Ignacio Sanz, MD
 |
Professor and Division Director, Division of Rheumatology, Department of Medicine, School of Medicine
Graduate Programs
- Full Member - Immunology and Molecular Pathogenesis
Education
MD, University of Santander Medical School, 1978Contact Information
Email: Ignacio.Sanz@emory.edu
Phone: 404-712-2945
Address:
Whitehead Biomedical Research Building, Room 248
615 Michael Street
Atlanta, GA 30322
1941-001-1AN
Human B cell heterogeneity and function; the basis of human B cell autoreactivity [1]:
We strive to understand the great degree of B cell heterogeneity that exists in healthy people and how abnormal B cell homeostasis can provide clues for the pathogenesis and treatment of different autoimmune diseases (including SLE, RA, Sjogren's Syndrome and Type 1 Diabetes) as well as a number of other important conditions where B cells are known to play major roles such as organ transplantation. We use an array of research tools to understand B cell phenotype and function. This immunological toolbox includes multicolor flow cytometry for the analysis and sorting of large as well as rare populations of B cells and plasma cells; new analytical tools for the supervised and automated analysis of the multidimensional data generated by multiparametric flow; bioinformatics and computational biology for the analysis of complex systems that integrate multidimensional flow –omics data and clinical and immunological parameters. More recently, we have also incorporated transcriptomics analysis of well-defined B cell subsets and in collaboration with the Boss' lab have also started to perform epigenetics analysis of these populations to understand their activation or silencing and the epigenetic and molecular roadmaps responsible for their functional properties. The study of specific populations in different autoimmune diseases and their analysis before and after treatment with biological agents that target well-defined activation and survival pathways allow us to dissect the nature of intrinsic and extrinsic abnormalities responsible for B cell malfunction in human disease
Human B-cell tolerance and autoimmunity [2]
We have shown that in SLE patients the germinal centers are defective in their ability to censor the maturation and selection of autoreactive B-cells. Currently, we are pursuing a multidisciplinary approach to understand the cellular and molecular bases that underlie the regulation of B-cell tolerance. Additional studies in this area include the identification of anergy B cells, the establishment of a transcriptional signature of anergy and the application of this signature as a biomarker of disease activity in SLE. As discussed above we also use transcriptome and epigenome approaches to understand the regulation of intrinsically autoreactive B cells that are specifically expanded in the germinal centers of patients with SLE thereby contributing a major pathogenic component of this disease. These cells, named 9G4 cells owing to the expression of the 9G4 idiotype, are intrinsically autoreactive and highly censored in healthy subjects but not in patients with SLE. This experimental model provides a unique opportunity to understand not only the functional and molecular properties of pathogenic autoreactive B cells but also to identify the triggering and selecting autoantigens involved in the initiation, amplification and maintenance of the autoimmune response. To accomplish the latter objectives, we have developed highly efficient methods to analyze the human B cell repertoire using high-throughput amplification and generation of monoclonal antibodies from single B cells. In addition we have developed all the experimental and computational tools required for the global analysis of the diversity and molecular properties of the human B cell repertoire using Next Generation sequencing.
Innovative approaches to the study and treatment of autoimmune diseases [3]
Our group is one of the pioneers in the use of in vivo B-cell depletion (using the anti-CD20 monoclonal antibody Rituximab) or modulation (using multiple other anti-B cell and anti-cytokine agents) for the therapy of autoimmune diseases. Our studies indicate that B-cell depletion may offer the immune system a second chance to re-establish B-cell tolerance and therefore hold promise for the long-term treatment and prevention of autoimmune diseases. Our goals are to: i) understand the clinical benefit of B cell depletion-modulation therapy in different autoimmune diseases; ii) understand the immunological basis of the clinical benefit (or lack thereof); iii) elucidate whether immunological tolerance is restored by B cell therapies; iv) understand the actual roles played by B cells in health and disease; v) explore the impact of B cell therapies on other arms of the immune system (lymphoid organization, T cells and DC).
In addition to the lab efforts in this area, Emory is now one of only seven national Autoimmunity Centers of Excellence (ACE) funded by the NIH. Dr. Sanz is the ACE Center Director. The Emory ACE center (also integrated by Drs. Boss and Jacobs) focuses on the analysis of B cells, T cells and plasma cells in SLE and will collaborate with other ACE centers to study other immune cells and other autoimmune diseases through an integration of both basic and clinical studies.
B cells in HIV [4]
Breakdown of B cell tolerance and recruitment of autoreactive B cells in the anti-viral response appears to be critical for the ability of persons living with HIV to mount broadly neutralizing anti-HIV antibody responses. Based on our interest in B cell autoreactivity and tolerance, we have been funded by the NIH to study 9G4 and other autoreactive B cells in the HIV response. WE have already shown that these autoantibodies, typically seen expanded in SLE, can also be increased and correlate with anti-HIV neutralization. Our efforts are currently aimed at elucidating the type of autoreactivity responsible for the viral neutralization responses and identifying the mechanisms preventing the selection of such autoreactivities in most patients and in vaccination responses.
We strive to understand the great degree of B cell heterogeneity that exists in healthy people and how abnormal B cell homeostasis can provide clues for the pathogenesis and treatment of different autoimmune diseases (including SLE, RA, Sjogren's Syndrome and Type 1 Diabetes) as well as a number of other important conditions where B cells are known to play major roles such as organ transplantation. We use an array of research tools to understand B cell phenotype and function. This immunological toolbox includes multicolor flow cytometry for the analysis and sorting of large as well as rare populations of B cells and plasma cells; new analytical tools for the supervised and automated analysis of the multidimensional data generated by multiparametric flow; bioinformatics and computational biology for the analysis of complex systems that integrate multidimensional flow –omics data and clinical and immunological parameters. More recently, we have also incorporated transcriptomics analysis of well-defined B cell subsets and in collaboration with the Boss' lab have also started to perform epigenetics analysis of these populations to understand their activation or silencing and the epigenetic and molecular roadmaps responsible for their functional properties. The study of specific populations in different autoimmune diseases and their analysis before and after treatment with biological agents that target well-defined activation and survival pathways allow us to dissect the nature of intrinsic and extrinsic abnormalities responsible for B cell malfunction in human disease
Human B-cell tolerance and autoimmunity [2]
We have shown that in SLE patients the germinal centers are defective in their ability to censor the maturation and selection of autoreactive B-cells. Currently, we are pursuing a multidisciplinary approach to understand the cellular and molecular bases that underlie the regulation of B-cell tolerance. Additional studies in this area include the identification of anergy B cells, the establishment of a transcriptional signature of anergy and the application of this signature as a biomarker of disease activity in SLE. As discussed above we also use transcriptome and epigenome approaches to understand the regulation of intrinsically autoreactive B cells that are specifically expanded in the germinal centers of patients with SLE thereby contributing a major pathogenic component of this disease. These cells, named 9G4 cells owing to the expression of the 9G4 idiotype, are intrinsically autoreactive and highly censored in healthy subjects but not in patients with SLE. This experimental model provides a unique opportunity to understand not only the functional and molecular properties of pathogenic autoreactive B cells but also to identify the triggering and selecting autoantigens involved in the initiation, amplification and maintenance of the autoimmune response. To accomplish the latter objectives, we have developed highly efficient methods to analyze the human B cell repertoire using high-throughput amplification and generation of monoclonal antibodies from single B cells. In addition we have developed all the experimental and computational tools required for the global analysis of the diversity and molecular properties of the human B cell repertoire using Next Generation sequencing.
Innovative approaches to the study and treatment of autoimmune diseases [3]
Our group is one of the pioneers in the use of in vivo B-cell depletion (using the anti-CD20 monoclonal antibody Rituximab) or modulation (using multiple other anti-B cell and anti-cytokine agents) for the therapy of autoimmune diseases. Our studies indicate that B-cell depletion may offer the immune system a second chance to re-establish B-cell tolerance and therefore hold promise for the long-term treatment and prevention of autoimmune diseases. Our goals are to: i) understand the clinical benefit of B cell depletion-modulation therapy in different autoimmune diseases; ii) understand the immunological basis of the clinical benefit (or lack thereof); iii) elucidate whether immunological tolerance is restored by B cell therapies; iv) understand the actual roles played by B cells in health and disease; v) explore the impact of B cell therapies on other arms of the immune system (lymphoid organization, T cells and DC).
In addition to the lab efforts in this area, Emory is now one of only seven national Autoimmunity Centers of Excellence (ACE) funded by the NIH. Dr. Sanz is the ACE Center Director. The Emory ACE center (also integrated by Drs. Boss and Jacobs) focuses on the analysis of B cells, T cells and plasma cells in SLE and will collaborate with other ACE centers to study other immune cells and other autoimmune diseases through an integration of both basic and clinical studies.
B cells in HIV [4]
Breakdown of B cell tolerance and recruitment of autoreactive B cells in the anti-viral response appears to be critical for the ability of persons living with HIV to mount broadly neutralizing anti-HIV antibody responses. Based on our interest in B cell autoreactivity and tolerance, we have been funded by the NIH to study 9G4 and other autoreactive B cells in the HIV response. WE have already shown that these autoantibodies, typically seen expanded in SLE, can also be increased and correlate with anti-HIV neutralization. Our efforts are currently aimed at elucidating the type of autoreactivity responsible for the viral neutralization responses and identifying the mechanisms preventing the selection of such autoreactivities in most patients and in vaccination responses.
