The family of receptors for IgG (Fc gamma R) plays an essential role in antibody-mediated effector functions of the immune system. However, the specific contribution of each of the Fc gamma R classes to in vivo immune reactions is still unclear. Here, we demonstrate that mice deficient for the ligand-binding alpha chain of Fc gamma RIII lack NK cell-mediated antibody-dependent cytotoxicity and phagocytosis of IgG1-coated particles by macrophages. Strikingly, these mice lack IgG-mediated mast cell degranulation, are resistant to IgG-dependent passive cutaneous anaphylaxis, and exhibit an impaired Arthus reaction. These results indicate a prominent role for Fc gamma RIII in inflammatory and anaphylactic responses, making this receptor a potential target in immunotherapy.

There are no conventional lymphatic vessels within the CNS parenchyma, although it has been hypothesized that lymphatics near the cribriform plate or dura maintain fluid homeostasis and immune surveillance during steady-state conditions. However, the role of these lymphatic vessels during neuroinflammation is not well understood. We report that lymphatic vessels near the cribriform plate undergo lymphangiogenesis in a VEGFC – VEGFR3 dependent manner during experimental autoimmune encephalomyelitis (EAE) and drain both CSF and cells that were once in the CNS parenchyma. Lymphangiogenesis also contributes to the drainage of CNS derived antigens that leads to antigen specific T cell proliferation in the draining lymph nodes during EAE. In contrast, meningeal lymphatics do not undergo lymphangiogenesis during EAE, suggesting heterogeneity in CNS lymphatics. We conclude that increased lymphangiogenesis near the cribriform plate can contribute to the management of neuroinflammation-induced fluid accumulation and immune surveillance.

Experimental autoimmune encephalomyelitis (EAE) is an animal model for multiple sclerosis (MS) characterized by chronic inflammatory demyelination of the central nervous system (CNS). The pathology of EAE involves autoimmune CD4(+) T(h)1 cells. There is a striking inverse correlation between the occurrence of parasitic and autoimmune diseases. We demonstrate that in mice with Schistosoma mansoni ova immunization, the severity of EAE is reduced as measured by decreased clinical scores and CNS cellular infiltrates. Disease suppression is associated with immune deviation in the periphery and the CNS, demonstrated by decreased IFN-gamma and increased IL-4, transforming growth factor-beta and IL-10 levels in the periphery, and increased frequency of IL-4 producing neuroantigen-specific T cells in the brain. S. mansoni helminth ova treatment influenced the course of EAE in wild-type mice, but not in STAT6-deficient animals. This indicates that STAT6 plays a critical role in regulating the ameliorating effect of S. mansoni ova treatment on the autoimmune response, and provides the direct link between helminth treatment, T(h)2 environment and improved EAE. As some intestinal helminthic infections induce minimal pathology, they might offer a safe and inexpensive therapy to prevent and/or ameliorate MS.

The contribution of dendritic cells (DCs) to initiating T cell-mediated immune response in and T cell homing into the CNS has not yet been clarified. In this study we show by confocal microscopy and flow cytometry that cells expressing CD11c, CD205, and MHC class II molecules and containing fluorescently labeled, processed Ag accumulate at the site of intracerebral Ag injection. These cells follow a specific pattern upon migrating out of the brain. To track their pathway out of the CNS, we differentiated DCs from bone marrow of GFP-transgenic mice and injected them directly into brains of naive C57BL/6 mice. We demonstrate that DCs migrate from brain to cervical lymph nodes, a process that can be blocked by fixation or pertussis toxin treatment of the DCs. Injection of OVA-loaded DCs into brain initiates a SIINFEKL (a dominant OVA epitope)-specific T cell response in lymph nodes and spleen, as measured by specific tetramer and LFA-1 activation marker staining. Additionally, a fraction of activated SIINFEKL-specific T cells home to the CNS. Specific T cell homing to the CNS, however, cannot be induced by i.v. injection of OVA-loaded DCs alone. These data suggest that brain-emigrant DCs are sufficient to support activated T cells to home to the tissue of DC origination. Thus, initiation of immune reactivity against CNS Ags involves the migration of APCs from nervous tissue to peripheral lymphoid tissues, similarly to that in other organs.