of action and avenues of therapy. New protocols in Coccidioides infections and pathogenesis of mycobacterial infections are in progress.

Selected Publications

Kuhns DB, Fink DL, Choi U, Sweeney C, Lau K, Long Priel D, Riva D, Mendez L, Uzel G, Freeman AF, Olivier KN, Anderson VL, Currens R, Mackley V, Kang A, Al-Adeli M, Mace E, Orange JS, Kang E, Lockett SJ, Chen, Steinbach PJ, Hsu AP, Zarember KA, Malech HL, Gallin JI, Holland SM. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood. 2016 Aug 24. Epub ahead of print.

Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee  J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014 Sept 10;345(6204):1623-7.

Spinner MA, Sanchez LA, Hsu AP, Shaw PA, Zerbe CS, Calvo KR, Arthur DC, Gu W, Gould CM, Brewer CC, Cowen EW, Freeman AF, Olivier KN, Uzel G, Zelazny AM, Daub JR, Spalding CD, Claypool RJ, Giri NK, Alter BP, Mace EM, Orange JS, Cuellar-Rodriguez J, Hickstein DD, Holland SM. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014 Feb 6;123(6):809-21.

Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, Chandrasekaran P, Rosen LB, Carvalho DS, Ding L, Vinh DC, Browne SK, Datta S, Milner JD, Kuhns DB, Long Priel DA, Sadat MA, Shiloh M, De Marco B, Alvares M, Gillman JW, Ramarathnam V, de la Morena M, Bezrodnik L, Moreira I, Uzel G, Johnson D, Spalding C, Zerbe CS, Wiley H, Greenberg DE, Hoover SE, Rosenzweig SD, Galgiani JN, Holland SM. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013 Jun;131(6):1624-34.

Browne SK, Burbelo PD, Chetchotisakd P, Suputtamongkol Y, Kiertiburanakul S, Shaw PA, Kirk JL, Jutivorakool K, Zaman R, Ding L, Hsu AP, Patel SY, Olivier KN, Lulitanond V, Mootsikapun P, Anunnatsiri S, Angkasekwinai N, Sathapatayavongs B, Hsueh PR, Shieh CC, Brown MR, Thongnoppakhun W, Claypool R, Sampaio EP, Thepthai C, Waywa D, Dacombe C, Reizes Y, Zelazny AM, Saleeb P, Rosen LB, Mo A, Iadarola M, Holland SM. Adult-onset immunodeficiency in Thailand and Taiwan. N Engl J Med.2012 Aug 23;367(8):725-34.

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Additional Information

Research Group

Li Ding, M.D.

Emilia Falcone, M.D.

Yu Han, Ph.D.

Alexandra F. Freeman, M.D.

Amy P. Hsu, B.A.

Beatriz Marciano, M.D.

Masashi Matsuyama, M.D., Ph.D.

Katelyn McCann, B.S.

Lindsey Rosen, B.S.

Gulbu Uzel, M.D.

Elizabeth P. Sampiao, M.D., Ph.D.

Christa S. Zerbe, M.D.

Ofer Zimmerman, M.D.

 

Major Areas of Research
  • Immune defects of phagocytes: GATA2 deficiency (MonoMAC), nontuberculous mycobacterial infections, chronic granulomatous disease, hyper IgE (Job’s) syndrome, leukocyte adhesion deficiency
  • Cytokines and their receptors in the pathogenesis and therapy of infections
  • Susceptibility to disseminated mycobacterial infections, such as GATA2, autoantibodies to interferon gamma and defects in the interferon gamma/IL-12 pathway
  • Mechanisms of mycobacterial pathogenesis
  • Mechanisms of bacterial pathogenesis (e.g., Burkholderia)
  • Mechanisms of Coccidioides immitis pathogenesis
  • Mechanisms of airway dysfunction leading to mycobacterial and fungal infection

Michael O'Connell, Ph.D.

Staff Clinician, Translational Allergic Immunopathology Unit

Major Areas of Research

  • Characterizing the effects of inherited and acquired genetic variation on myeloid cell reactivity and myeloproliferation
  • Define pathways critical for allergic inflammation and severe hypersensitivity reactions

Program Description

The prevalence of severe allergic disease is on the rise globally; consequently, severe systemic allergic inflammation and reactions are also becoming far more frequent, representing a major public health burden causing morbidity for patients, distress for families, and substantial costs for the healthcare system. We seek to develop methods and strategies to identify individuals at with or at high risk of developing severe allergic inflammation and anaphylaxis in order to identify specific pathways leading to these phenotypes and enable the development of new therapies that can successfully limit and/or prevent these potentially devastating consequences.

Biography

Dr. O'Connell received his Ph.D. in development origins of health and disease (cell and molecular biology) from the University of Southampton School of Medicine in the United Kingdom, in collaboration with the University of Pennsylvania. He obtained postdoctoral training in the areas of Wnt5a-mediated progression of metastatic melanoma at the National Institute on Aging from 2006 to 2011. Prior to joining the Laboratory of Allergic Diseases in 2014, Dr. O'Connell was a staff scientist at the Wistar Institute, Philadelphia, from 2011 to 2014, where he investigated mechanisms of drug resistance in cancer. Dr. O’Connell joined the Laboratory of Allergic Diseases from the Wistar Institute in 2015. Working in the Genetics and Pathology of Allergy Section, he has endothelial cell-driven mechanisms promoting atopy. He joined the Translational Allergic Immunopathology Unit in 2019 bringing with him expertise in molecular biology and cancer and is leading efforts to understand how inherited and acquired genetic variation in endothelial and myeloid cells can promote severe allergic reactions and myeloproliferation.

Selected Publications

Desai, A., Sowerwine, K., Liu, Y., Lawrence, M.G., O’Connell, M.P., Chovanec, J., Hsu, A.P., Boris, L., Jones, N., Zerbe, C., Wisch, L., Maric, I., Lee, R.C., Gilfillan, A., Stone, K.D., Milner, J.D., Holland, S.M., Metcalfe, D.D., Lyons, J.J. GATA2-deficient mast cells limit type I hypersensitivity reactions in humans. J Allergy Clin Immunol. 2019 May 15.

Lyons, J.J., Liu, Y., Ma, C., Yu, X., O'Connell, M.P., Lawrence, M., Zhang, Y., Karpe, K., Zhao, M., Siegel, A., Stone, K.D., Nelson, C., Jones, N., Dimaggio, T., Darnell, D., Mendoza-Caamal, E., Orozco, L., Hughes, J., McElwee, J., Hohman, R., Frischmeyer-Guerrerio, P., Rothenberg, M., Freeman, A., Holland, S., and Milner, J.D. ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans. J Exp Med. 2017 Mar 6.

Lyons, J.J., Yu, X., Hughes, J.D., Le, Q.T., Jamil, A., Bai, Y., Ho, N., Zhao, M., Liu, Y., O'Connell, M.P., Trivedi, N.N., Nelson, C., DiMaggio, T., Jones, N., Matthews, H., Lewis, K.L., Oler, A.J., Carlson, R.J., Arkwright, P.D., Hong, C., Agama, S., Wilson, T.M., Tucker, S., Zhang, Y., McElwee, J.J., Pao, M., Glover, S.C., Rothenberg, M.E., Hohman, R.J., Stone, K.D., Caughey, G.H., Heller, T., Metcalfe, D.D., Biesecker, L.G., Schwartz, L.B., Milner, J.D. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec.

Kaur, A., Webster, M.R., Marchbank, K., Behera, R., Ndoye, A., Kugell III, C.H., Dang, V.M., Appleton, J., O’Connell, M.P., Cheng, P., Valiga, A.A., Morissette, R., McDonnell, N.B., Ferrucci, L., Kossenkov, A.V., Meeth, K., Tang, H., Yin, X., Wood III, W.H., Lehrmann, E., Becker, K.G., Flaherty, K.T., Frederick, D.T., Wargo, J.A., Cooper, Z.A., Tetzlaff, M.T., Hudgens, C., Aird, K.M., Zhang, R., Xu, X., Liu, Q., Bartlett, E., Karakousis, G., Eroglu, Z., Lo, R.S., Chan, M., Menzies, A.M., Long, G.V., Johnson, D.B., Sosman, J., Schilling, B., Schadendorf, D., Speicher, D.W., Bosenberg, M., Ribas, A., and Weeraratna, A.T. sFRP2 in the aged microenvironment drives melanoma metastasis and resistance to targeted therapy. Nature. 2016 Apr 14.

O’Connell, M.P.*, Hox, V.*, Lyons, J.J., Sackstein, P., Dimaggio, T., Jones, N., Nelson, C., Boehm, M., Holland, S.M., Freeman, A.F., Tweardy, D.J., Olivera, A., Metcalfe, D.D., Milner, J.D. Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis. J Allergy Clin Immunol. 2016 Jul;138(1):187-99. doi: 10.1016/j.jaci.2015.11.024. * Co-first author

O’Connell M.P., Marchbank K., Webster M.R., Valiga A., Kaur A.A., Vultur A.M., Li L., Herlyn M., Villanueva J., Liu Q., Yin X., Widura S., Nelson J., Ruiz N., Camilli T.C., Indig F.E., Flaherty K.T, Wargo J.A., Frederick D.T.,. Cooper Z.A., Nair S., Amaravadi R.K., Schuchter L.M., Karakousis G., Xu W., Xu X., Weeraratna A.T. Hypoxia induces phenotypic plasticity and therapy resistance in melanoma via the tyrosine kinase receptors ROR1 and ROR2. Cancer Discov. 2013 Dec;3(12):1378-93.

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Section or Unit Name
Translational Allergic Immunopathology Unit
First Name
Michael
Last Name
O'Connell
Suffix
Ph.D.
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Program Description

The prevalence of severe allergic disease is on the rise globally; consequently, severe systemic allergic inflammation and reactions are also becoming far more frequent, representing a major public health burden causing morbidity for patients, distress for families, and substantial costs for the healthcare system. We seek to develop methods and strategies to identify individuals at with or at high risk of developing severe allergic inflammation and anaphylaxis in order to identify specific pathways leading to these phenotypes and enable the development of new therapies that can successfully limit and/or prevent these potentially devastating consequences.

Selected Publications

Konnikova L, Robinson TO, Owings AH, Shirley JF, Davis E, Tang Y, Wall S, Li J, Hasan MH, Gharaibeh RZ, Mendoza Alvarez LB, Ryan LK, Doty A, Chovanec JF, O'Connell MP, Grunes DE, Daley WP, Mayer E, Chang L, Liu J, Snapper SB, Milner JD, Glover SC, Lyons JJ. Small intestinal immunopathology and GI-associated antibody formation in hereditary alpha-tryptasemia. J Allergy Clin Immunol. 2021 Sep;148(3):813-821.e7.

Lyons JJ, Chovanec J, O'Connell MP, Liu Y, Šelb J, Zanotti R, Bai Y, Kim J, Le QT, DiMaggio T, Schwartz LB, Komarow HD, Rijavec M, Carter MC, Milner JD, Bonadonna P, Metcalfe DD, Korošec P. Heritable risk for severe anaphylaxis associated with increased α-tryptase-encoding germline copy number at TPSAB1. J Allergy Clin Immunol. 2021 Feb;147(2):622-632.

O'Connell MP, Lyons JJ. Hymenoptera venom-induced anaphylaxis and hereditary alpha-tryptasemia. Curr Opin Allergy Clin Immunol. 2020 Oct;20(5):431-437.

Zhang Y, Ma CA, Lawrence MG, Break TJ, O'Connell MP, Lyons JJ, López DB, Barber JS, Zhao Y, Barber DL, Freeman AF, Holland SM, Lionakis MS, Milner JD. PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients. J Exp Med. 2017 Sep 4;214(9):2523-2533.

Lyons JJ, Liu Y, Ma CA, Yu X, O'Connell MP, Lawrence MG, Zhang Y, Karpe K, Zhao M, Siegel AM, Stone KD, Nelson C, Jones N, DiMaggio T, Darnell DN, Mendoza-Caamal E, Orozco L, Hughes JD, McElwee J, Hohman RJ, Frischmeyer-Guerrerio PA, Rothenberg ME, Freeman AF, Holland SM, Milner JD. ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans. J Exp Med. 2017 Mar 6;214(3):669-680.

Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Ho N, Zhao M, Liu Y, O'Connell MP, Trivedi NN, Nelson C, DiMaggio T, Jones N, Matthews H, Lewis KL, Oler AJ, Carlson RJ, Arkwright PD, Hong C, Agama S, Wilson TM, Tucker S, Zhang Y, McElwee JJ, Pao M, Glover SC, Rothenberg ME, Hohman RJ, Stone KD, Caughey GH, Heller T, Metcalfe DD, Biesecker LG, Schwartz LB, Milner JD. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016 Dec;48(12):1564-1569.

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Major Areas of Research
  • Characterizing the effects of inherited and acquired genetic variation on myeloid cell reactivity and myeloproliferation
  • Define pathways critical for allergic inflammation and severe hypersensitivity reactions