Molecular Pathogenesis of Neuroinflammation M Bradl, R Hohlfeld

1364 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1364 on 20 October 2003. Downloaded from NEUROSCIENCE FOR NEUROLOGISTS Molecular pathogenesis of neuroinflammation M Bradl, R Hohlfeld ............................................................................................................................... J Neurol Neurosurg Psychiatry 2003;74:1364–1370 The past few years have seen significant progress towards EXPERIMENTAL AUTOIMMUNE understanding the mechanisms of immune surveillance and ENCEPHALOMYELITIS—AN ANIMAL MODEL TO STUDY INTERACTIONS OF THE inflammation in the nervous system. In this review, the IMMUNE SYSTEM WITH THE CNS milestones of scientific discovery in this field are discussed, Most of our current knowledge about neuro- and the strengths and limitations of the different ways of inflammation has been obtained from experimental autoimmune encephalomyelitis (EAE), examining the molecular pathogenesis of neuro- which for decades has served as the best animal inflammation examined. The review is limited to the model to study the aspects of CNS inflammation inflammatory reactions of the central nervous system that and demyelination seen in human patients with multiple sclerosis. It is quite bizarre that this occur in multiple sclerosis and experimental autoimmune invaluable animal model had its origin in a series encephalomyelitis. of neuroparalytic accidents in humans receiving ........................................................................... anti-rabies treatments with killed carbolised virus isolated from infected animal brains. The discovery that brain material contaminating the oday we are well aware that there is vaccine was responsible for paralysis10 paved the substantial communication between the way for pioneering experiments in which CNS Timmune system and the central nervous inflammation and demyelination were induced system (CNS), and that interactions between in experimental animals by immunisation with these two systems occur both in the brain material.11 The resulting disease model was healthy organism and in pathological situa- termed EAE, and has been markedly refined over copyright. tions.1 However, this was not always the the years. At the start, crude spinal cord or brain case. extracts were used for immunisation12; later, Some 20 to 30 years ago, the CNS and the purified CNS proteins were used, such as myelin immune system were considered strictly separate basic protein (MBP),13 proteolipid protein structures, and the CNS was viewed as the (PLP),14 myelin oligodendrocyte glycoprotein classical example of an ‘‘immunoprivileged site.’’ (MOG),15 S100b,16 and now often only small This assumption was based on the prolonged peptides (of about 20 amino acids in length) survival of tissue grafts within the CNS,2 derived from CNS proteins.7 the presence of the blood–brain barrier (an A breakthrough came when it was observed endothelial barrier between blood and brain, that EAE can be transferred between animals by 17 which forms tight junctions and prevents an lymph node cells, that pure CNS antigen http://jnnp.bmj.com/ uncontrolled influx of molecules and cells into specific T cells can be cultured and activated in the CNS3), the lack of classical lymphatic vitro,18 and that these cells were also able to drainage pathways,3 the lack of professional initiate EAE upon transfer in naive recipient antigen presenting cells such as dendritic animals.18 In fact, T cell transferred EAE has cells,4 and the infrequent expression of major considerable advantages over immunisation histocompatibility complex (MHC) molecules induced EAE in that it starts earlier and shows 7 needed to present CNS antigens to infiltrating less variation between animals. T cells.4 Other refinements of the EAE model applied to on September 30, 2021 by guest. Protected All these observations seemed to indicate the choice of animals. As seen in human patients that the immune system and the CNS are with multiple sclerosis, different strains of animal display different types of disease course, See end of article for separate domains. However, over the years novel experimental evidence challenged this tradi- different symptoms, and different pathological authors’ affiliations 7 ....................... tional viewpoint: the intact CNS parenchyma changes within the CNS. The most recent 56 developments in the field are: Correspondence to: regularly contains small numbers of T cells, Dr M Bradl, Institute for T cells may also enter the CNS in the course Brain Research, of CNS inflammation and degeneration,78 ................................................... Department of and interstitial/cerebrospinal fluid and proteins Neuroimmunology, Abbreviations: BDNF, brain derived neurotrophic factor; Spitalgasse 4, A-1090 drain from the brain to the blood and may EAE, experimental autoimmune encephalitis; EAN, Vienna, Austria; affect immune responses in the draining lymph experimental autoimmune neuritis; IMDS, isolated [email protected] nodes.9 monosymptomatic demyelinating syndrome; INFc, It is now clear that the CNS is under constant interferon c; MBP, myelin basic protein; MHC, major Received 19 May 2003 histocompatibility complex; MOG, myelin In revised form 4 July 2003 immune surveillance, and that it interacts with oligodendrocyte glycoprotein; PLP, proteolipid protein; Accepted 8 July 2003 cells of the immune system in both health and TNFa, tumour necrosis factor a; CNS, central nervous ....................... disease. system; PCR, polymerase chain reaction www.jnnp.com Molecular pathogenesis of neuroinflammation 1365 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.10.1364 on 20 October 2003. Downloaded from N the use of genetically modified animals with defined example DRB1*1501 loaded with an MBP peptide and changes in cells of the immune or central nervous systems; DRB5*0101 loaded with an Epstein-Barr virus peptide).23 N the production and transfer of fluorescent CNS antigen Finally, a ‘‘humanised mouse model’’ of multiple sclerosis specific T cells to trace their migration and cellular has been developed using multiply transgenic mice.24 These changes in the course of the disease; mice express three human components involved in T cell N microdissection and molecular analyses of single cells recognition of the multiple sclerosis related autoantigen involved in the disease process; MBP: HLA-DR2, an MHC class II antigen associated with multiple sclerosis in north Europeans; a T cell receptor from a N spectratyping of disease relevant T cell receptors; T cell clone specific for the MBP peptide 84–102 derived from N the search for antigens recognised by CNS infiltrating T a multiple sclerosis patient; and the human co-receptor CD4. cells in biopsy/necropsy material from patients suffering When backcrossed to Rag2 deficient mice, these transgenic from inflammatory CNS disease; humanised mice spontaneously develop inflammatory dis- N the use of DNA microarrays to study simultaneously the ease of the CNS.24 interactions between many different genes in CNS The EAE experiments described above clearly show that inflammation; CNS antigen specific T cells which had been activated N the development of new treatments based on the unique somewhere in the body—whether by direct antigen contact property of activated CNS antigen specific T cells to cross in the course of immunisation or by the antigen independent the blood–brain barrier. action of certain bacterial or viral proteins—are able to cross the intact blood–brain barrier and enter the CNS parenchyma. It is assumed that these cells find ‘‘their’’ specific HOW MODERN TECHNIQUES CONTRIBUTED TO antigen upon entry into the CNS, are further activated, and OUR UNDERSTANDING OF NEUROINFLAMMATION then interact with local glial cells, leading to a locally IN EAE AND MULTIPLE SCLEROSIS confined release of chemokines and cytokines. These proteins Genetically manipulated animals activate the blood–brain barrier and attract further cells from Probably the most fruitful—and currently most popular— the immune system. A second wave of immune cell technology is the genetic manipulation of experimental infiltration into the CNS follows, which seems to be animals so that factors or even entire cell populations are independent of the antigen recognition or the activation 1 missing (‘‘knock-out animals’’), or so that proteins under status of the recruited cells. Inflammatory lesions develop. investigation are produced in a temporally or spatially controllable way (conditionally ‘‘transgenic’’ animals). Such Progression of CNS inflammation and the resulting strategies have furthered our understanding of the different tissue damage phases of autoimmune CNS inflammation. Like multiple sclerosis, EAE can take different clinical courses. In some animal strain or antigen combinations the copyright. The initiation of inflammatory lesions in the CNS course is monophasic; in others it is fulminant/lethal, It is well established that CNS antigen specific T cells are relapsing/remitting, or chronically progressive. In animals normal components of the immune system of every healthy with relapsing/remitting or chronically progressive types of organism.19 20 However, spontaneous CNS inflammation EAE, and in human patients with isolated monosymptomatic provoked by these cells is exceedingly rare. Why? To answer demyelinating syndrome (IMDS), the proliferative response this question, transgenic mice were constructed which carry of T cells to the ‘‘priming’’ myelin

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