Emory University School of Medicine
Emory University School of Medicine
Department of Medicine

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Department of Medicine

Lowance Center Research

The main research interest in the Ignacio Sanz Lowance Center laboratory is to investigate how the immune system goes awry in autoimmune diseases, with a particular emphasis on the roles of B cells in the pathogenesis of systemic lupus erythematosus (SLE). 

Efforts in the lab focus on getting an in-depth knowledge of the diversity, function and regulation of human B cells, which is fundamental to the understanding of autoimmune diseases.  The ultimate goal is to be able to apply this knowledge to the identification of new targets and the development of more effective strategies in B-cell directed therapy for autoimmune diseases.

Recognizing the importance of properly identifying the diverse B cell subsets in studying their function and regulation, we have undertaken a comprehensive B cell phenotyping approach using polychromatic flow cytometry.  With this approach, we are able to not only recognize the disturbances of B cell homeostasis in a number of human diseases but also identify several novel B cell and plasma cell subsets that are dysregulated in disease

Over the last few years, we have incorporated several cutting-edge technologies to advance our research inquiries.  For example, Next Gen Sequencing (NGS) enables us to scrutinize the diversity and clonal make-up of the antibody repertoire expressed by sorted B cell populations.  Of particular interest is to understand the origin and composition of circulating plasmablasts in SLE during acute flares, since SLE is a prototypic autoantibody-mediated disease in which disease exacerbations are characterized by profound ASC abnormality.  Interrogations of the repertoire and clonal relationship between plasmablasts and other B cell subsets in the circulation as well as resident bone marrow plasma cells in a temporal fashion will allow us to elucidate the origin, diversification, and maturation of the B cell response in a chronic, systemic autoimmune setting.  In addition to exogenous factors that have been shown to cause B cell dysregulation in SLE, it is postulated that altered epigenetic programming of autoreactive B cells causes their activation and recruitment to the effector compartment, resulting in autoantibody production and disease pathogenesis.  This hypothesis is currently being addressed in collaboration with Jerry Boss’ lab first by searching for key genes involved in the aberrant activation of B cell subsets in SLE through global epigenetic profiling and transcriptional profiling analyses using MeDIP-Seq and RNA-Seq, respectively. 

Studies of the initial breakdown of tolerance and the subsequent expansion of pathogenic B cells are hampered by challenges in the identification of disease-specific autoreactive B cells in SLE.  To circumvent these limitations, my lab has employed a subset of B cells that is recognized by an anti-idiotype 9G4 antibody.  Given their autoreactivity against multiple lupus antigens and the shared expression of VH4-34 gene, the study of 9G4+ cells represents a highly informative experimental model to understand the breakdown of B cell tolerance in SLE.  In healthy subjects, effective tolerance ensures that 9G4 responses are restricted to acute infections with Mycoplasma and EBV, and that they do not persist in the long-lived IgG memory and plasma cell compartments.  In contrast, we have shown that 9G4+ B cells are substantially expanded in these compartments in SLE owing to defective germinal center censoring that is unique to SLE among the autoimmune diseases.  The 9G4 model is also instrumental in identifying the autoreactivity at a clonal level.  Conventionally, this has to rely on the reconstruction of individual recombinant monoclonal antibodies from sorted single cells, which is a time-consuming and expensive process.  We have collaborated with Dr. Georgiou’s group (UT Austin) to incorporate his large throughput technologies for the interrogation of >100,000 single cells/sample using microfluidics and emulsion-based PCR for the amplification of linked VH and VL genes and the generation of selected monoclonal antibodies.  These approaches will enable the identification of autoantigens and investigation of their relative roles in the initiation of tolerance breakdown and selection of pathogenic B cells that culminate in disease manifestation.



Publications

For a more complete list of publications please visit PubMed

  1. Sanz. I. Pharmacological Effects and Mechanisms of Action of Agents Blocking B cells. In: Bosch X, Ramos-Casals M, Khamashta MA (eds). Drugs Targeting B-cells in Autoimmune Diseases. Springer: Basel, 2014, pp 37-65.
  2. Sanz I. Rationale for B cell targeting in SLE. Semin Immunopathol 2014, 36(3):365-375.
  3. Sanz I, Yasothan U, Kirkpatrick P. Belimumab. Nat Rev Drug Discov 2011, 10(5):335-336.
  4. Sanz I. Connective tissue diseases: Targeting B cells in SLE: good news at last! Nat Rev Rheumatol 2011, 7(5): 255-256.
  5. Sanz I, Lee FE. B cells as therapeutic targets in SLE. Nat Rev Rheumatol 2010,6(6): 326-337.
  6. John Looney R, Anolik J, Sanz I. A perspective on B-cell-targeting therapy for SLE.Modern Rheumatology 2010, 20(1): 1-10.
  7. Manjarrez-Orduno N, Quach TD, Sanz I. B Cells and Immunological Tolerance. J Invest Dermatol 2009, 129(2): 278-288.
  8. Sanz I, Anolik JH, Looney RJ. B cell depletion therapy in autoimmune diseases.Front Biosci 2007, 12: 2546-2567
  9. Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, Sloand J, Rosenblatt J, Sanz I. B cell depletion as a novel treatment for systemic lupus erythematosus: A phase I/II dose-escalation trial of rituximab. Arthritis & Rheumatism 2004, 50(8): 2580-2589.
  10. Looney RJ, Anolik J, Sanz I. B cells as therapeutic targets for rheumatic diseases. Curr Opin Rheumatol 2004, 16(3): 180-185.
  11. Anolik JH, Barnard J, Cappione A, Pugh-Bernard A, Felgar RE, Looney RJ, Sanz I. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis & Rheumatism 2004, 50(11): 3580-3590.
  12. Anolik J, Sanz I. B cells in human and murine systemic lupus erythematosus. Curr Opin Rheumatol 2004, 16(5): 505-512.
  13. Anolik JH, Campbell D, Felgar RE, Young F, Sanz I, Rosenblatt J, Looney RJ. The relationship of FcgammaRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum 2003, 48(2): 455-459.
  14. Roberts MEP, Kaminski D, Jenks SA, Maguire C, Ching K, Burbelo PD, Iadarola M, Rosenberg A, Coca A, Anolik J, Sanz I. Primary Sjögren's Syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory cells. Arthritis & Rheumatology 2014: n/a-n/a.
  15. Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Frontiers in immunology 2012, 3: 302.
  16. Kaminski D, Wei C, Rosenberg A, Lee FE-H, Sanz I. Multiparameter Flow Cytometry and Bioanalytics for B Cell Profiling in Systemic Lupus Erythematosus. In: Perl A (ed). Autoimmunity, vol. 900. Humana Press, 2012, pp 109-134.
  17. Barr PM, Wei C, Roger J, Schaefer-Cutillo J, Kelly JL, Rosenberg AF, Jung J, Sanz I, Friedberg JW. Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion.Clinical Immunology 2012, 142(3): 237-242.
  18. Wei C, Jung J, Sanz I. OMIP-003: Phenotypic analysis of human memory B cells. Cytometry Part A 2011: n/a-n/a.
  19. Quách TD, Manjarrez-Orduño N, Adlowitz DG, Silver L, Yang H, Wei C, Milner ECB, Sanz I. Anergic Responses Characterize a Large Fraction of Human Autoreactive Naive B Cells Expressing Low Levels of Surface IgM. The Journal of Immunology 2011, 186(8):4640-4648.
  20. Qian Y, Wei C, Eun-Hyung Lee F, Campbell J, Halliley J, Lee JA, Cai J, Kong YM, Sadat E, Thomson E, Dunn P, Seegmiller AC, Karandikar NJ, Tipton CM, Mosmann T, Sanz I, Scheuermann RH. Elucidation of seventeen human peripheral blood B-cell subsets and quantification of the tetanus response using a density-based method for the automated identification of cell populations in multidimensional flow cytometry data. Cytometry Part B: Clinical Cytometry 2010, 78B(S1): S69-S82.
  21. Newell KA, Asare A, Kirk AD, Gisler TD, Bourcier K, Suthanthiran M, Burlingham WJ, Marks WH, Sanz I, Lechler RI, Hernandez-Fuentes MP, Turka LA, Seyfert-Margolis VL. Identification of a B cell signature associated with renal transplant tolerance in humans. The Journal of Clinical Investigation 2010, 120(6): 1836-1847.
  22. Palanichamy A, Barnard J, Zheng B, Owen T, Quach T, Wei C, Looney RJ, Sanz I, Anolik JH. Novel human transitional B cell populations revealed by B cell depletion therapy. J Immunol 2009, 182(10): 5982-5993.
  23. Wei C, Anolik J, Cappione A, Zheng B, Pugh-Bernard A, Brooks J, Lee EH, Milner EC, Sanz I. A new population of cells lacking expression of CD27 represents a notable component of the B cell memory compartment in systemic lupus erythematosus. J Immunol 2007, 178(10): 6624-6633
  24. Richardson C, Chida AS, Adlowitz D, Silver L, Fox E, Jenks SA, Palmer E, Wang Y, Heimburg-Molinaro J, Li QZ, Mohan C, Cummings R, Tipton C, Sanz I. Molecular basis of 9G4 B cell autoreactivity in human systemic lupus erythematosus. J Immunol 2013,191(10): 4926-4939.
  25. Pugh-Bernard AE, Silverman GJ, Cappione AJ, Villano ME, Ryan DH, Insel RA, Sanz I. Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J Clin Invest 2001, 108(7): 1061-1070.
  26. Cappione AJ, Pugh-Bernard, A. E., Sanz, I. Lupus VH4.34-Encoded Antibodies Bind to a B220-Specific Glycoform of CD45 on the Surface of Human B Lymphocytes. Arthritis & Rheumatism 2002, 46(9): S222-S223.
  27. Cappione AJ, Pugh-Bernard AE, Anolik JH, Sanz I. Lupus IgG VH4.34 antibodies bind to a 220-kDa glycoform of CD45/B220 on the surface of human B lymphocytes. J Immunol 2004, 172(7): 4298-4307.
  28. Cappione A, 3rd, Anolik JH, Pugh-Bernard A, Barnard J, Dutcher P, Silverman G, Sanz I. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest 2005, 115(11): 3205-3216.
  29. Milner EC, Anolik J, Cappione A, Sanz I. Human innate B cells: a link between host defense and autoimmunity? Springer Semin Immunopathol 2005, 26(4): 433-452.
  30. Kobie JJ, Alcena DC, Zheng B, Bryk P, Mattiacio JL, Brewer M, LaBranche C, Young FM, Dewhurst S, Montefiori DC, Rosenberg AF, Feng C, Jin X, Keefer MC, Sanz I. 9G4 Autoreactivity Is Increased in HIV-Infected Patients and Correlates with HIV Broadly Neutralizing Serum Activity. PLoS ONE 2012, 7(4): e35356.
  31. Alcena DC, Kobie JJ, Kaminski DA, Rosenberg AF, Mattiacio JL, Brewer M, Dewhurst S, Dykes C, Jin X, Keefer MC, Sanz I. 9G4+ antibodies isolated from HIV-infected patients neutralize HIV-1 and have distinct autoreactivity profiles. PLoS One 2013, 8(12):e85098.
  32. Jenks SA, Palmer EM, Marin EY, Hartson L, Chida AS, Richardson C, Sanz I. 9G4+ Autoantibodies Are an Important Source of Apoptotic Cell Reactivity Associated With High Levels of Disease Activity in Systemic Lupus Erythematosus. Arthritis & Rheumatism 2013,65(12): 3165-3175.