Zorn Lab

Location and Contact Information

650 West 168th Street, 15th Floor
New York, NY 10032
United States

Principal Investigator

The Zorn Lab's primary research interest is on B cell immunity from B cell ontogeny to the development of antibody response in health and disease. An important area of focus is the study of "innate" B cells, also named B1 B cells in mice. These understudied cells are thought to constitute either a separate lineage of B cells or at least a separate subset with distinct properties. Innate B cells are mostly known for the secretion of "natural" antibodies with a polyreactive profile. We have accumulated solid evidence implicating these cells in various pathological situations.

Projects

B cell immunity and human transplant rejection

Ongoing studies in my lab investigate antibody responses associated with chronic rejection of human kidney and heart transplants. In addition to allospecific antibodies recognizing mismatched donor MHC molecules, we are examining the development of autoantibodies as well as polyreactive natural antibodies (Nabs). Large multi-center studies, including centers in the USA, Canada, France, and the Netherlands, provided evidence that the presence of Nabs pre-transplant as well as their development post-transplant is tightly associated with rejection and kidney graft loss. We are also actively investigating the mechanisms whereby these antibodies contribute to tissue injury.

A second study directly looks at B cell and plasma cell infiltrates around coronary arteries in allografts with documented rejection following heart transplantation. These B cell infiltrates are frequently observed in rejected grafts but their specificity and function remain unclear. In previous studies, we successfully cloned over 100 such B cells directly from the infiltrates of several explanted graft and revealed a consistent predominance of innate B cell clones secreting Nabs. We have now begun the molecular characterization of these cells. Our most recent research focuses predominantly on plasma cells infiltrating the graft tissue during rejection and secreting antibodies locally. We plan to identify the specificity of these cells and uncover their role in rejection.

Significance of plasma cells in the human thymus

My lab also investigates the role of B cells in the human thymus. In previous studies, using a large collection of thymus specimens collected from infants to adults, we observed the age-dependent recruitment of differentiated antibody-producing plasma cells (PC) in the thymic perivascular space. The thymus is primary known as the lymphoid organ where T cells are generated, hence their name. Uncovering a PC niche is this organ was unexpected. Moreover, we demonstrated that these thymic PC included high frequency clones specific to common viruses, which likely resulted from past immunizations. In more recent studies, we also observed the accumulation of PC specific to common dietary antigens present in egg, wheat, and cow’s milk, in the thymus of young children concomitantly with the development of serum antibodies to the same antigens. We are now studying the significance of these PC in mechanisms of tolerance, especially toward food antigens. Our working hypothesis is that thymic PC could contribute to T cell negative selection through local immunoglobulin secretion, formation of immune complexes with specific antigens (e.g. food antigens) and routing these complexes to antigen-presenting cells in the thymic medulla.

Development of humoral immunity in human newborns

Humans are born with natural antibodies conferring protective innate immunity against endemic pathogens. The source of these natural antibodies is still largely unknown. Ongoing studies in my lab have uncovered the differentiation of B cells into natural antibody-producing cells in the newborn thymus. Using a cloning expression method, we generated >350 such recombinant monoclonal natural antibodies from thymic plasma cells. Remarkably, ~7% of these antibodies cross-reacted to common pathogenic bacterial species such as Staphylococcus aureus or Haemophilus influenzae. We are now investigating their anti-bacterial functional properties and assessing their therapeutic value. In particular, we are exploring the possibility of engineering a recombinant polyclonal antibody with a set of monoclonal antibodies derived from neonatal thymic plasma cells to use for replacement therapy in children born with antibody deficiency.

Understanding the local T cell response in graft rejection

T cells play a central role in the rejection of solid organ grafts. It has long been thought that allospecific T cells recognizing mismatched donor antigens are the most prominent T cells involved in rejection. However, a recent study in my lab revealed that a majority of T cells infiltrating cardiac allografts during chronic rejection may in fact correspond to bystander T cells recruited from the blood in a non-specific manner. This unexpected finding casts a new light on the local immune response during graft rejection. Using single-cell transcriptomics and next generation sequencing-based repertoire analysis, we are further investigating these bystander T cells. We are particularly interested in understanding how these cells are stimulated in the graft and what their contribution to graft injury may be.

 

Lab Members

  • Sarah See, PhD

    • Associate Research Scientist
  • Hector Cordero, PhD

    • Postdoctoral Researcher
  • Shunya Mashiko, PharmD, PhD

    • Postdoctoral Researcher
  • Poulomi Roy, BSc

    • Clinical Research Coordinator

Select Publications

  • Zorn E. and See SB. Antibody Responses to Minor Histocompatibility Antigens After Solid Organ Transplantation. Transplantation. 2021. In press.

  • Mantell  BS, Cordero  H, See  SB, Clerkin  KJ, Vasilescu  R, Marboe  CC, Naka  Y, Restaino  S, Colombo  PC, Addonizio  LJ, Farr  MA, Zorn  E. Transcriptomic heterogeneity of antibody mediated rejection after heart transplant with or without donor specific antibodies. J Heart Lung Transplant. 2021. In press

  • Cordero H, King RG, Dogra P, Dufeu C, See SB, Chong AM, Uhlemann AC, Ho SH, Kalfa DM, Bacha EA, Kearney JF, Zorn E. Intrathymic differentiation of natural antibody-producing plasma cells in human neonates. Nature Communications. 2021. 12: 5761

  • Habal MV, Miller AM, Rao S, Lin S, Obradovic A, Khosravi-Maharlooei M, See SB, Roy P, Shihab R, Ho SH, Marboe C, Naka Y, Takeda K, Restaino S, Han A, Mancini D, Givertz M, Madsen JC, Sykes M, Addonizio L, Zorn E. T cell repertoire analysis suggest a prominent bystander response in human cardiac allograft vasculopathy. American J. Transplant. 2020. 21: 1465-1476.

  • See SB, Mantell BS, Clerkin KJ, Ray B, Vasilescu ER, Marboe CC, Naka Y, Restaino S, Colombo PC, Addonizio LJ, Farr MA, Zorn E. Profiling non-HLA antibody responses in antibody-mediated rejection following heart transplantation. American J. Transplant. 2020. 20:2571-2580.

  • Moore C, Gao B, Roskin KM, Vasilescu R, Addonizio L, Givertz MM, Madsen JC, Zorn E. B cell clonal expansion within immune infiltrates in human cardiac allograft vasculopathy. American J. Transplant. 2020. 20:1431-1438.

  • Zorn E. and See SB. Is there a role for natural antibodies in rejection following transplantation? Transplantation. 2019. 103(8):1612-1619

  • Zorn E. New insights on innate B cell immunity in transplantation. Xenotransplantation. 2018. 25(3):e12417.

  • Chatterjee D, Moore, C, Gao B, Clerkin KJ, See SB, Shaked D, Rogers K, Nunez S, Veras Y, Addonizio L, Givertz MM, Naka Y, Mancini D, Vasilescu R, Marboe C, Restaino S, Madsen JC, Zorn E. Prevalence of polyreactive innate clones among graft infiltrating B cells in human cardiac allograft vasculopathy. J Heart Lung Transplant. 2018. 37(3):385-393. 

  • Clerkin KJ, See SB, Farr MA, Restaino SW, Serban G, Farhana Latif F, Li L, Colombo PC, Vlad G, Ray Bryan, Vasilescu ER and Zorn E. Comparative assessment of anti-HLA antibodies using 2 commercially available Luminex-based assays. Transplantation Direct. 2017. Oct 2;3(11):e218.

  • Zorn E. and See SB. Polyreactive natural antibodies in transplantation. Curr. Opin. Organ Transplant. 2017. 22(1):8-13

  • Gao B, Gu Y, Rong C, Moore C, Porcheray F, Wong W, Preffer F, Saidman SL, Fu Y, Cosimi AB, Sachs DH, Kawai T, Sykes M, Zorn E. Dynamics of B cell recovery following kidney/bone marrow transplant recipients.  Transplantation. 2017; 101: 2722-2730

  • See SB, Clerkin KJ, Kennel PJ, Zhang F, Weber MP, Rogers K, Chatterjee D, Vasilescu ER, Vlad G, Naka Y, Restaino S, Farr M, Topkara VK, Colombo PC, Mancini DM,  Schulze PC, Levin B, Zorn E.  Ventricular assist device elicits serum natural IgG that correlate with the development of primary graft dysfunction following heart transplantation. J Heart Lung Transplant. 2017. 36: 862-870.

  • Nuñez S, Moore C, Gao B, Rogers K, Hidalgo Y, del Nido P, Restaino S, Naka Y, Bhagat G, Madsen JC, Bono MR and Zorn E. The human thymus perivascular space is a functional niche for viral-specific plasma cells. Science Immunology. 2016. Dec; 1(6) eaah4447