Brain macrophages as APCs
As described in the Introduction, infiltrating CD4+ T-helper cells in the CNS recognize antigenic peptides that have been processed and presented in the context of major histocompatibility complex (MHC) II molecules on the cell surface of the local APC. This antigen recognition is considered to be the first signal necessary for peripheral T-cell activation. A second signal is required, this time antigen-independent, which is provided by the interaction of costim-ulatory molecules (CD40, CD80, CD86) expressed by APCs with receptors/ligands on the T-cells (CD154,
CD28, CTLA-4). In addition to MHC II and costimu-latory molecule expression, several other features allow APCs to function efficiently.2 Phagocytosis of particulate antigens is a prerequisite for competent antigen processing. Macrophages and microglia sample their mileau by endocytosis, and process and present these various ingested antigens on their surface. Receptors that mediate active endocytosis, include Fc7 and mannose receptors. Perivascular macrophages have been demonstrated to be competent APCs both in vitro and in vivo. These cells not only exhibit constitutive expression of MHC II and costimulatory molecules, but also upregulate these molecules following exposure to inflammatory stimuli.38,39 Similarly, resting parenchymal human microglia constitutively express MHC II, costimula-tory molecules (B7.2, CD40) and the Fc7 receptor class of immunoglobulin.38,39 Parenchymal microglia activated following exposure to interferon gamma (IFN-7) demonstrate enhanced expression of these molecules.40 Macrophages and microglia in MS lesions express MHC class II antigens and costimu-latory molecules such as CD40, CD86 (B7.2) and CD80 (B7.1), indicating that these microglia are 'activated' and can perform immune functions such as antigen presentation and phagocytosis.40 In the periphery, the most professional APCs are the dendritic cells (DCs). DCs acquire antigen in the periphery and then migrate to T-cell-rich areas of lymph nodes and spleen, where they are proficient at presenting protein antigens to naive T-helper cells. To date, DCs have not been described as residing in the CNS; however, IFN-7-treated microglia have been shown to be capable of stimulating naive T-cells, and activated microglia induce secretion of Thl-type cytokines (IL-2, IFN-7, TNF-a), albeit with a lower efficiency than DCs.42 Furthermore, activated microglia are equally as capable as DCs in stimulating polarized Th1 and Th2 cell lines to proliferate. Together, these observations suggest that microglia may play the role of DCs in the brain.
Encounter of peripheral T-cells with antigen presented by APCs in the absence of a co-stimulating signal renders the T-cells anergic. Classical anergy is described as the inability to proliferate or produce cytokines upon challenge with antigen.43,44 Subsequent exposure of the T-cells to IL-12, however, is sufficient to convert the T-cells into potent effectors.45 Therapeutic treatments that would decrease APC functions, such as the inhibition of MHC II expression, or costimulatory molecules could possibly relieve the inflammation induced by the infiltrating T-cells by rendering these T-cells anergic.
Importance of IL-12 cytokine secretion by brain macrophages
Activated T-helper cells can be separated into at least two distinct phenotypes on the basis of their cytokine production profiles: IFN-7, IL-2 and TNF-a are considered to be hallmarks of a Th1-type response, while IL-4, IL-5, IL-l0 and IL-13 represent a Th2-type response. Proinflammatory Th1 T-cells are considered central to the development of MS and its animal model (EAE).46,47 In most experimental systems, IL-12 plays a critical role in the differentiation of naive T-cells into Th1 cells.48 IL-12 also induces IFN-7 production by NK cells and T-cells, macrophage activation, and B-cell production of complement-fixing antibodies.49 In adoptive transfer models of EAE, the inclusion of recombinant IL-12 during in vitro priming of the reactive T-cells resulted in increased severity and duration of the disease, and accelerated onset of the disease.49 Neutralization of IL-12 following adoptive transfer of T-cells attenuated the incidence and severity of disease.50 In the active immunization model of EAE, IL-12-knockout mice are completely resistant, suggesting that IL-12 is essential for pathogenesis.51 In humans, increased expression of mRNA encoding IL-12p40 has been found in acute MS plaques but not in inflammatory cerebral infarcts or disease-free brain.52
Ligation of the costimulatory molecule CD40 on monocyte/macrophages with its ligand CD154 on T-cells is a potent stimulus for IL-12 secretion by monocytes. Immunohistochemical studies have colocalized Th cells expressing the CD40 ligand (CD154) and monocytic cells expressing CD40 in active MS and EAE lesions.53 Murine microglia secrete IL-12 upon antigen-specific interactions with Th1 cells, CD40 ligation and TNF receptor ligation.54 Similar increased T-cell-driven IL-12 secretion has been observed in peripheral blood mono-nuclear cells (PBMCs) from patients with progressive MS.55 Culture of human microglia in vitro demonstrated that IL-12 secretion was triggered by microglia contact with T-cells that express CD40, with ligation playing an important role as a triggering signal. Addition of antagonists for IFN-7 and TNF-a reduced cytokine production, demonstrating that IL-12 was subject to both autocrine and paracrine regulation.56,57
In EAE, treatment of animals with a monoclonal antibody to CD154 inhibited IL-12 secretion and completely prevented disease.53 Interference with CD154:CD40 ligation reduced the cytokine secretion by human microglia observed in culture.58 The APC role of microglia and the subsequent production of
IL-12 following T-cell contact would suggest a mechanism whereby interactions between T-cells and microglial cells contribute to the persistent or recurrent proinflammatory Th1 immune response within human CNS. This initial inflammatory response facilitates the recuitment and activation of additional T-cells thereby perpetuating this cascade event.
Myelin membranes and oligodendrocytes do not express MHC class II molecules, suggesting that they are unlikely to be direct targets of T-cells. Although myelin-specific T-cells are clearly needed for triggering EAE, macrophages and microglia are integral to the tissue destruction that is associated with the disease.49 As described previously, activated brain macrophages and microglia secrete a variety of inflammatory mediators, some of which may be neurotoxic and damage oligodendrocytes and myelin, and alter neuronal function. Potential therapeutics for MS would downregulate not only microglial APC functions for T-cell responses, but also inhibit many of the innate immune functions of microglia that may be causing oligodendrocyte damage.
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