Fig. 1.

Model for development of secondary intracellular debris-specific antibodies in CSF OCB. (1) Upon activation in peripheral secondary lymphoid tissues, myelin-specific T cells, including T cells that recognize cross-reactive epitopes of infectious organisms (i.e., molecular mimicry), enter the blood, traffic to the CNS, cross the blood–brain barrier, and infiltrate the parenchyma. Similarly, B cells may comigrate with the activated T cells. (2) Within the CNS, myelin-specific T cells may initiate focal inflammation by cytokine production and activation of resident microglia, which may serve as APC to those T cells. This initial CNS inflammatory response leads to recruitment of infiltrating macrophages and dendritic cells that can also serve as APC, as well as other immune cells, culminating in the destruction and release of debris from myelin and the myelin-forming oligodendrocytes. (3) Intracellular and myelin debris are phagocytosed and processed by APC, then presented to infiltrating T cells that may recognize those neoantigens. (4) Activated antigen-specific T cells (e.g., T follicular helper cells) help infiltrating B cells that may recognize intracellular debris differentiate into antibody-producing plasma cells. (5) These clonally expanded plasma cells produce IgG in the CSF, which are depicted as discrete “oligoclonal” bands when analyzed by protein gel electrophoresis. Because this immune response is compartmentalized to the CNS, the corresponding bands are not detected by serum protein electrophoresis. Brändle et al. (4) demonstrated that IgG antibodies within three separate bands recognize ubiquitous intracellular antigens (i.e., MKNK1/2, FAM84A, and AKAP17A). Other investigators have identified clonally expanded CSF plasma cells that recognize myelin proteins (11). Currently, it is not known whether antibodies produced by those myelin debris-specific B cells also contribute to formation of discrete bands (indicated by a question mark in step 4). Image courtesy of Xavier Studio.