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ABSTRACT: This review explores the principle features of the immunopathology of multiple sclerosis (MS), particularly relapsing-remitting MS. It highlights the emerging concepts in the pathogenesis of MS in the context of known features of pathology, including the characterization of cytokine networks promoting inflammatory damage of the central nervous system, B-cell involvement, and inflammatory damage of axons and neurons. This article preferentially focuses on MS rather than animal models of the disease, such as experimental autoimmune encephalomyelitis.
Neurologic Clinics 05/2011; 29(2):257-78. · 2.34 Impact Factor
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ABSTRACT: The adaptor protein Src homology 2 domain-containing leukocyte-specific protein of 76 kDa (SLP-76) is central to the organization of intracellular signaling downstream of the T-cell receptor (TCR). Evaluation of its role in mature, primary T cells has been hampered by developmental defects that occur in the absence of WT SLP-76 protein in thymocytes. Here, we show that following tamoxifen-regulated conditional deletion of SLP-76, mature, antigen-inexperienced T cells maintain normal TCR surface expression but fail to transduce TCR-generated signals. Conditionally deficient T cells fail to proliferate in response to antigenic stimulation or a lymphopenic environment. Mice with induced deletion of SLP-76 are resistant to induction of the CD4+ T-cell-mediated autoimmune disease experimental autoimmune encephalomyelitis. Altogether, our findings demonstrate the critical role of SLP-76-mediated signaling in initiating T-cell-directed immune responses both in vitro and in vivo and highlight the ability to analyze signaling processes in mature T cells in the absence of developmental defects.
European Journal of Immunology 04/2011; 41(7):2064-73. · 5.10 Impact Factor
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ABSTRACT: Experimental autoimmune encephalomyelitis (EAE), a model for the human disease multiple sclerosis (MS), is dependent upon the activation and effector functions of autoreactive CD4 T cells. Multiple interactions between CD4 T cells and major histocompatibility class II (MHCII)+ antigen presenting cells (APCs) must occur in both the periphery and central nervous system (CNS) to elicit autoimmunity. The identity of the MHCII+ APCs involved throughout this process remains in question. We investigated which APC in the periphery and CNS mediates disease using transgenic mice with MHCII expression restricted to dendritic cells (DCs). MHCII expression restricted to DCs results in normal susceptibility to peptide-mediated EAE. Indeed, radiation-sensitive bone marrow-derived DCs were sufficient for all APC functions during peptide-induced disease. However, DCs alone were inefficient at promoting disease after immunization with the myelin protein myelin oligodendrocyte glycoprotein (MOG), even in the presence of MHCII-deficient B cells. Consistent with a defect in disease induction following protein immunization, antigen presentation by DCs alone was incapable of mediating spontaneous optic neuritis. These results indicate that DCs are capable of perpetuating CNS-targeted autoimmunity when antigens are readily available, but other APCs are required to efficiently initiate pathogenic cognate CD4 T cell responses.
Journal of Autoimmunity 02/2011; 36(1):56-64. · 7.37 Impact Factor
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Nature Reviews Neurology 11/2010; 6(11):588-9. · 12.46 Impact Factor
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Meredith H Shaffer,
Yanping Huang,
Evann Corbo, Gregory F Wu,
Marielena Velez,
John K Choi,
Ichiko Saotome,
Judy L Cannon,
Andrea I McClatchey,
Anne I Sperling,
Jonathan S Maltzman,
Paula M Oliver,
Avinash Bhandoola,
Terri M Laufer,
Janis K Burkhardt
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ABSTRACT: Ezrin/radixin/moesin (ERM) proteins are highly homologous proteins that function to link cargo molecules to the actin cytoskeleton. Ezrin and moesin are both expressed in mature lymphocytes, where they play overlapping roles in cell signaling and polarity, but their role in lymphoid development has not been explored.
We characterized ERM protein expression in lymphoid tissues and analyzed the requirement for ezrin expression in lymphoid development. In wildtype mice, we found that most cells in the spleen and thymus express both ezrin and moesin, but little radixin. ERM protein expression in the thymus was differentially regulated, such that ezrin expression was highest in immature thymocytes and diminished during T cell development. In contrast, moesin expression was low in early thymocytes and upregulated during T cell development. Mice bearing a germline deletion of ezrin exhibited profound defects in the size and cellularity of the spleen and thymus, abnormal thymic architecture, diminished hematopoiesis, and increased proportions of granulocytic precursors. Further analysis using fetal liver chimeras and thymic transplants showed that ezrin expression is dispensable in hematopoietic and stromal lineages, and that most of the defects in lymphoid development in ezrin(-/-) mice likely arise as a consequence of nutritional stress.
We conclude that despite high expression in lymphoid precursor cells, ezrin is dispensable for lymphoid development, most likely due to redundancy with moesin.
PLoS ONE 01/2010; 5(8):e12404. · 4.09 Impact Factor
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ABSTRACT: Current therapies for immune-mediated diseases, such as rheumatoid arthritis and MS, could represent the proverbial bird in the hand - a known entity, yet limited in potential. Emerging biologic therapeutics for these diseases carry with them the potential for known as well as unknown adverse effects. Alemtuzumab, a biologic that depletes leukocytes, shows great promise for the treatment of MS. However, a significant number of patients develop autoimmunity after treatment, raising the level of caution for the use of this drug. In this issue of the JCI, Jones et al. describe a link between IL-21 levels and alemtuzumab-associated autoimmunity (see the related article beginning on page 2052). They show that proliferation of lymphocytes in those patients with autoimmunity is higher than in those without autoimmunity and suggest that the lymphopenia-driven proliferation of T cells, in combination with higher IL-21 levels, results in autoimmunity. This study helps inspire new enthusiasm for making a grab for the proverbial two birds in the bush - representing undiscovered therapies - with greater confidence.
The Journal of clinical investigation 08/2009; 119(7):1852-3. · 15.39 Impact Factor
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Emma H Wilson,
Tajie H Harris,
Paulus Mrass,
Beena John,
Elia D Tait, Gregory F Wu,
Marion Pepper,
E John Wherry,
Florence Dzierzinski,
David Roos,
Philip G Haydon,
Terri M Laufer,
Wolfgang Weninger,
Christopher A Hunter
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ABSTRACT: To understand lymphocyte behavior in the brain, we used two-photon microscopy to visualize effector CD8(+) T cells during toxoplasmic encephalitis. These cells displayed multiple behaviors with two distinct populations of cells apparent: one with a constrained pattern of migration and one with a highly migratory subset. The proportion of these populations varied over time associated with changes in antigen availability as well as T cell expression of the inhibitory receptor PD1. Unexpectedly, the movement of infiltrating cells was closely associated with an infection-induced reticular system of fibers. This observation suggests that, whereas in other tissues pre-existing scaffolds exist that guide lymphocyte migration, in the brain specialized structures are induced by inflammation that guide migration of T cells in this immune-privileged environment.
Immunity 02/2009; 30(2):300-11. · 21.64 Impact Factor
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ABSTRACT: Although multiple sclerosis (MS) is a presumed T-cell- mediated disease, it is unclear what triggers the development of neuroantigen-specific T cells. Autoreactive CD4(+) T cells are activated by antigen presenting cells; dendritic cells (DCs) are the primary antigen presenting cells directing T-cell functions and are, therefore, extremely important in directing the immune pathology characteristic of MS. Three important concepts have emerged regarding DCs in MS. First, DCs are present within the healthy central nervous system (CNS) in association with the cerebrospinal fluid space and microvasculature. Therefore, the potential for sampling of CNS antigens in similar fashion to other tissues and organs exists and likely plays an integral role in CNS immunity. The degree of involvement, as well as the source, of these CNS DCs has been addressed by several studies using the experimental autoimmune encephalomyelitis animal model. Second, DCs are found within MS lesions and have been shown to be functionally abnormal in patients with MS. Lastly, therapeutics directed at DCs could potentially be engineered for treatment in MS and in fact may already be involved in the mechanisms of current immunomodulatory therapies.
Current Neurology and Neuroscience Reports 06/2007; 7(3):245-52. · 3.45 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis, Parkinson's disease, atypical parkinsonian syndromes, and multiple sclerosis are progressive neurologic disorders that cumulatively afflict a large number of people. Effective end-of-life palliative care depends upon an understanding of the clinical aspects of each of these disorders.
The authors review the unique and overlapping aspects of each of these disorders with an emphasis upon the clinical management of symptoms. Design: The authors review current management and the supporting literature.
Clinicians have many effective therapeutic options to choose from when managing the symptoms produced by these disorders.
Journal of Palliative Medicine 05/2007; 10(2):433-57. · 1.85 Impact Factor
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ABSTRACT: The cause of transient global amnesia (TGA) remains controversial. Focal cerebral ischemia, seizure, venous congestion, and migraine have all been proposed as underlying mechanisms. We describe a patient presenting with typical TGA who two days later developed a posterior circulation stroke due to basilar artery occlusion. He was treated successfully with intra-arterial thrombolytic therapy. Shortly thereafter, he had recurrent basilar artery thrombosis and jugular vein thrombosis, and was found to have a mucinous adenocarcinoma believed to be causing a hypercoagulable state. We believe this case supports the hypothesis that TGA can on occasion be caused by cerebral ischemia.
Clinical Neurology and Neurosurgery 01/2006; 108(1):60-2. · 1.58 Impact Factor
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ABSTRACT: Endocrine and metabolic disorders that cause neuro-ophthalmologic manifestations are frequently encountered by ophthalmologists in clinical practice. This review focuses on three of the most common entities for which neuro-ophthalmologic signs and symptoms are a prominent feature. These entities include pituitary disorders (adenoma, apoplexy, and hypophysitis), thyroid-associated ophthalmopathy, and neuro-ophthalmologic complications of diabetes mellitus, such as ischemic ocular motor mononeuropathies and diabetic papillopathy.
Ophthalmology Clinics of North America 10/2004; 17(3):427-34, vii.
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ABSTRACT: Dialysis disequilibrium syndrome is a disorder of the central nervous system in patients on dialysis. The underlying etiology is thought to be primarily due to cerebral edema; however, neuroradiologic findings have not been described previously. We describe a patient who presented with new onset headaches and status epilepticus after beginning hemodialysis. Her neuroimaging studies revealed white matter changes in the posterior parietal and occipital lobes similar to those seen in patients with reversible posterior leukoencephalopathy syndrome (RPLS). This case suggests that dialysis disequilibrium syndrome and RPLS may represent a spectrum of disorders in which the underlying mechanism is vasogenic edema.
Clinical Neurology and Neurosurgery 10/2003; 105(4):249-52. · 1.58 Impact Factor
