The role of dendritic cells in CNS autoimmunity

Abstract

Multiple sclerosis (MS) is a chronic immune-mediated, central nervous system (CNS) demyelinating disease. Clinical and histopathological features suggest an inflammatory etiology involving resident CNS innate cells as well as invading adaptive immune cells. Encephalitogenic myelin-reactive T cells have been implicated in the initiation of an inflammatory cascade, eventually resulting in demyelination and axonal damage (the histological hallmarks of MS). Dendritic cells (DC) have recently emerged as key modulators of this immunopathological cascade, as supported by studies in humans and experimental disease models. In one such model, experimental autoimmune encephalomyelitis (EAE), CNS microvessel-associated DC have been shown to be essential for local antigen recognition by myelin-reactive T cells. Moreover, the functional state and compartmental distribution of DC derived from CNS and associated lymphatics seem to be limiting factors in both the induction and effector phases of EAE. Moreover, DC modulate and balance the recruitment of encephalitogenic and regulatory T cells into CNS tissue. This capacity is critically influenced by DC surface expression of co-stimulatory or co-inhibitory molecules. The fact that DC accumulate in the CNS before T cells and can direct T-cell responses suggests that they are key determinants of CNS autoimmune outcomes. Here we provide a comprehensive review of recent advances in our understanding of CNS-derived DC and their relevance to neuroinflammation.

Fulfilling the dream: tolerogenic dendritic cells to treat multiple sclerosis

“…Despite these central tolerance mechanisms, some low avidity autoreactive T cells escape into the periphery, where peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms have been identified for myelin-specific T cells, most importantly Treg cells and tolerogenic DCs [5,12]. TolDCs keep autoreactive T cells under control by inducing anergy, apoptosis, phenotypic skewing, and/or Treg cells [13][14][15].…”

“…In MS, both immunogenic and tolerogenic features of different DC subsets are disrupted [7,12]. Elevated numbers of mature mDCs have been found in the peripheral blood of MS patients, and the occurrence of both mDCs and pDCs in the CSF of MS patients suggests their active participation in disease pathogenesis [12].…”

“…Multiple peripheral tolerance mechanisms have been identified for myelin-specific T cells, most importantly Treg cells and tolerogenic DCs [5,12]. TolDCs keep autoreactive T cells under control by inducing anergy, apoptosis, phenotypic skewing, and/or Treg cells [13][14][15].In MS, both immunogenic and tolerogenic features of different DC subsets are disrupted [7,12]. Elevated numbers of mature mDCs have been found in the peripheral blood of MS patients, and the occurrence of both mDCs and pDCs in the CSF of MS patients suggests their active participation in disease pathogenesis [12].…”

“…Elevated numbers of mature mDCs have been found in the peripheral blood of MS patients, and the occurrence of both mDCs and pDCs in the CSF of MS patients suggests their active participation in disease pathogenesis [12]. Furthermore, alterations in phenotype and/or function of different DC subsets have been observed in MS [7,12]. pDCs for example show an imbalance in the ratio between tolerogenic and immunogenic subtypes generating a propensity to generate proinflammatory Th17 cell responses in MS [16].…”

Mechanisms of autoimmunity in the central nervous system: Disturbance of natural autoimmunity, infectious agents, cell contribution and antibody signatures

“…101 DC are professional APC that can modulate adaptive immune responses. Such cells process antigens, and present antigen peptide fragments on major histocompatibility complex (MHC) molecules to naive T cells.…”