Brain Dendritic Cells and Macrophages/Microglia in Central Nervous System Inflammation

Abstract

Microglia subpopulations were studied in mouse experimental autoimmune encephalomyelitis and toxoplasmic encephalitis. CNS inflammation was associated with the proliferation of CD11b+ brain cells that exhibited the dendritic cell (DC) marker CD11c. These cells constituted up to 30% of the total CD11b+ brain cell population. In both diseases CD11c+ brain cells displayed the surface phenotype of myeloid DC and resided at perivascular and intraparenchymatic inflammatory sites. By lacking prominent phagocytic organelles, CD11c+ cells from inflamed brain proved distinct from other microglia, but strikingly resembled bone marrow-derived DC and thus were identified as DC. This brain DC population comprised cells strongly secreting IL-12p70, whereas coisolated CD11c− microglia/brain macrophages predominantly produced TNF-α, GM-CSF, and NO. In comparison, the DC were more potent stimulators of naive or allogeneic T cell proliferation. Both DC and CD11c− microglia/macrophages from inflamed brain primed naive T cells from DO11.10 TCR transgenic mice for production of Th1 cytokines IFN-γ and IL-2. Resting microglia that had been purified from normal adult brain generated immature DC upon exposure to GM-CSF, while CD40 ligation triggered terminal maturation. Consistently, a functional maturation of brain DC was observed to occur following the onset of encephalitis. In conclusion, these findings indicate that in addition to inflammatory macrophage-like brain cells, intraparenchymatical DC exist in autoimmune and infectious encephalitis. These DC functionally mature upon disease onset and can differentiate from resident microglia. Their emergence, maturation, and prolonged activity within the brain might contribute to the chronicity of intracerebral Th1 responses.

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

“…28 This may reflect the fact that the central nervous system represents an immunologically challenging environment, 29,30 at least partially due to a paucity of professional APCs under normal circumstances. 31 With regard to antigen presentation in the CNS and CNS tumors, although microglia are proposed to be resident APCs in the CNS, their capability for stimulating cellular immune responses is controversial (reviewed by Carson 32 and Graeber et al 33 ). In the case of experimental autoimmune encephalomyelitis (EAE), these CD11c+ cells exhibit a maturational phenotype similar to immature BM-derived DC or splenic DCs, and were unable to prime naïve T cells, and in some cases inhibited T-cell proliferation.…”

Increased islet antigen presentation leads to type‐1 diabetes in mice with autoimmune susceptibility

“…A number of studies have shown that GM-CSF can regulate the activation of APC necessary for T cell activation and effector function [27][28][29][30]. We monitored the ability of APC to mediate the expansion of autoreactive T cells in vivo.…”

Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences

“…59 Cells displaying immunoreactivity towards markers of dendritic cells have been observed in several experimental brain inflammatory conditions. 12,[50][51][52][53][54][55][56][57][58] In addition, the phenomenon of epitope spreading 59,60 also suggests that, once brain inflammation occurs, new antigens being released from the brain during inflammatory processes can stimulate additional immune responses. However, evidence against antigens released from the brain causing autoimmune diseases is strong, and includes the lack of autoimmunity following stroke, brain surgery, brain tumors, and brain infarcts.…”

“…The presence of dendritic cells within the brain ventricles, choroid plexus, and meninges, together with lymphatics present within these structures, could represent the cellular basis for these effects. [52][53][54]56,61 Long-term transgene expression, in the presence of transitory inflammation, and in the absence of priming of either a humoral or cellular immune response, can be achieved in the brain. In other organs, this remains more difficult, since they contain, even in the resting stage, professional antigen-presenting cells with migratory properties, as well as lymphatics channels.…”