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. NR4A nuclear receptors restrain B cell responses to antigen when second signals are absent or limiting.
  2. Synthetic liposomal mimics of biological viruses for the study of immune responses to infection and vaccination.
  3. Self-reactivity on a spectrum: A sliding scale of peripheral B cell tolerance.
  4. Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.
  5. Reporters of TCR signaling identify arthritogenic T cells in murine and human autoimmune arthritis.
  6. Optimal Development of Mature B Cells Requires Recognition of Endogenous Antigens.
  7. GC B cells 'AKT' to blunt BCR signaling.
  8. Nur77 Links Chronic Antigen Stimulation to B Cell Tolerance by Restricting the Survival of Self-Reactive B Cells in the Periphery.
  9. Control of autoreactive B cells by IgM and IgD B cell receptors: maintaining a fine balance.
  10. IgM and IgD B cell receptors differentially respond to endogenous antigens and control B cell fate.
  11. Nur77 Is Upregulated in B-1a Cells by Chronic Self-Antigen Stimulation and Limits Generation of Natural IgM Plasma Cells.
  12. B cell autoimmunity at the extremes.
  13. Tonic Signals: Why Do Lymphocytes Bother?
  14. Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells.
  15. IL-2 Modulates the TCR Signaling Threshold for CD8 but Not CD4 T Cell Proliferation on a Single-Cell Level.
  16. An extracatalytic function of CD45 in B cells is mediated by CD22.
  17. Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production.
  18. Cutting edge: An in vivo reporter reveals active B cell receptor signaling in the germinal center.
  19. The role of T cell receptor signaling thresholds in guiding T cell fate decisions.
  20. A sharp T-cell antigen receptor signaling threshold for T-cell proliferation.
  21. Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development.
  22. Protein kinase Cd promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance.
  23. Novel tools to dissect the dynamic regulation of TCR signaling by the kinase Csk and the phosphatase CD45.
  24. The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity.
  25. Monovalent and multivalent ligation of the B cell receptor exhibit differential dependence upon Syk and Src family kinases.
  26. Endogenous antigen tunes the responsiveness of naive B cells but not T cells.
  27. Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival.
  28. Unraveling the functional implications of GWAS: how T cell protein tyrosine phosphatase drives autoimmune disease.
  29. CD45-Csk phosphatase-kinase titration uncouples basal and inducible T cell receptor signaling during thymic development.
  30. Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes.
  31. PTPN22 deficiency cooperates with the CD45 E613R allele to break tolerance on a non-autoimmune background.
  32. CD45, CD148, and Lyp/Pep: critical phosphatases regulating Src family kinase signaling networks in immune cells.
  33. Antigen receptor signaling in the rheumatic diseases.
  34. Digital signaling and hysteresis characterize ras activation in lymphoid cells.
  35. Differential impact of the CD45 juxtamembrane wedge on central and peripheral T cell receptor responses.
  36. Alternative splicing of CD45: the tip of the iceberg.
  37. Origin of the sharp boundary that discriminates positive and negative selection of thymocytes.