Advances in neuroimmunology最新文献

Clinical research has focused on autoimmune disease (AID) for a couple of decades. More sensitive and specific methods have been developed for neuroimmunological research. Gamma fraction bands (bands separated by electrophoresis and visualized by amino black staining) and IgG fraction bands (bands separated by iso-electric focusing and visualized by immunostaining) are used instead of oligoclonal bands. Myasthenia gravis (MG) mainly involves acetylcholine receptors of the postsynaptic membrane at the neuromuscular junction. Myasthenia gravis has been considered to be a generalized AID, because 7% of patients with myasthenia gravis associate with other AIDs and more than one autoimmune antibody is detected in 52.5% patients with myasthenia gravis. Pyramidal signs in myasthenia gravis patients are described; the possible mechanism may at least be partly due to the acetylcholine receptor antibody. P2 protein and its antibody are studied in patients with acute and chronic inflammatory demyelinating polyneuropathy.

This paper reviews research literature on the links between human immune functioning and mood disorders. It summarizes the initial steps of this fledgling research area since its inception in the late 1970s, and outlines a range of studies that are needed to increase our neuroimmunological sophistication. Future investigations will require greater specificity in several interrelated realms of inquiry: diagnostic, epidemiologic, and physiologic. In particular, this paper highlights basic physiological studies needed in both neurophysiology and immunology to provide a foundation for meaningful examination of their interface.

Among the areas that require more specific investigation in both immunologic and mood disorders research is that of temporal organization. Just as psychiatric researchers have begun to scrutinize temporal cycles of mood, behavior, and neurophysiology, so too exploration of immune functioning must take into account predictable temporal cycles such as circadian and ultradian rhythms, as they shape responses to unanticipated external perturbations. Clarification of the temporal dimension will add significantly to our analysis of the links between immune functioning and mood disorders.

The basic science of psychoneuroimmunology continues to mature, bringing new discoveries and revealing hitherto unknown mechanisms and interactions. This is a field of study in many ways still on the frontier, and explication of the long suspected links between mood disorders and immune functioning continues to beckon.

The effects of vasoactive intestinal peptide (VIP) on human immunoglobulin (Ig) production were studied in (1) B cell lines; (2) anti-CD40 mAb-stimulated B cells from non-atopic donors; and (3) unstimulated mononuclear cells from atopic patients. In B cell lines, GM-1056, IM-9, and CBL, VIP enhanced IgA1, IgG1 and IgM production, respectively, in a dose-dependent fashion, while the other neuropeptides somatostatin (SOM) or substance P (SP) failed to do so. Among the various cytokines examined including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, and G-CSF, IL-6 and IL-10 also enhanced Ig production. However, VIP-induced enhancement of Ig production was specific, and was not mediated via these cytokines, since enhancement was blocked by the VIP antagonist, while SOM and SP antagonists, anti-IL-6 mAb, or anti-IL-10 Ab failed to do so. In anti-CD40 mAb-stimulated B cells from non-atopic donors, VIP selectively induced IgA1 and IgA2 production without affecting IgG1, IgG2, IgG3, IgG4, IgM, or IgE production. This stimulatory effect was specifically blocked by the VIP antagonist, but not by SOM or SP antagonists, anti-IL-5 mAb, anti-IL-10 Ab, or anti-TGF-β Ab. VIP induced IgA1 and IgA2 production by surface IgA1⁻ (sIgA1−) and sIgA2⁻ B cells, respectively, while this agent had no effect on sIgA1⁺ and sIgA2⁺ B cells. In contrast, in unstimulated mononuclear cells from atopic patients, VIP selectively inhibited spontaneous IgE and IgG4 production without affecting IgG1, IgG2, IgG3, IgM, IgA1, or IgA2 production. This inhibitory effect was specifically blocked by the VIP antagonist, but not by anti-IFN-α Ab, anti-IFN-γ mAb, anti-IL-12 Ab, or anti-TGF-β Ab. VIP did not inhibit IgE or IgG4 production in B cells or in B cells cultured with either T cells or monocytes. However, VIP inhibited IgE and IgG4 production when B cells were cultured with both T cells and monocytes.

Microglial cells are brain macrophages which serve specific functions in the defense of the central nervous system (CNS) against microorganisms, the removal of tissue debris in neurodegenerative diseases or during normal development, and in autoimmune inflammatory disorders of the brain. In cultured microglial cells, several soluble inflammatory mediators such as cytokines and bacterial products like lipopolysaccharide (LPS) were demonstrated to induce a wide range of microglial activities, e.g. increased phagocytosis, chemotaxis, secretion of cytokines, activation of the respiratory burst and induction of nitric oxide synthase. Since heightened microglial activation was shown to play a role in the pathogenesis of experimental inflammatory CNS disorders, understanding the molecular mechanisms of microglial activation may lead to new treatment strategies for neurodegenerative disorders, multiple sclerosis and bacterial or viral infections of the nervous system.

Nitric oxide, in recent years, has emerged as an important substance capable of modifying many biological processes. It is involved with both neural and immune processes. In my laboratory I will be examining the relationship of nitric oxide and its involvement with modifying dopaminergic processes. In this review, I examine reports that already document this relationship. Nitric oxide appears to be able to facilitate the release of various monoamines, especially dopamine. Furthermore, this gas has the ability to block the presynaptic re-uptake of dopamine as well. Taken together, it would appear that nitric oxide can prolong the ‘life’ of dopamine in the synapse. Given the significance of dopamine in motor and psychological processes the significance of nitric oxide involvement increases exponentially.

Evidence for VIP influences on immune function comes from studies demonstrating VIP-ir nerves in lymphoid organs in intimate anatomical association with elements of the immune system, the presence of high-affinity receptors for VIP, and functional studies where VIP influences a variety of immune responses. Anatomical studies that examine the relationship between VIP-containing nerves and subpopulations of immune effector cells provide evidence for potential target cells. Additionally, the presence of VIP in cells of the immune system that also possess VIP receptors implies an autocrine function for VIP. The functional significance of VIP effects on the immune system lies in its ability to help coordinate a complex array of cellular and subcellular events, including events that occur in lymphoid compartments, and in musculature and intramural blood circulation. Clearly, from the work described in this chapter, the modulatory role of VIP in immune regulation is not well understood. The pathways through which VIP can exert an immunoregulatory role are complex and highly sensitive to physiological conditions, emphasizing the importance of in vivo studies. Intracellular events following activation of VIP receptors also are not well elucidated. There is additional evidence to suggest that some of the effects of VIP on cells of the immune system are not mediated through binding of VIP to its receptor.

Despite our lack of knowledge regarding VIP immune regulation, the evidence is overwhelming that VIP can interact directly with lymphocytes and accessory cells, resulting in most cases, but not always in cAMP generation within these cells, and a subsequent cascade of intracellular events that alter effector cell function. VIP appears to modulate maturation of specific populations of effector cells, T cell recognition, antibody production, and homing capabilities. These effects of VIP are tissue-specific and are probably dependent on the resident cell populations within the lymphoid tissue and the surrounding microenvironment. Different microenvironments within the same lymphoid tissue may influence the modulatory role of VIP also. Effects of VIP on immune function may result from indirect effects on secretory cells, endothelial cells, and smooth muscle cells in blood vessels, ducts, and respiratory airways. Influences of VIP on immune function also may vary depending on the presence of other signal molecules, such that VIP alone will have no effect on a target cell by itself, but may greatly potentiate or inhibit the effects of other hormones, transmitters, or cytokines. The activational state of target cells may influence VIP receptor expression in these cells, and therefore, may determine whether VIP can influence target cell activity.

Several reports described in this chapter also indicate that VIP contained in neural compartments is involved in the pathophysiology of several disease states in the gut and lung. Release of in