The Clinical Course of Experimental Autoimmune Encephalomyelitis and Inflammation Is Controlled by the Expression of Cd40 within the Central Nervous System

Abstract

Although it is clear that the function of CD40 on peripheral hematopoietic cells is pivotal to the development of autoimmunity, the function of CD40 in autoimmune disease outside this compartment is unresolved. In a model of experimental autoimmune encephalomyelitis (EAE), evidence is presented that CD40–CD154 interactions within the central nervous system (CNS) are critical determinants of disease development and progression. Using bone marrow (BM) chimeric mice, the data suggest that the lack of expression of CD40 by CNS-resident cells diminishes the intensity and duration of myelin oligodendrocyte glycoprotein (MOG)-induced EAE and also reduces the degree of inflammatory cell infiltrates into the CNS. Although CNS inflammation is compromised in the CD40+/+→CD40−/− BM chimeric mice, the restricted CD40 expression had no impact on peripheral T cell priming or recall responses. Analysis of RNA expression levels within the CNS demonstrated that encephalitogenic T cells, which entered a CNS environment in which CD40 was absent from parenchymal microglia, could not elicit the expression of chemokines within the CNS. These data provide evidence that CD40 functions outside of the systemic immune compartment to amplify organ-specific autoimmunity.

CD40 Expression by Microglial Cells Is Required for Their Completion of a Two-Step Activation Process during Central Nervous System Autoimmune Inflammation

“…Peripheral macrophages express high levels of CD40 in the CNS during EAE (Figs. 3 and 4) and chimera mice with a CD40 deficiency in the periphery develop mild symptoms of EAE (17). Although infiltrating macrophages express a higher level of activation markers as compared with activated microglial cells (Figs.…”

“…Although CD40 is implicated in EAE susceptibility, only one study has investigated the role of CD40 expression in the CNS during EAE (17). This study demonstrated that bone marrow (BM) chimera mice with a deficiency in CD40 expression in the CNS, and not in the periphery, exhibited a less severe EAE disease course with reduced numbers of infiltrating macrophages and lymphocytes in the CNS.…”

“…CD40-CD40L interactions were reported to be important for EAE/MS pathogenesis (16). It was demonstrated that CD40 Ϫ/Ϫ and CD40L Ϫ/Ϫ animals were resistant to EAE (17,18), and that myelin self-Ag-pulsed CD40 Ϫ/Ϫ dendritic cells were not able to induce EAE, while wild-type (WT) dendritic cells were (19). In addition, Abs that blocked either CD40 or CD40L ameliorated EAE disease symptoms in both mice and marmoset monkeys (20 -22).…”

Neuroprotective properties of the innate immune system and bone marrow stem cells in Alzheimer's disease

“…Bone marrowderived microglia are known to infiltrate regions suffering from demyelination and remyelination 56 and microglia are responsible for the majority of TNF-a production in the brain in response to immune stimuli. 57 Their presence and activation at demyelination sites would thus be beneficial for the CNS in order to promote remyelination.…”

Roles of Sema4D–Plexin-B1 Interactions in the Central Nervous System for Pathogenesis of Experimental Autoimmune Encephalomyelitis

“…In fact, the mechanisms of how activation of microglia is regulated have been extensively studied. For example, CD40, a member of the TNF receptor family, has been reported to be involved in microglial activation (5,6). Interactions of CD40 with its ligand (CD154), which is primarily expressed by activated T cells, promote the activation of microglia in the context of enhanced expression of costimulatory molecules and production of proinflammatory cytokines or chemokines and NO (5).…”