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Julie Zikherman
M_MED-RHEU-CORE
Associate Professor

513 Parnassus Ave
San Francisco, CA 94143
415-476-1689

Our laboratory is interested in understanding how autoreactive B cells, despite chronic antigen engagement of the B cell receptor, are restrained from inappropriate activation and differentiation. We are interested in how this process is disrupted in autoimmune disease, and how tolerance mechanisms can be harnessed to treat autoimmunity. To do so, we are taking advantage of novel reporter mice in which autoreactive B cells are fluorescently marked (Nur77-eGFP BAC transgenic line). Current funded projects include dissecting the distinct roles of the IgM and IgD B cell receptor isotypes in regulating immune responses by autoreactive B cells. More recent work is focused on defining how Nur77 and related orphan nuclear hormone receptors function selectively to restrain activation of chronically antigen-activated B cells.

Related Web Sites

Recent Articles (27)

  1. 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. Immunohorizons. 2017 Nov 01; 1(9):188-197.

  2. Zikherman J, Lowell CA. B cell autoimmunity at the extremes. Nat Immunol. 2017 Sep 19; 18(10):1065-1066.

  3. Myers DR, Zikherman J, Roose JP. Tonic Signals: Why Do Lymphocytes Bother? Trends Immunol. 2017 Jul 25.

  4. 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. Cell Rep. 2017 May 23; 19(8):1558-1571.

  5. 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. J Immunol. 2017 Mar 15; 198(6):2445-2456.

  6. 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. Proc Natl Acad Sci U S A. 2015 Nov 24; 112(47):E6515-24.

  7. 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. J Immunol. 2015 Apr 15; 194(8):3675-86.

  8. Mueller J, Matloubian M, Zikherman J. Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center. J Immunol. 2015 Apr 01; 194(7):2993-7.

  9. Zikherman J, Au-Yeung B. The role of T cell receptor signaling thresholds in guiding T cell fate decisions. Curr Opin Immunol. 2015 Apr; 33:43-8.

  10. 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. Proc Natl Acad Sci U S A. 2014 Sep 02; 111(35):E3679-88.

  11. 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. Nat Immunol. 2014 Jul; 15(7):687-94.

  12. 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. Mol Cell Biol. 2014 Apr; 34(8):1474-85.

  13. Tan YX, Zikherman J, Weiss A. Novel tools to dissect the dynamic regulation of TCR signaling by the kinase Csk and the phosphatase CD45. Cold Spring Harb Symp Quant Biol. 2013; 78:131-139.

  14. 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. J Immunol. 2013 Mar 15; 190(6):2527-35.

  15. 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. Sci Signal. 2013 Jan 01; 6(256):ra1.

  16. Zikherman J, Parameswaran R, Weiss A. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature. 2012 Sep 06; 489(7414):160-4.

  17. 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. Proc Natl Acad Sci U S A. 2012 Jan 03; 109(1):E3-12.

  18. Zikherman J, Weiss A. Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease. J Clin Invest. 2011 Dec; 121(12):4618-21.

  19. 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. Immunity. 2010 Mar 26; 32(3):342-54.

  20. 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. Sci Signal. 2009 Apr 14; 2(66):pt2.

  21. 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. J Immunol. 2009 Apr 01; 182(7):4093-106.

  22. Hermiston ML, Zikherman J, Zhu JW. CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells. Immunol Rev. 2009 Mar; 228(1):288-311.

  23. Zikherman J, Weiss A. Antigen receptor signaling in the rheumatic diseases. Arthritis Res Ther. 2009; 11(1):202.

  24. 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. Cell. 2009 Jan 23; 136(2):337-51.

  25. 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. Proc Natl Acad Sci U S A. 2009 Jan 13; 106(2):546-51.

  26. 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. Proc Natl Acad Sci U S A. 2009 Jan 13; 106(2):528-33.

  27. Zikherman J, Weiss A. Alternative splicing of CD45: the tip of the iceberg. Immunity. 2008 Dec 19; 29(6):839-41.

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