Antigen Presentation by B cells and Macrophages in CNS Autoimmunity

Scott Zamvil, M.D., Ph.D.

University of California, San Francisco

Funded in September, 2005: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

back to top

B cells in CNS Autoimmune Disease

This study will determine whether immune B cells play two roles in the development of multiple sclerosis (MS). Additionally, the investigators will examine the consequences of reducing B cells as a therapy for MS.

MS is an autoimmune disease of the brain and spinal cord. Research suggests that faulty adaptive immune T cells mistake as "foreign" the myelin sheath, which insulates brain and spinal cord cells and helps conduct electrical signals from one cell to another. The researchers suspect, however, that immune B cells set off these faulty T cell MS attacks by instructing the T cells to attack myelin. Additionally, the researchers suspect, B cells secrete antibodies that also attack myelin. The investigators will test these two hypothesized roles of B cells in a mouse model of MS. They also will determine the effects of the current MS drug Rituxan, which depletes B cells, on reducing inflammation and demyelination in this mouse model.

Significance: This study may provide new evidence of B cell involvement in  MS and of the actions of a current MS drug on these cells. This information may lead to development of stronger, more effective immunotherapies.

ABSTRACT

back to top

Antigen Presentation by B cells and Macrophages in CNS Autoimmunity

Myelin-specific CD4+ T cells are thought to have a central role in the pathogenesis of multiple sclerosis (MS) and its model, experimental autoimmune encephalomyelitis (EAE). Activation of myelin-specific T cells within the central nervous system (CNS) requires recognition of fragments myelin antigen in association with MHC class II molecules expressed on antigen presenting cells (APC). Different types of APC may participate in CNS activation of myelin-specific T cells. In order to develop therapies that may selectively inhibit antigen presentation, it is advantageous to clarify the relative contribution by individual APC subsets. Infiltrating (non-resident) bone marrow-derived APC appear to have an important role in initial CNS demyelinating disease. B cells, perivascular macrophages and dendritic cells are detected in EAE and MS lesions. While it has been demonstrated that class II-restricted antigen presentation by dendritic cells alone is sufficient to induce EAE, other data suggest that perivascular macrophages and antigen-specific B cells have key roles in CNS antigen presentation in EAE and MS. B cells may have a dual role, also serving as source for differentiation of myelin-specific antibody-secreting plasma cells. In fact, myelin-specific antibodies are sometimes detected in demyelinating lesions in MS and EAE. Based upon these findings enthusiasm has developed for testing B cell depletion in MS.

My laboratory is utilizing a Tg approach by targeting the MHC class II transactivator (CIITA), the "master regulator" of class II expression, to different APC subpopulations (B cells, macrophages, and dendritic cells) in order to evaluate their individual contribution in antigen presentation and T cell activation in EAE. When bred onto the CIITA-deficient background, CIITA and class II expression can be restricted to the transgene-targeted APC.

(1) We will test the hypothesis that class II restricted antigen presentation by B cells or myelin-specific B cells alone will be sufficient to initiate CNS inflammation. (2) In order to discriminate the role of APC function by B cells from the role of myelin-specific antibodies in EAE and CNS demyelination, we propose to create Tg mice that express myelin-specific membrane Ig only, and to compare EAE and demyelination in these mice to mice containing B cells with the same myelin antigen specificity and are also capable of secreting myelin-specific antibodies as plasma cells. (3) We hypothesize that B cell depletion will be beneficial in treatment of chronic and relapsing EAE and will test these possibilities using a human CD20 Tg mouse that permits depletion of CD20 B cells.

INVESTIGATOR BIOGRAPHIES

back to top
Scott Zamvil, M.D., Ph.D.

Scott S. Zamvil, M.D., Ph.D., is a clinical neurologist and immunologist at the University of California, San Francisco (UCSF) who is devoted to developing novel treatments for multiple sclerosis (MS). In his laboratory research, Dr. Zamvil investigates mechanisms involved in myelin antigen presentation and T cell activation in the MS model, experimental autoimmune encephalomyelitis (EAE). His research has shown that cholesterol-lowering statin drugs can alter antigen presentation and modulate T cell activation. Dr. Zamvil is involved in translating his research from "bench to bedside" and is the Principal Investigator for the NIH-sponsored multicenter clinical trial testing Lipitor in early MS.

Dr. Zamvil received his M.D. and Ph.D. in Medical Microbiology and Immunology from Stanford University, California, where he trained in internal medicine. After completing his neurology residency at Brigham and Women's Hospital in Boston he joined the Harvard neurology faculty. In 1994 he was recipient of the National Multiple Sclerosis Society's Harry Weaver Neuroscience Scholarship. Since 1998, he has been on neurology faculty at UCSF, where he is Associate Professor of Neurology. Dr. Zamvil has joint appointments as a faculty member in the Program in Immunology and the Biomedical Sciences Graduate Program at UCSF.