Disconnecting CR2/CD21 from Its C3d Ligand to Ameliorate Lupus

Summary

Principal Investigator: VERNON MICHAEL HOLERS
Abstract: DESCRIPTION (provided by applicant): Complement receptor type 2 (CR2/CD21) and its primary C3 activation fragment-derived ligand designated C3d play a central role in the development of high affinity antibodies to foreign antigens. The primary B cell receptors for antigen-bound C3 fragments in mice are CR2 and complement receptor type 1 (CR1/CD35). As opposed to humans, where unique genes encode these proteins, mouse CR2 and CR1 are derived through alternative splicing from a common gene designated Cr2. The larger CR1 protein is the primary receptor for the C3b form of C3 as well as antigen-bound C4b, while the smaller CR2 protein only binds C3d with a high affinity. High affinity autoantibodies and B lymphocytes play central roles in the immunopathogenesis of human systemic lupus erythematosus (SLE). In principle, given our current understanding of the immune basis for the development of SLE through subversion of normal tolerance checkpoints and development of autoreactive responses, one might expect a similar enhancing role as found with foreign antigens to be played by CR2 interactions with C3d-bound self-antigens in SLE. However, prior studies using gene-targeted Cr2-/- mice, which lack both CR2 and CR1, in murine models of SLE have not supported this presumption and have suggested that CR2, in addition to CR1, expression is necessary to maintain tolerance to lupus-related self- antigens. It is straightforward to understand how CR1 could play this role as a high affinity receptor for C4b, which is itself necessary to maintain tolerance to self-antigen in mice and humans. However, no similar experimentally supported role exists for CR2, and thus how expression of this particular receptor could be needed to protect from autoimmune disease development in SLE remains enigmatic. To address this question, we have overcome the technical challenges that exist in the murine CR2/CR1 receptor system by developing new highly specific mouse anti-mouse monoclonal antibodies (mAbs). The first is a non-B cell depleting mAb that recognizes and blocks only CR2/CD21 function without directly affecting CR1 interactions with C4b or C3b. The second mAb recognizes the C3d fragment at its receptor binding site and blocks its interaction with CR2 without affecting C3b or C4b interactions with CR1. With these newly developed tools and pursuing the following specific aims, we will for the first time be able to test the hypothesis that disruption of the critical C3d- CR2 ligand-receptor binding step alone will ameliorate, rather than enhance, autoimmunity and clinical disease in SLE: Specific Aim #1. Evaluate the effects of specific monoclonal antibody-mediated blockade of CR2/CD21 function on the evolution of autoimmunity and clinical outcomes in the MRL/lpr model of human lupus;and Specific Aim #2. Using a novel C3d-specific monoclonal antibody to interrupt the interaction by C3d-bearing autoantigen complexes with CR2/CD21, characterize the ameliorative effects of this strategy on the evolution of autoimmunity and clinical outcomes in the MRL/lpr model.
Funding Period: 2013-02-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Complement and its receptors: new insights into human disease
    V Michael Holers
    Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045 email
    Annu Rev Immunol 32:433-59. 2014

Detail Information

Publications1

  1. ncbi Complement and its receptors: new insights into human disease
    V Michael Holers
    Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045 email
    Annu Rev Immunol 32:433-59. 2014
    ..It then focuses on new understandings gained from genetic studies, ex vivo analyses, therapeutic trials, and animal models as well as on new research opportunities. ..

Research Grants30

  1. A Novel B Cell Marker and Therapeutic Target in Lupus
    Joseph Craft; Fiscal Year: 2013
    ..Finally, PSGL- 1+CD38hi PC will be characterized in the peripheral blood of lupus patients, correlating their numbers with disease activity in an effort to support the idea that PSGL-1 on PC is an appropriate therapeutic target in SLE. ..
  2. Regulation of Migration of Autoreactive Germinal Centers and Precursor B Cells
    John D Mountz; Fiscal Year: 2013
    ..The results will help to identify novel therapeutic interventions as well as suggesting better approaches to the use of currently available therapies. ..
  3. Mechanisms of B cell activation by Complement Receptor 2
    Taras Lyubchenko; Fiscal Year: 2013
    ..This project will facilitate new mfithodolonifis for maninulation of nomnlfimRnt-rnfidiated B cell immunfi..
  4. Infectious Agents and B Cell Anergy
    John C Cambier; Fiscal Year: 2013
    ..g. EBV in human and gHV68 in mouse, re-awaken anergic B cells thereby leading to autoimmunity. Results of these studies may provide new strategies for prevention, diagnosis and treatment of autoimmunity. ..
  5. Loss of B cell tolerance in rheumatoid arthritis
    Eric Meffre; Fiscal Year: 2013
    ..In addition, understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies. ..
  6. Mechanisms of B-Cell Tolerance in a Mouse Model of Lupus
    Allison Sang; Fiscal Year: 2013
    ..A thorough understanding of B-cell tolerance and the breakdown that occurs in SLE will provide targets for future B-cell therapies. ..
  7. Philadelphia Autoimmunity Center of Excellence
    A M Rostami; Fiscal Year: 2013
    ..The Clinical Component proposes novel clinical trial concepts and studies to understand the mechanisms of action of the therapeutics being tested. As such, they are an integral part of this ACE. ..
  8. Immune Tolerance in Non-clonal Immune Systems
    David Nemazee; Fiscal Year: 2013
    ..The goal of this project is to determine how immune tolerance normally suppresses the generation of self reactive antibodies and to identify genes involved in the process. ..
  9. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  10. A Systems Biology Approach for Pediatric and Adult Autoimmune Diseases
    MARIA VIRGINIA PASCUAL; Fiscal Year: 2013
    ..This team proposes two important trials that will assess a-IL-1 treatment in Juvenile Dermatomyositis and IL-17 blockade in psoriatic diseases. ..
  11. Entry of antigen-presenting B cells into the follicle directed by IFNa and IL-17
    Hui Chen Hsu; Fiscal Year: 2013
    ....
  12. Somatic hypermutation and class switching in autoimmunity
    Paolo Casali; Fiscal Year: 2013
    ....
  13. Autoimmunity Center of Excellence - Rochester
    R John Looney; Fiscal Year: 2013
    ..Therefore, we propose inhibiting CXCL13 using a human monoclonal antibody. The primary clinical outcome will again be adverse events. The primary mechanistic outcome will be changes in peripheral blood memory B cells. ..
  14. B Cell Development Defects in Murine Lupus
    Laurence Morel; Fiscal Year: 2013
    ..The results from these studies will provide a better understanding of the defining features of autoreactive B cells and will help to target therapies toward these autoreactive B cells. ..
  15. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..