NeuroInflammation

SUMMARY

There has been a significant interest in neuroimmunology in recent years, primarily related to the improved understanding of autoantibody associated encephalitis and demyelination syndromes. This symposium will discuss recent developments outside of the classic ‘autoimmune CNS disorders’. The session will start by setting the scene regarding the different types of inflammation, and the reasons that inflammation may occur. The symposium then focuses on the role of inflammation in important and common neurological scenarios, such as autistic spectrum disorders, premature brain injury and neurodegeneration. The developments in this exciting, and sometimes controversial area will be highlighted. In addition, the opportunities and challenges of modifying the neuroinflammation will be discussed.

LEARNING OBJECTIVES

• Exchange the expertise among clinicians in order to define protocols for dealing with neuroinflammatory diseases in a broad sense.
• Concept innovative proposals via insertion of biomarkers in an attempt to make an early diagnosis possibly enabling an adequate therapeutic approach

INVITED SPEAKERS & TALKS

MING LIM

Dr Ming Lim MRCP PhD
Consultant Paediatric Neurologist
Evelina Children's Hospital 
Children's Neurosciences Centre, Newcomen Centre at St Thomas', Staircase D South Wing,
St Thomas' Hospital, London SE1 7EH

Ming Lim undertook his undergraduate medical training at the University of Nottingham, UK. Following completing his paediatric neurology training in South London, and a period of doctoral research in the neuroscience department of the Institute of Psychiatry (London), he was appointed as Consultant Paediatric Neurologist at the Evelina Children’s Hospital, London. He has a major interest in childhood inflammatory disorders and runs the regional paediatric brain and spine inflammation service. He works collaboratively with the Oxford Clinical Neurosciences Group (Professor Angela Vincent) on numerous studies to define childhood central nervous system autoimmune disorders. In addition, he also has a research interest in the inflammatory mechanisms in childhood onset neurodegenerative disorders, pursued via the Faculty of Translational Medicine and BRC of King Health Partners, London.

Talk: Overview of CNS inflammation: mechanisms and interventions
Immune responses in the central nervous system (CNS) are common, despite it being perceived as an immune privileged site. The orchestration of this process involves the complex interaction between the innate and adaptive immune system, both centrally and systemically, to achieve the physiological role of eliminating an environmental stressor such as infection or tissue damage, thus achieving an overall beneficial effect. Nevertheless there is now unequivocal evidence that neuroinflammation may also lead to neurodegeneration. Identifying and subsequently targeting pathogenic mechanisms of CNS inflammation has afforded the clinician with a growing repertoire of therapeutic strategies, although such treatments are often empirically employed as these processes cannot be reliably evaluated for each individual patient. This overview will highlight i) novel genetic and environmental determinants in brain inflammation; ii) the crucial role of the systemic immune system and inflammation in CNS inflammation and; iii) the increasing recognition of the secondary role of inflammation in a range of other “non-inflammatory” neurological conditions. Ultimately, the effective management of CNS inflammation is likely to require appropriately timed combination of therapies.

DR. ANDREW ZIMMERMAN
Pediatric Neurologist, Associate Professor, Director of Medical Neuroscience, Center for Autism and Related Disorders, Kennedy Krieger Institute, Johns Hopkins Medicine, Broadway, Baltimore.
E-mail: zimmerman@kennedykrieger.org
Phone: (443) 923-9150

Dr. Zimmerman is a pediatric neurologist and research scientist at UMass Medical School. He has been interested in immune aspects of autism and has conducted studies in the field over the past 20 years. In autism, a number of studies have shown that autistic patients have variously altered numbers and functions of lymphocytes, natural killer cells and cytokines in the peripheral circulation. Dr. Zimmerman and his collaborators first demonstrated that rheumatoid arthritis and other autoimmune disorders occur more commonly than expected in the families of children with autism, along with increased frequency of HLA-DR4. They also reported on serum antibodies from mothers of autistic children that react to fetal brain, and their antigenic targets have recently been described by Van de Water et al. Another study reported behavioral improvements during fever in children with autism and has provided impetus for further studies of underlying causes and possible new treatment approaches.

Inflammatory Component in the Pathogenesis of Autism Spectrum Disorders.

Typically ASDs are heterogeneous, are defined behaviorally and 20 per cent or more have discoverable genetic, metabolic or infectious etiologies. Inflammatory changes in the GI tract and allergies in patients with autism, along with systemic immune differences and discoveries of genes related to the immune system, have raised questions with regard to their possible roles in the cause or aggravation of autistic symptoms. Dr. Zimmerman and colleagues reported microglial activation in postmortem brain tissue from patients with different forms of ASD from 5 to44 years of age, as well as differences in cytokines, chemokines and growth factors in brain tissue and CSF. The nature of these changes in the brain in ASDs presents challenging questions with respect to their meaning and implications for research and possible therapeutic approaches. Are they the result of preceding infection, abnormal immune regulation, genetic or systemic abnormality? Are they injurious to other cells or cause synaptic dysfunction, or do they result from underlying dysmaturity or cellular signaling abnormalities? Are immunomodulatory approaches appropriate or should others be considered, such as stimulation of cellular stress responses or gene transcription? Current research will help to answer some of these questions while raising additional ones, and provide new directions for investigation and therapy.

BOBBI FLEISS

Dr Bobbi Fleiss is a translational perinatal brain injury researcher. The objectives of her research is to increase understanding of the pathophysiological mechanisms of brain damage in the newborn and to develop strategies for neuroprotection. This research involve experimental studies in animals, and where possible, studies in humans, leading to the mutual enrichment of these two complementary approaches within a translational research framework.

Talk: The role of neuroinflammation in the encephalopathy of prematurity

The neuropathology of encephalopathy of prematurity consists of diffuse, noncystic white matter injury without focal necrosis and an often-associated neuronal/axonal damage. Neuroinflammation and the severity of prematurity are important risk factors for encephalopathy, and for cerebral palsy and other lasting neurological deficits. Neuroinflammation is mediated by cytokines derived from immune cells, microglia and astrocytes and these cause injury to neurons and oligodendrocytes. In addition to immediate effects, this inflammatory response affects brain development increasing the risk of neurologic diseases. The absence of adequate therapeutic approaches for encephalopathy of prematurity is due to our limited knowledge of the highly complex molecular targets that underlie the crosstalk between the neurologic and immune systems and dysregulated developmental processes. As such, one important step for improving morbidity is to increase in our knowledge of the pathogenesis of microglia-mediated injury in the immature brain, including within the white matter and subplate regions. In addition, the identification of biomarkers for neuroinflammatory processes and prognosis as well as new therapeutic targets are needed in an attempt reduce the burden of deficits linked to encephalopathy of prematurity including cerebral palsy.

JONATHAN MINK

Pediatric Neurologist, Frederick A. Horner, MD Endowed Professor in Pediatric Neurology, Professor of Neurology, Neurobiology & Anatomy, Brain & Cognitive Sciences, and Pediatrics,
Chief, Division of Child Neurology and Vice Chair, Department of Neurology, University of Rochester, Rochester, NY USA.
E-mail: Jonathan_Mink@urmc.rochester.edu

Dr. Mink is a pediatric neurologist and neuroscientist at the University of Rochester. He has active research programs in the physiology of motor control, the pathophysiology and treatment of movement disorders, and experimental therapeutics for neurodegenerative diseases of childhood. His clinical interests include movement disorders and neurodegenerative disease in children. He has been interested in the neuronal ceroid lipofusinoses (NCLs; Batten disease) and has conducted clinical research in Juvenile NCL for the past 13 years. Dr. Mink serves on a number of medical and scientific advisory boards including the Batten Disease Support and Research Association. the Pediatric Neurotransmitter Disease Association, and the US National Advisory Neurological Disorders and Stroke Council. He is co-chair of the scientific advisory board of the Tourette Syndrome Association.

Talk: Inflammation in the Neuronal Ceroid Lipofusinoses (NCL)

The NCLs consist of more than 10 different lysosomal storage disorders characterized pathologically by accumulation of an autofluorescent material in the lysosomes and clinically by a constellation of symptoms that typically includes vision loss, progressive dementia, epilepsy, and a movement disorder. Over the past 10 years, several lines of evidence have emerged indicated that immune mechanisms and inflammation are likely to play a role in the pathobiology of Juvenile NCL (CLN3 disease) and in other forms of NCL. These data will be reviewed. Although neuroinflammation is not the primary pathological mechanism in these disorders, it may contribute to disease progress and provide an avenue for disease- modifying therapy. Indeed, immunomodulation has been shown to be neuroprotective in a rodent model of JNCL and is under investigation in human subjects. Preclinical studies in other forms of NCL have also shown promise for immunomodulation as a disease modifying therapy.