Julie Zikherman, MD

Professor

Division of Rheumatology

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.

Publications

  1. Wholey WY, Meyer AR, Yoda ST, Chackerian B, Zikherman J, Cheng W. Mechanisms of neutralizing antibody response probed using synthetic virus-like structures. bioRxiv : the preprint server for biology 2023. PMID: 36865112


  2. Wholey WY, Meyer AR, Yoda ST, Mueller JL, Mathenge R, Chackerian B, Zikherman J, Cheng W. An integrated signaling threshold initiates IgG response towards virus-like immunogens. bioRxiv : the preprint server for biology 2024. PMID: 38469153


  3. Rackaityte E, Proekt I, Miller HS, Ramesh A, Brooks JF, Kung AF, Mandel-Brehm C, Yu DJ, Zamecnik CR, Bair R, Vazquez SE, Sunshine S, Abram CL, Lowell CA, Rizzuto G, Wilson MR, Zikherman J, Anderson MS, DeRisi JL. Validation of a murine proteome-wide phage display library for identification of autoantibody specificities. JCI insight 2023. PMID: 37934865


  4. Brooks JF, Riggs J, Mueller JL, Mathenge R, Wholey WY, Meyer AR, Yoda ST, Vykunta VS, Nielsen HV, Cheng W, Zikherman J. Molecular basis for potent B cell responses to antigen displayed on particles of viral size. Nature immunology 2023. PMID: 37653247


  5. Bending D, Zikherman J. Nr4a nuclear receptors: markers and modulators of antigen receptor signaling. Current opinion in immunology 2023. PMID: 36764055


  6. Pelanda R, Zikherman J. Many Achilles' heels of B and T cell tolerance. TO REMOVE 2022. PMID: 35301733


  7. Rizzuto G, Brooks JF, Tuomivaara ST, McIntyre TI, Ma S, Rideaux D, Zikherman J, Fisher SJ, Erlebacher A. Establishment of fetomaternal tolerance through glycan-mediated B cell suppression. TO REMOVE 2022. PMID: 35236989


  8. Hiwa R, Brooks JF, Mueller JL, Nielsen HV, Zikherman J. NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance. TO REMOVE 2022. PMID: 35174510


  9. Cautivo KM, Matatia PR, Lizama CO, Mroz NM, Dahlgren MW, Yu X, Sbierski-Kind J, Taruselli MT, Brooks JF, Wade-Vallance A, Caryotakis SE, Chang AA, Liang HE, Zikherman J, Locksley RM, Molofsky AB. Interferon gamma constrains type 2 lymphocyte niche boundaries during mixed inflammation. TO REMOVE 2022. PMID: 35139352


  10. 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. Nature chemical biology 2021. PMID: 34556859


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


  12. 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. TO REMOVE 2021. PMID: 34469720


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


  14. 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. Nature immunology 2020. PMID: 32868928


  15. 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. Bioconjugate chemistry 2020. PMID: 31940172


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


  17. 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. Journal of the American Heart Association 2019. PMID: 31538835


  18. 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. Proceedings of the National Academy of Sciences of the United States of America 2019. PMID: 31455730


  19. Noviski M, Tan C, Huizar J, Vykunta V, Mueller JL, Zikherman J. Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens. Journal of immunology (Baltimore, Md. : 1950) 2019. PMID: 31167773


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


  21. 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. Journal of immunology (Baltimore, Md. : 1950) 2019. PMID: 30962292


  22. Noviski M, Zikherman J. Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance. Current opinion in immunology 2018. PMID: 30292928


  23. 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. eLife 2018. PMID: 29521626


  24. 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. ImmunoHorizons 2017. PMID: 29152611


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


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


  27. 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. Cell reports 2017. PMID: 28538176


  28. 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. Journal of immunology (Baltimore, Md. : 1950) 2017. PMID: 28159902


  29. 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. Proceedings of the National Academy of Sciences of the United States of America 2015. PMID: 26561584


  30. 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. Journal of immunology (Baltimore, Md. : 1950) 2015. PMID: 25769918


  31. 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. Journal of immunology (Baltimore, Md. : 1950) 2015. PMID: 25725108


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


  33. 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. Proceedings of the National Academy of Sciences of the United States of America 2014. PMID: 25136127


  34. 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. Nature immunology 2014. PMID: 24908390


  35. 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. Molecular and cellular biology 2014. PMID: 24515435


  36. Tan YX, Zikherman J, Weiss A. Novel tools to dissect the dynamic regulation of TCR signaling by the kinase Csk and the phosphatase CD45. Volume 78. Cold Spring Harbor symposia on quantitative biology 2013. PMID: 24100586


  37. 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. Journal of immunology (Baltimore, Md. : 1950) 2013. PMID: 23396948


  38. 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. Science signaling 2013. PMID: 23281368


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


  40. 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. Proceedings of the National Academy of Sciences of the United States of America 2011. PMID: 22135465


  41. Zikherman J, Weiss A. Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease. Volume 121 of Issue 12. The Journal of clinical investigation 2011. PMID: 22080861


  42. 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. Immunity 2010. PMID: 20346773


  43. 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. Science signaling 2009. PMID: 19366993


  44. 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. Journal of immunology (Baltimore, Md. : 1950) 2009. PMID: 19299707


  45. 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. Immunological reviews 2009. PMID: 19290935


  46. Zikherman J, Weiss A. Antigen receptor signaling in the rheumatic diseases. Volume 11 of Issue 1. Arthritis research & therapy 2009. PMID: 19232064


  47. 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. Cell 2009. PMID: 19167334


  48. 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. Proceedings of the National Academy of Sciences of the United States of America 2009. PMID: 19129486


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


  50. 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. Proceedings of the National Academy of Sciences of the United States of America 2008. PMID: 19098101