Felix Bischof

Microglial Expression of the B7 Family Member B7 Homolog 1 Confers Strong Immune Inhibition: Implications for Immune Responses and Autoimmunity in the CNS

Inflammation of the CNS is usually locally limited to avoid devastating consequences. Critical players involved in this immune regulatory process are the resident immune cells of the brain, the microglia. Interactions between the growing family of B7 costimulatory ligands and their receptors are increasingly recognized as important pathways for costimulation and/or inhibition of immune responses. Human and mouse microglial cells constitutively express B7 homolog 1 (B7-H1) in vitro. However, under inflammatory conditions [presence of interferon-γ (IFN-γ) or T-helper 1 supernatants], a significant upregulation of B7-H1 was detectable. Expression levels of B7-H1 protein on microglial cells were substantially higher compared with astrocytes or splenocytes. Coculture experiments of major histocompatibility complex class II-positive antigen-presenting cells (APC) with syngeneic T cells in the presence of antigen demonstrated the functional consequences of B7-H1 expression on T-cell activation. In the presence of a neutralizing anti-B7-H1 antibody, both the production of inflammatory cytokines (IFN-γ and interleukin-2) and the upregulation of activation markers (inducible costimulatory signal) by T cells were markedly enhanced. Interestingly, this effect was clearly more pronounced when microglial cells were used as APC, compared with astrocytes or splenocytes. Furthermore, B7-H1 was highly upregulated during the course of myelin oligodendrocyte glycoprotein-induced and proteolipid protein-induced experimental allergic encephalomyelitis in vivo. Expression was predominantly localized to areas of strongest inflammation and could be colocalized with microglial cells/macrophages as well as T cells. Together, our data propose microglial B7-H1 as an important immune inhibitory molecule capable of downregulating T-cell activation in the CNS and thus confining immunopathological damage.

Diffusion restriction of the optic nerve in patients with acute visual deficit

Diffusion magnetic resonance imaging (MRI) is commonly used in acute stroke, but not considered diagnostic in ischemic optic neuropathy. This study evaluates the presence of diffusion restriction in patients with acute visual loss by analyzing diffusion‐weighted images (DWI).

Dendritic cell-regulatory T-cell interactions control self-directed immunity

In addition to their immunostimulatory capacity, dendritic cells (DCs) play a crucial role in central and peripheral tolerance mechanisms. In the absence of an infection, immature DCs constantly take up, process and present self‐antigens to specific T cells, which leads to the induction of T‐cell anergy or deletion. In recent years, several additional mechanisms have been identified by which DCs constantly downregulate immune responses to maintain immunological tolerance. Among these are the complex interactions between several DC subtypes and different types of regulatory T cells. In this review, we summarize recent key findings and concepts in this field.

A Structurally Available Encephalitogenic Epitope of Myelin Oligodendrocyte Glycoprotein Specifically Induces a Diversified Pathogenic Autoimmune Response

Multiple sclerosis is an inflammatory disease of the CNS that involves immune reactivity against myelin oligodendrocyte glycoprotein (MOG), a type I transmembrane protein located at the outer surface of CNS myelin. The epitope MOG92–106 is a DR4-restricted Th cell epitope and a target for demyelinating autoantibodies. In this study, we show that the immune response elicited by immunization with this epitope is qualitatively different from immune responses induced by the well-defined epitopes myelin basic protein (MBP) 84–96 and proteolipid protein (PLP) 139–151. Mice with MOG92–106-, but not with MBP84–96- or PLP139–151-induced experimental autoimmune encephalomyelitis developed extensive B cell reactivity against secondary myelin Ags. These secondary Abs were directed against a set of encephalitogenic peptide Ags derived from MBP and PLP as well as a broad range of epitopes spanning the complete MBP sequence. The observed diversification of the B cell reactivity represents a simultaneous spread toward a broad range of antigenic epitopes and differs markedly from T cell epitope spreading that follows a sequential cascade. The Abs were of the isotypes IgG1 and IgG2b, indicating that endogenously recruited B cells receive help from activated T cells. In sharp contrast, B cell reactivity in MBP84–96- and PLP139–151-induced experimental autoimmune encephalomyelitis was directed against the disease-inducing Ag only. These data provide direct evidence that the nature of the endogenously acquired immune reactivity during organ-specific autoimmunity critically depends on the disease-inducing Ag. They further demonstrate that the epitope MOG92–106 has the specific capacity to induce a widespread autoimmune response.

Specific treatment of autoimmunity with recombinant invariant chains in which CLIP is replaced by self-epitopes

The invariant chain (Ii) binds to newly synthesized MHC class II molecules with the CLIP region of Ii occupying the peptide-binding groove. Here we demonstrate that recombinant Ii proteins with the CLIP region replaced by antigenic self-epitopes are highly efficient in activating and silencing specific T cells in vitro and in vivo. The Ii proteins require endogenous processing by antigen-presenting cells for efficient T cell activation. An Ii protein encompassing the epitope myelin basic protein amino acids 84–96 (Ii-MBP84–96) induced the model autoimmune disease experimental allergic encephalomyelitis (EAE) with a higher severity and earlier onset than the peptide. When applied in a tolerogenic manner, Ii-MBP84–96 abolished antigen-specific T cell proliferation and suppressed peptide-induced EAE more effectively than peptide alone. Importantly, i.v. administration of Ii proteins after EAE induction completely abrogated the disease, whereas peptides only marginally suppressed disease symptoms. Ii fusion proteins are thus more efficient than peptide in modulating CD4+ T cell-mediated autoimmunity, documenting their superior qualities for therapeutic antigen delivery in vivo.

Induction of Autoimmunity by Expansion of Autoreactive CD4+CD62Llow Cells In Vivo

The prerequisites of peripheral activation of self-specific CD4+ T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139–151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IAs/PLP139–151 tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN-γ production by self-specific CD4+ T cells. In addition, PT promoted the generation of CD4+CD62Llow effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4+CD62Lhigh cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c+CD4+ dendritic cells whereas CD11c+CD8α+ dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4+CD62Llow cells and indicate that CD4+CD62Llow effector T cells and CD11c+CD4+ dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.

Dendritic Cells and Anergic Type I NKT Cells Play a Crucial Role in Sulfatide-Mediated Immune Regulation in Experimental Autoimmune Encephalomyelitis

CD1d-restricted NKT cells can be divided into two groups: type I NKT cells use a semi-invariant TCR, whereas type II express a relatively diverse set of TCRs. A major subset of type II NKT cells recognizes myelin-derived sulfatides and is selectively enriched in the CNS tissue during experimental autoimmune encephalomyelitis (EAE). We have shown that activation of sulfatide-reactive type II NKT cells by sulfatide prevents induction of EAE. In this article, we have addressed the mechanism of regulation, as well as whether a single immunodominant form of synthetic sulfatide can treat ongoing chronic and relapsing EAE in SJL/J mice. We have shown that the activation of sulfatide-reactive type II NKT cells leads to a significant reduction in the frequency and effector function of myelin proteolipid proteins 139–151/I-As–tetramer+ cells in lymphoid and CNS tissues. In addition, type I NKT cells and dendritic cells (DCs) in the periphery, as well as CNS-resident microglia, are inactivated after sulfatide administration, and mice deficient in type I NKT cells are not protected from disease. Moreover, tolerized DCs from sulfatide-treated animals can adoptively transfer protection into naive mice. Treatment of SJL/J mice with a synthetic cis-tetracosenoyl sulfatide, but not α-galactosylceramide, reverses ongoing chronic and relapsing EAE. Our data highlight a novel immune-regulatory pathway involving NKT subset interactions leading to inactivation of type I NKT cells, DCs, and microglial cells in suppression of autoimmunity. Because CD1 molecules are nonpolymorphic, the sulfatide-mediated immune-regulatory pathway can be targeted for development of non-HLA–dependent therapeutic approaches to T cell–mediated autoimmune diseases.

CD62Lhigh Treg cells with superior immunosuppressive properties accumulate within the CNS during remissions of EAE

The role of regulatory T cell populations within the CNS in the regulation of CNS-autoimmunity is controversial. We show that during recovery from relapsing remitting experimental autoimmune encephalomyelitis, regulatory T cells accumulate within the CNS that express high levels of CD62L. These CD62L(high) Treg cells express increased amounts of CTLA-4, ICOS and TGF-β and are more potent than CD62L(low) Treg cells in suppressing proliferation and inducing apoptosis in effector T cells. CD62L(high) Treg cells thus represent a population of Treg cells that display superior immunosuppressive properties and accumulate in the CNS during recovery from CNS-autoimmunity.

Suppression of experimental autoimmune encephalomyelitis by interleukin-10 transduced neural stem/progenitor cells

Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPCIL-10) suppressed myelin oligodendrocyte glycoprotein aa 35–55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPCIL-10 migrated to peripheral lymphoid organs and into the CNS. NSPCIL-10 suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE.

Suppression of verbal hallucinations and changes in regional cerebral blood flow after intravenous lidocaine: a case report.

Simple and complex auditory phantom-perceptions such as tinnitus and musical hallucinations occur predominantly in elderly subjects and are often associated with hearing impairment. Isolated verbal hallucinations without other psychotic features are rare. It has been shown that an intravenous (i.v.) injection of lidocaine can transiently suppress tinnitus. Here we present the case of a 74 year old left-handed women with severely distressing, continuous verbal auditory hallucinations without other psychotic features. I.v. injections of 100 mg lidocaine but not saline resulted in substantial transient suppressions of the hallucinations for several hours. Using [(15)O]H(2)O positron-emission tomography (PET) decreased regional cerebral blood flow associated with reduced perception of voices was found in the right angular and supramarginal gyrus, right inferior frontal gyrus, orbitofronal cortex and in major parts of the cingulate cortex. These data suggest to further investigate the clinical relevance of i.v. lidocaine in patients with therapy-resistant verbal hallucinations, support the notion of common pathophysiological mechanisms in different forms of auditory phantom-perception and demonstrate the feasibility of a new strategy for imaging studies on auditory hallucinations.