A pathogenic role for autoantibodies in neuroinflammatory diseases has been established in neuromyelitis optica (NMO), where autoantibodies directed against aquaporin-4 (AQP4) are present in the majority of patients and are believed to be pathogenic. The vast majority of autoantibodies is produced by long-lived plasma cells (LLPCs) in bone marrow, but current MS treatments, such as anti-CD20 antibody treatment or interferons do not specifically target these cells and therefore lack therapeutic efficacy and show significant side effects. Novel approaches to eliminating autoantibody-producing LLPCs are therefore urgently needed. Plasma cells (PCs) are terminally differentiated from germinal center (GC) B cells and they are the main source for antibodies found in serum and other body fluids. GC B cells can give rise to short-lived plasmablasts, which enter the blood stream and recirculate for a short period until they find a survival niche in the bone marrow (BM), where they develop into LLPCs. The molecular players that guide the differentiation of GC B cells towards the plasmablast fate and further direct their differentiation into PCs and promote their survival and antibody-production are only partially understood. PCs are also found in the CNS in MS lesions, and data from the experimental autoimmune encephalomyelitis (EAE) model suggest that they contribute to disease severity. The extracellular signal-regulated kinases 1 (ERK1) and 2 (ERK2) are the best-studied members of the mitogen-activated protein kinase (MAPK) family and are located downstream of many critical signaling pathways in plasmablasts and PCs. Experimental evidence suggests that they may play a key role in the formation, survival, and/or antibody-producing function of PCs. However, the data concerning the requirements of ERK1 versus ERK2 in PCs are controversial, and the role of these MAPKs in generating and/or sustaining autoantibody-producing LLPCs, and their antibody-producing function in BM or CNS in neuroinflammatory disease has not been investigated. We have developed a novel Mx1creYFP+/-Erk2fl/fl mouse model in which the deletion of Erk2 is accompanied by the expression of the fluorescent reporter protein, eYFP. This model allows us to follow the fate of antigen-specific Erk2- deficient (Erk2? eYFP+) B cells and B cell subsets, their identification and isolation using flow cytometry cell sorting, and functional studies to investigate key molecules for cell proliferation, function and survival. Our preliminary studies show that Erk2? B cells fail to develop into LLPCs and are virtually absent from BM. Our data strongly suggest that ERK2 signaling is critical for the survival of PCs and that targeting this pathway may be a viable strategy to eliminate autoantibody- producing LLPCs from BM and CNS. We propose that exploring the underlying mechanisms could lead to novel therapies. We will test the central hypothesis that ERK2-signaling is critical for generation and survival of autoantibody- producing LLPCs in bone marrow and CNS niches. We will determine the requirement for ERK2 for generating autoantibody-producing long-lived plasma cells in bone marrow and CNS in neuroinflammation. We will determine the role of ERK2 for sustaining already established autoantibody-producing LLPCs in BM and CNS in neuroinflammation.
A pathogenic role for autoantibodies in neuroinflammatory diseases has been established in a number of autoimmune diseases, including neuromyelitis optica, where autoantibodies directed against AQP4 are present in the majority of patients and are believed to promote the disease. The vast majority of autoantibodies is produced by long-lived plasma cells in bone marrow, but current treatments do not specifically target these cells and therefore lack therapeutic efficacy and have significant side effects. The present proposal will test a novel treatment strategy to eliminate autoantibody- producing plasma cells from the bone marrow and CNS by inhibiting the ERK signaling pathway.
