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.