Julie Zikherman, MD

Associate Professor

Our laboratory is interested in understanding how B cell behavior is regulated after encounter with either “self” or “foreign” antigens. We postulate that overlapping mechanisms are at play in both scenarios. The lab seeks to define the rules that govern B cell responses to specific features of foreign antigens, including antigen affinity, valency and co-stimulatory signals. We are also interested in how the clonal composition of both the pre- and post-immune B cell repertoires is regulated. Against this backdrop, we want to understand how self-reactive B cells, despite chronic antigen engagement of the B cell receptor, are restrained from inappropriate activation and differentiation into antibody-secreting plasma cells. We want to define how this process is disrupted in a variety of autoimmune disease states, and how normal regulatory mechanisms (both biochemical and transcriptional) can be harnessed to restore tolerance and optimize vaccine responses.

To do so, our lab takes a range of creative approaches that span mouse genetics, cellular immunology, and genomics in order to address these questions. In particular, we have characterized and exploited novel reporter mice (NUR77-eGFP BAC transgenic) in which B cell receptor signaling drives expression of eGFP. This reporter serves as an in vivo sensor of both self and foreign antigen encounter, and serves to unmask enormous clonal heterogeneity among superficially uniform populations of B cells. Recent work has focused on dissecting the distinct roles of the IgM and IgD B cell receptor isotypes in regulating the immune responses of self-reactive B cells. Newer projects seek to define how NUR77 and related orphan nuclear hormone receptors of the NR4A family function to restrain activation of chronically antigen-activated B cells and to regulate B responses to foreign antigen.
Education
2008 - Rheumatology Fellowship, UCSF
2005 - Internal Medicine Residency, Brigham and Women's Hospital
M.D., 2002 - School of Medicine, Cornell University
B.A., 1996 - Chemistry, Harvard University
Websites
Publications
  1. Feldman HC, Ghosh R, Auyeung VC, Mueller JL, Kim JH, Potter ZE, Vidadala VN, Perera BGK, Olivier A, Backes BJ, Zikherman J, Papa FR, Maly DJ. ATP-competitive partial antagonists of the IRE1α RNase segregate outputs of the UPR. 2021. PMID: 34556859


  2. Hiwa R, Nielsen HV, Mueller JL, Mandla R, Zikherman J. NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity. 2021. PMID: 34343134


  3. Brooks JF, Tan C, Mueller JL, Hibiya K, Hiwa R, Vykunta V, Zikherman J. Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses. 2021. PMID: 34469720


  4. Brooks JF, Zikherman J. The BAFFling persistence of memory B cells. 2021. PMID: 33185684


  5. Tan C, Hiwa R, Mueller JL, Vykunta V, Hibiya K, Noviski M, Huizar J, Brooks JF, Garcia J, Heyn C, Li Z, Marson A, Zikherman J. NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting. 2020. PMID: 32868928


  6. Wholey WY, Mueller JL, Tan C, Brooks JF, Zikherman J, Cheng W. Synthetic liposomal mimics of biological viruses for the study of immune responses to infection and vaccination. 2020. PMID: 31940172


  7. Tan C, Noviski M, Huizar J, Zikherman J. Self-reactivity on a spectrum: A sliding scale of peripheral B cell tolerance. 2019. PMID: 31631352


  8. Rosenthal DG, Parwani P, Murray TO, Petek BJ, Benn BS, De Marco T, Gerstenfeld EP, Janmohamed M, Klein L, Lee BK, Moss JD, Scheinman MM, Hsia HH, Selby V, Koth LL, Pampaloni MH, Zikherman J, Vedantham V. Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis. 2019. PMID: 31538835


  9. Ashouri JF, Hsu LY, Yu S, Rychkov D, Chen Y, Cheng DA, Sirota M, Hansen E, Lattanza L, Zikherman J, Weiss A. Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis. 2019. PMID: 31455730


  10. Noviski M, Tan C, Huizar J, Vykunta V, Mueller JL, Zikherman J. Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens. 2019. PMID: 31167773


  11. Zikherman J. GC B cells 'AKT' to blunt BCR signaling. 2019. PMID: 31011188


  12. Tan C, Mueller JL, Noviski M, Huizar J, Lau D, Dubinin A, Molofsky A, Wilson PC, Zikherman J. Nur77 Links Chronic Antigen Stimulation to B Cell Tolerance by Restricting the Survival of Self-Reactive B Cells in the Periphery. 2019. PMID: 30962292


  13. Noviski M, Mueller JL, Satterthwaite A, Garrett-Sinha LA, Brombacher F, Zikherman J. IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate. Volume 7. 2018. PMID: 29521626


  14. Huizar J, Tan C, Noviski M, Mueller JL, Zikherman J. Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells. Volume 1 of Issue 9. 2017. PMID: 29152611


  15. Zikherman J, Lowell CA. B cell autoimmunity at the extremes. Volume 18 of Issue 10. 2017. PMID: 28926534


  16. Myers DR, Zikherman J, Roose JP. Tonic Signals: Why Do Lymphocytes Bother? Volume 38 of Issue 11. 2017. PMID: 28754596


  17. Myers DR, Lau T, Markegard E, Lim HW, Kasler H, Zhu M, Barczak A, Huizar JP, Zikherman J, Erle DJ, Zhang W, Verdin E, Roose JP. Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells. Volume 19 of Issue 8. 2017. PMID: 28538176


  18. Au-Yeung BB, Smith GA, Mueller JL, Heyn CS, Jaszczak RG, Weiss A, Zikherman J. IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level. Volume 198 of Issue 6. 2017. PMID: 28159902


  19. Coughlin S, Noviski M, Mueller JL, Chuwonpad A, Raschke WC, Weiss A, Zikherman J. An extracatalytic function of CD45 in B cells is mediated by CD22. Volume 112 of Issue 47. 2015. PMID: 26561584


  20. Mills RE, Lam VC, Tan A, Cresalia N, Oksenberg N, Zikherman J, Anderson M, Weiss A, Hermiston ML. Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production. Volume 194 of Issue 8. 2015. PMID: 25769918


  21. Mueller J, Matloubian M, Zikherman J. Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center. Volume 194 of Issue 7. 2015. PMID: 25725108


  22. Zikherman J, Au-Yeung B. The role of T cell receptor signaling thresholds in guiding T cell fate decisions. Volume 33. 2015. PMID: 25660212


  23. Au-Yeung BB, Zikherman J, Mueller JL, Ashouri JF, Matloubian M, Cheng DA, Chen Y, Shokat KM, Weiss A. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation. Volume 111 of Issue 35. 2014. PMID: 25136127


  24. Au-Yeung BB, Melichar HJ, Ross JO, Cheng DA, Zikherman J, Shokat KM, Robey EA, Weiss A. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Volume 15 of Issue 7. 2014. PMID: 24908390


  25. Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP. Protein kinase Cd promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance. Volume 34 of Issue 8. 2014. PMID: 24515435


  26. Zikherman J, Parameswaran R, Hermiston M, Weiss A. The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity. Volume 190 of Issue 6. 2013. PMID: 23396948


  27. Mukherjee S, Zhu J, Zikherman J, Parameswaran R, Kadlecek TA, Wang Q, Au-Yeung B, Ploegh H, Kuriyan J, Das J, Weiss A. Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases. Volume 6 of Issue 256. 2013. PMID: 23281368


  28. Zikherman J, Parameswaran R, Weiss A. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Volume 489 of Issue 7414. 2012. PMID: 22902503


  29. Zikherman J, Doan K, Parameswaran R, Raschke W, Weiss A. Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival. Volume 109 of Issue 1. 2011. PMID: 22135465


  30. Zikherman J, Jenne C, Watson S, Doan K, Raschke W, Goodnow CC, Weiss A. CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development. Volume 32 of Issue 3. 2010. PMID: 20346773


  31. Chakraborty AK, Das J, Zikherman J, Yang M, Govern CC, Ho M, Weiss A, Roose J. Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes. Volume 2 of Issue 66. 2009. PMID: 19366993


  32. Zikherman J, Hermiston M, Steiner D, Hasegawa K, Chan A, Weiss A. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background. Volume 182 of Issue 7. 2009. PMID: 19299707


  33. Hermiston ML, Zikherman J, Zhu JW. CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells. Volume 228 of Issue 1. 2009. PMID: 19290935


  34. Zikherman J, Weiss A. Antigen receptor signaling in the rheumatic diseases. Volume 11 of Issue 1. 2009. PMID: 19232064


  35. Das J, Ho M, Zikherman J, Govern C, Yang M, Weiss A, Chakraborty AK, Roose JP. Digital signaling and hysteresis characterize ras activation in lymphoid cells. Volume 136 of Issue 2. 2009. PMID: 19167334


  36. Hermiston ML, Zikherman J, Tan AL, Lam VC, Cresalia NM, Oksenberg N, Goren N, Brassat D, Oksenberg JR, Weiss A. Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses. Volume 106 of Issue 2. 2009. PMID: 19129486


  37. Zikherman J, Weiss A. Alternative splicing of CD45: the tip of the iceberg. Volume 29 of Issue 6. 2008. PMID: 19100695


  38. Prasad A, Zikherman J, Das J, Roose JP, Weiss A, Chakraborty AK. Origin of the sharp boundary that discriminates positive and negative selection of thymocytes. Volume 106 of Issue 2. 2008. PMID: 19098101