FIGURE 3 | Epitope spreading.

From the following article:

Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease

Stephen D. Miller, Danielle M. Turley & Joseph R. Podojil

Nature Reviews Immunology 7, 665-677 (September 2007)

doi:10.1038/nri2153

Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease

Animal models of multiple sclerosis (MS) have helped to identify putative mechanisms by which epitope spreading occurs. In relapsing–remitting experimental autoimmune encephalomyelitis (EAE), the activation of the autoreactive CD4+ T cells that are specific for the initiating antigen epitope (CD4+ T cell depicted in green) occurs in the draining lymph node. Following activation, the effector CD4+ T cells enter the circulation and extravasate into the CNS. Once in the CNS, the autoreactive CD4+ T cells initiate myelin destruction through the activation of resident and infiltrating antigen-presenting cells (APCs). The activated infiltrating immune cells secrete cytokines and chemokines that not only recruit immune cells into the central nervous system (CNS), but also help to open the blood–brain barrier (BBB). Besides the re-activation of the CD4+ T cells that are specific for the initiating antigen, myelin antigens are released, phagocytosed, processed, and presented principally within the CNS by peripherally derived myeloid dendritic cells (DCs) to naive CD4+ T cells, both of which can enter through the compromised BBB. For example, in proteolipid protein (PLP) peptide PLP139–151-induced relapsing–remitting EAE in SJL/J mice the initiating epitope is PLP139–151, and the population of CD4+ T cells that recognize this peptide is responsible for the initial acute phase of disease. During the acute phase of disease the destruction of myelin allows for the release of both PLP and myelin basic protein (MBP). Due to antigen availability and CD4+ T-cell precursor frequency, the activation of the secondary population of CD4+ T cells specific for PLP178–191 occurs during the primary relapse (known as intramolecular epitope spreading). During the secondary relapse, CD4+ T cells specific for MBP84–104 are activated (known as intermolecular epitope spreading). TCR, T-cell receptor.

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