Selective Dysregulation of an Fcy Receptor on Activated B Cells in SLE

Betty Diamond, M.D.

Feinstein Institute for Medical Research

Funded in January, 2005: $300000 for 3 years


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Are African-Americans at an Increased Genetic Risk for Developing Autoimmune Lupus?

Consortium researchers will study whether autoimmune lupus is associated with a genetically determined failure to regulate certain immune cells and whether this condition is more prevalent in African-Americans than other population groups.

Lupus is an inflammatory autoimmune disease affecting organs, joints, skin, and the brain. Immune cells mistake components of the body's cells as foreign and attack them. Initial studies of lupus patients' cells suggest that a certain receptor on immune B cells fails to curtail errant B-cell attacks on the body's tissues. Since this receptor ("FcRIIB") is also located on dendritic cells, which summon immune B cells to attack, regulatory dysfunction of dendritic cells also may contribute to the disease.

In previous studies, B cells in 30 of 60 lupus patients were found to have low receptor levels when the B cells were developing the capacity to attack. This situation occurred disproportionately in African-American study participants. In immune cells from a more ethnically diverse patient group, investigators will study this receptor throughout B cell development, and look for alterations in the gene that directs the receptor's production. Researchers will see whether low receptor levels produce, or are a consequence of, dysfunctional dendritic and B cell regulation, in cells of lupus patients receiving "autologous" (own body) stem cell transplantation. They then will try to increase receptors in stem cells that give rise to these immune cells, as a potential therapy.

Significance: A finding that genetically determined low receptor levels facilitate immune B cell attacks in lupus would spur potential genetic or stem cell therapy studies.


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Selective Dysregulation of an Fcy Receptor on Activated B Cells in SLE

FcRIIB is an inhibitory receptor that functions to diminish B cell and dendritic cell activation. It has been shown that increasing the level of FcRIIB expression on B cells in several murine models of systemic lupus can diminish disease activity. Examining a cohort of 62 lupus patients, we have demonstrated that in 50% of these patients FcRIIB expression fails to be upregulated as B cells mature from the nave to the memory stage. We have further shown that this is a feature of African-American patients, and appears to be unrelated to disease activity. We hypothesize that this alteration in FcRIIB regulation contributes significantly to disease expression and that FcRIIB may be a useful therapeutic target in lupus.

We now propose to examine a larger number of patients with lupus—Caucasian, Asian, African-American and Hispanic—to determine FcRIIB expression on transitional, nave, marginal zone, and memory B cells and on plasmablasts, as well as on peripheral blood dendritic cells. We will also determine whether there are polymorphisms of the gene encoding FcRIIB that regulate expression. We will determine the functional consequences of diminished FcRIIB expression on B cells and dendritic cells by analyzing FcRIIB signaling cascades in cells incubated with immune complexes and with DNA containing immune complexes. We will attempt to understand the factor(s) responsible for upregulating FcRIIB expression on normal memory cells and whether the same factors govern FcRIIB expression on dendritic cells.

Finally, we will analyze FcRIIB expression in lupus patients who are autoreconstituting dendritic cell and B cell populations following ablative therapy and autologous stem cell transplantation. This approach will demonstrate whether altered FcRIIB expression occurs only after disease expression is present only after disease expression or whether it pre-exists a disease phenotype. Finally, we will attempt in vitro to increase expression of FcRIIB in stem cells, as this approach might prevent recurrence of disease after stem cell therapy.


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Betty Diamond, M.D.

Betty Diamond received an M.D. from Harvard Medical School in 1973. She performed a residency in Internal Medicine at Columbia Presbyterian Medical Center, and then a post-doctoral fellowship in Immunology with Dr. Matthew Scharff at the Albert Einstein College of Medicine. She was on the faculty at Einstein from 1979 until September 2004, when she joined the faculty of Columbia University College of Physician & Surgeons as a Professor of Microbiology and Medicine and the Chief of the Division of Rheumatology. Dr. Diamond is currently Head of the Autoimmune Disease Center at the Feinstein Institute for Medical Research.

Dr Diamond's research has focused on the induction and pathogenicity of anti-DNA antibodies in Systemic Lupus Erythematosus. She received the Outstanding Investigator Award of the ACR in 2001 and the Lee Howley Award from the Arthritis Foundation in 2002. Recognition Award, National Association of M.D.-Ph.D. Programs in 2004. Dr. Diamond's primary interests are in the mechanisms of central and peripheral tolerance of autoreactive B cells, and the defects in these mechanisms that are present in autoimmune disease.

Her laboratory has been studying the regulation of DNA-reactive B cells. Dr. Diamond's laboratory has also developed a model of SLE induced by immunization with a peptide mimetope of DNA. Dr. Diamond continues to study anti-DNA antibodies from patients with SLE. These antibodies have been shown to have structural and genetic features in common with myeloma proteins. Finally, Dr. Diamond's laboratory has demonstrated that a subset of anti-DNA antibodies cross-reacts with the NMDA receptor. These studies show that lupus antibodies can cause aspects of neuropsychiatric lupus in a non-inflammatory fashion.

Jeffrey V. Ravetch, M.D., Ph.D., is currently the Theresa and Eugene Lang Professor at the Rockefeller University and has been Head of the Leonard Wagner Laboratory of Molecular Genetics and Immunology since 1996. Dr. Ravetch, a native of New York City, received his undergraduate training in molecular biophysics and biochemistry at Yale University, earning his B.S. degree in 1973, where he pursued research studies with Donald M. Crothers on the thermodynamic and kinetic properties of synthetic oligoribonucleotides. He continued his training at the Rockefeller University and Cornell Medical School M.D./Ph.D. program, earning his doctorate in 1978 in genetics with Norton Zinder and Peter Model by investigating the genetic basis for the regulation of viral replication and gene expression for the single stranded DNA bacteriophage f1. In 1979 Dr. Ravetch earned his M.D. from Cornell University Medical School. Following postdoctoral studies at the NIH with Phil Leder where he identified and characterized the genes for the human IgM antibody and the DNA elements involved in switch recombination, in 1982 he joined the faculty of Memorial Sloan-Kettering Cancer Center and Cornell Medical College.

Dr. Ravetch's laboratory cloned the first genes for Fc receptors, identified the SHIP inhibitory receptor signaling pathway and contributed significantly to understanding the mechanisms of antibody mediated effector responses, establishing the FcR pathways as fundamental components of the immune response. In addition to his studies on antibody receptors, Dr. Ravetch has made fundamental contributions to the genetics of the malaria parasite and, with the identification of the first cytokine, IP-10, established this class of molecules as novel mediators of inflammation. Additionally, Dr. Ravetch has contributed extensively to the scientific community by serving as a member of the Scientific Advisory Boards of the Cancer Research Institute, the Irvington Institute for Medical Research, and the Damon Runyon Foundation.


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Mackay M., Stanevsky A., Wang T., Aranow C., Li M., Koenig S., Ravetch J.V., and Diamond B.   Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE.  J Exp Med. 2006 Sep 4;203(9):2157-64.