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West Nile virus (WNV) is a flavivirus belonging to the Japanese encephalitis subgroup (1,2). This subgroup also includes the serologically closely related St. Louis encephalitis virus. Flaviviruses are small single-stranded RNA viruses, with spherical (or more precisely, icosahedral) envelopes between 40 and 50 nm in diameter. [ABSTRACT FROM AUTHOR]

Human T-cell lymphotropic virus type 1 (HTLV-1), the first human retrovirus discovered, has a tropism for T lymphocytes and has been established as the causative agent of adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4 T-cell malignancy (1-4). HTLV-2 was subsequently isolated and found to share approximately 60% nucleotide sequence homology with HTLV-1 (5). In the mid-1980s, HTLV-1 began to be associated through epidemiologic studies as a contributing factor in chronic neurodegenerative disorders. These clinical syndromes were first reported in Japan and Martinique (French West Indies), both regions that were endemic for HTLV-1 infection (6,7). Through important international cooperative studies, both syndromes were revealed to be identical in clinical presentation and are now known collectively as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 has been sporadically associated with lymphoproliferative diseases and recently has been implicated in isolated case reports of neurological disease (8,9). [ABSTRACT FROM AUTHOR]

In past decades, the prime methods used for the study of genes and their respective products were Northern blots, Western blots, in situ hybridization, and immunocytochemistry. The applicability of these methods was restricted to the study of single genes or a few simultaneously (1,2). [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting multiple organ systems. The incidence of SLE is 5.6 per 100,000, with an estimated prevalence of 130 per 100,000 people in the United States (1). Thus, about 380,000 Americans have SLE. Women are affected nine times more frequently than men (2). African Americans and Hispanics are affected much more frequently than Euro-Americans and have more disease morbidity (2-6). Although SLE-related morbidity remains high, the prognosis for survival has improved in recent years, from a 5-yr survival of 51% in the 1950s to more than 90% in recent studies (3). A bimodal pattern of mortality, in which early deaths are caused by SLE disease activity or infections and later deaths are owing primarily to vascular causes (7-9) has been described. Because of this greater survival, emphasis has shifted towards improving health status and quality of life. [ABSTRACT FROM AUTHOR]

Among the inflammatory disorders, sarcoidosis is one of the most intriguing. It is a complex disorder with unknown etiology. New insights regarding epidemiology, immunology, and pathogenesis have expanded our knowledge of this disease in the last one to two decades. More novel therapeutic applications from the knowledge of immunopathogensis will hopefully improve our treatment armamentarium against this disorder. [ABSTRACT FROM AUTHOR]

The vasculitides are a heterogenous group of multisystemic disorders that are pathologically characterized by inflammation of the blood vessels, structural damage to vessels, and usually vascular necrosis. Because involvement of blood vessels can result from inflammation of any type, vasculitis may be a presentation of diverse disorders. Vasculitis can occur either as a primary vasculitic disease or secondarily to another underlying pathology (1-3). Vasculitis of the nervous system is both a diagnostic and management challenge for clinicians. Both the central nervous system (CNS) and peripheral nervous system (PNS) may be involved in the vasculitic process. [ABSTRACT FROM AUTHOR]

The incidence of optic neuritis (ON) is approximately three to five cases per 100,000 individuals per year in northern latitudes, where multiple sclerosis (MS) is common (1-4). It affects women more often than men (female to male ratio 2:1) and is more common in younger age groups (1). The age distribution is slightly different from that of MS, showing peaks in young (age group 15-25 yr) and old patients (age group 55-65 yr) of the distribution spectrum. Major histocompatibility complex (MHC) class H antigens are associated with ON, suggesting a genetic predisposition for specific immune responses (5). In particular, the results of the Optic Neuritis Treatment Trial (ONTT) (6) showed that the human leukocyte antigen (HLA)-DR2 genotype predicted a higher susceptibility for conversion to clinically definite MS over 5 yr, especially in MS patients with signal abnormalities on brain magnetic resonance imaging (MRI). Usually, episodes of ON are more common at high latitudes (1,2), in spring (7), and in summer (8), although one study showed that 43% of 42 patients who developed MS, had onset of ON between October and March (9). [ABSTRACT FROM AUTHOR]

First described in 1882, and termed acute transverse myelitis (TM) in 1948 (1), TM is a rare syndrome with an incidence of between one and eight new cases per million people per year (2). TM is characterized by focal inflammation within the spinal cord and clinical manifestations are caused by resultant neural dysfunction of motor, sensory, and autonomic pathways within and passing through the inflamed area. There is often a clearly defined rostral border of sensory dysfunction and evidence of acute inflammation demonstrated by a spinal magnetic resonance imaging (MRI) and lumbar puncture. When the maximal level of deficit is reached, approx 50% of patients have lost all movements of their legs, virtually all patients have some degree of bladder dysfunction, and 80 to 94% of patients have numbness, paresthesias, or band-like dysesthesias (2-7). Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty or inability to void, incomplete evacuation or bowel, constipation, and sexual dysfunction (8). Like multiple sclerosis (MS) (9), TM is the clinical manifestation of a variety of disorders with distinct presentations and pathologies (10). Recently, we proposed a diagnostic and classification scheme that has defined TM as either idiopathic or associated with a known inflammatory disease (i.e., MS, systemic lupus erythematosus [SLE], Sjogren's syndrome, or neurosarcoidosis) (11). Most TM patients have monophasic disease, although up to 20% will have recurrent inflammatory episodes within the spinal cord (Johns Hopkins Transverse Myelitis Center [JHTMC] case series, unpublished data) (12,13). [ABSTRACT FROM AUTHOR]

Idiopathic inflammatory demyelinating central nervous system (CNS) diseases include the various clinical types of multiple sclerosis (MS), acute transverse myelitis (TM), optic neuritis (ON), recurrent forms of TM and ON, the Marburg variant of MS, Balo's concentric sclerosis, and neuromyelitis optica (NMO; Devic's syndrome or Devic's disease) (1). The association of spinal cord disease and visual impairment was first recognized in 1870 by Allbutt (2). In 1894, Devic reported a case of bilateral ON and myelitis occurring in rapid succession, leading to the eponymous designation of Devic neuromyelitis optica (3). Stansbury's extensive 1949 review influenced the clinical concept of NMO; thereafter, the term was typically applied to patients with a monophasic disorder consisting of acute or subacute, usually bilateral, ON occurring in close temporal association with severe myelitis (4-7). [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS), which has been postulated to be a T-cell-mediated autoimmune disease (1,2). Although the etiology of MS is unknown, most investigators believe that the immune system is intimately involved in the progression of the disease (3). MS is clinically associated with periods of disability (relapse) alternating with periods of recovery (4) but often leading to progressive neurological disability (2,5). The lesions in the CNS are similar to the lesions produced by T-lymphocyte delayed-type hypersensitivity (DTH) reactions. [ABSTRACT FROM AUTHOR]

Acute disseminated encephalomyelitis (ADEM) is a rare monophasic inflammatory demyelinating disorder of the central nervous system (CNS) that occurs more often in children or young adults than in older people and has been recognized for more than 200 yr (1). The lack of a universally accepted definition of ADEM is a major impediment to understanding and describing its clinical-pathological boundaries (2,3). [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is considered an immune-mediated, demyelinating, and degenerative disease of the central nervous system (CNS). The immune-mediated pathogenesis is supported by the significant infiltration of leukocytes into the CNS parenchyma and by the finding of a substantial similarity between active MS plaques and lesions in the CNS of animals with experimental autoimmune encephalomyelitis (EAE); EAE is produced by an autoreactive T-cell response. The favorable response of many MS patients to immunomodulatory drugs, including use of β interferons (IFNs) and glatiramer acetate to decrease the number of relapses and reduce magnetic resonance imaging (MRI) disease activity (1-4), also corroborates the hypothesis of immune-mediated injury. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) was first described by Charcot in mid-19th century Paris. Charcot, however, attributed the original recognition of this disorder to Cruveillier, the famed professor of anatomy. Although others also described the pathological anatomy of the disease in remarkable detail, it was Charcot who characterized the clinical illness and correlated the illness with its unique neuropathology (1). From the outset, researchers recognized that the illness differed from one patient to another, with the majority of patients experiencing a relapsing-remitting disease (relapsing-remitting MS) (1,2). Charcot recognized that a minority of patients had a fundamentally different illness, which he described as an "incomplete" form of the disease (1,2). From their first symptoms, these patients showed signs of a progressive spinal cord disease without relapses. These patients are now designated as having primary progressive MS (PPMS) (2). [ABSTRACT FROM AUTHOR]

It is now recognized that all circulating blood cells, as well as endothelial cells (EC), continuously shed small membranous vesicles (microparticles [MPs]), which are approximately less than 1 µm, and that levels of circulating MPs are sensitive indicators of disease activity. The first type extensively studied in patients was platelet MP (PMPs) (1). Currently, endothelial-derived MP (EMPs) have risen to the fore as sensitive markers of EC perturbation, recently reviewed (2) and further considered in this article. Although other reviews may differ in viewpoint and emphasis (3,4), it is generally agreed that circulating MPs comprise different subspecies of membrane vesicles released from endothelium and blood cells, such as platelets, leukocytes, and red blood cells (RBCs). MPs containing negatively charged phospatidylserine (PS) and/or tissue factor are highly procoagulant. MPs that express specific adhesion molecules are capable of interacting with leukocytes and endothelia to initiate inflammatory responses. [ABSTRACT FROM AUTHOR]

Chemokines are small molecular-weight chemotactic cytokines that can be classified into four subfamilies based on the position of the amino-terminal cysteines (1,2). The CXC chemokines can be further categorized based on the presence or absence of a glutamate-leucine-arginine (ELR) motif in the amino terminus. Chemokines that possess the ELR motif are generally chemotactic for neutrophils and are angiogenic, whereas the non-ELR CxC chemokines are chemotactic for activated T cells and are angiostatic (3). The CC family of chemokines are chemoattractant for a variety of cell types, including monocytes/macrophages, T lymphocytes, basophils, eosinophils, and dendritic cells (4-6). The C family, lymphotactin, is chemotactic for T cells and natural killer (NK) cells (7) and the CX3C chemokine contains a chemokine domain attached to a membrane-bound mucin chain that produces a soluble chemoattractant after proteolysis or mRNA processing (8). This chemokine is a chemoattractant for T cells, NK cells, and neutrophils (2). Chemokines and chemokine receptor-like molecules are also encoded by viruses and used in a variety of strategies to subvert the immune response (9). [ABSTRACT FROM AUTHOR]

The presence of proinflammatory cytokines in normal central nervous system (CNS) tissues remains an area of controversy (1). Several cytokines have been demonstrated in the normal CNS, and among them, tumor necrosis factor (TNF)-α, interleukin-1 (IL-1), transforming growth factor (TGF)-β, and macrophage migration inhibitory factor (MIF) have been studied in detail. The functions of TNF-α, IL-1, and TGF-β in the context of neuroinflammation have been described in detail elsewhere in this chapter; therefore, in this section, we will discuss only the potential roles these cytokines have in CNS development and physiological functions. [ABSTRACT FROM AUTHOR]

A functional central nervous system (CNS) is essential for mammalian survival; therefore, the CNS must be defended from insults and other pathogens. The molecules (e.g., free radicals, cytokines, proteases) produced in vast quantities by the activated immune system to combat pathogens have the demonstrated potential to disrupt CNS function (1-3). To balance these opposing needs, (sufficient defense of the CNS without loss of CNS function), the CNS and immune system have developed a unique relationship referred to as immune privilege. Disruptions in this unique relationship leading to disregulated CNS inflammation are now thought to contribute to the onset and progression of many diverse types of CNS pathology, including CNS autoimmune diseases such as multiple sclerosis (MS), Rasmussen's encephalitis, and narcolepsy; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and stroke; and the secondary neurodegeneration associated with spinal cord injury (3-10). [ABSTRACT FROM AUTHOR]

Inflammation is a reactive response to infection or injury that involves many complex interactions between formed blood elements, vascular and tissue cells, which is controlled by the release and synthesis of several classes of soluble mediators in response to tissue injury, bacterial, or viral products. Some mediators are stored within several cell types (e.g., histamine, 5-hydroxytryptamine, proteases, and cationic proteins), whereas others are synthesized or induced cell-derived factors (e.g., prostanoids, leukotrienes, platelet-activating factor, and cytokine/chemokines), as well as products of proteolytic cascades in plasma (complement products, blood-coagulation cascade products, kinins). The extent, timing, and specificity of this response is related to the lability, metabolism, and scavenging/inactivation of these mediators. The recruitment of leukocytes to the sites of injury or infection is a central event in the inflammatory response, and often results in "bystander" tissue dysfunction and damage from leukocyte oxidants, proteases, and other mediators in several disease states. [ABSTRACT FROM AUTHOR]