Positive or Negative Involvement of Heat Shock Proteins in Multiple Sclerosis PathogenesisAn Overview

J Neuropathol Exp Neurol Copyright Ó 2014 by the American Association of Neuropathologists, Inc. Vol. 73, No. 12 December 2014 pp. 1092Y1106 REVIEW ARTICLE Positive or Negative Involvement of Heat Shock Proteins in Multiple Sclerosis Pathogenesis: An Overview Giuseppina Turturici, PhD, Rosaria Tinnirello, PhD, Gabriella Sconzo, PhD, Alexzander Asea, PhD, Giovanni Savettieri, MD, Paolo Ragonese, MD, PhD, and Fabiana Geraci, PhD Abstract Multiple sclerosis (MS) is the most diffuse chronic inflammatory disease of the central nervous system. Both immune-mediated and neurodegenerative processes apparently play roles in the pathogenesis of this disease. Heat shock proteins (HSPs) are a family of highly evolutionarily conserved proteins; their expression in the nervous system is induced in a variety of pathologic states, including cerebral ischemia, neurodegenerative diseases, epilepsy, and trauma. To date, investigators have observed protective effects of HSPs in a variety of brain disease models (e.g. of Alzheimer disease and Parkinson disease). In contrast, unequivocal data have been obtained for their roles in MS that depend on the HSP family and particularly on their localization (i.e. intracellular or extracellular). This article reviews our current understanding of the involvement of the principal HSP families in MS. Key Words: Heat shock proteins, Innate immunity, Multiple sclerosis, Myelin antigens, Toll-like receptors. MULTIPLE SCLEROSIS Multiple sclerosis (MS) is a complex disease that is influenced by genetic, epigenetic, and environmental factors, including gender, sex hormones, ethnic origin, latitude of early life residence, smoking, pathogen exposure, and vitamin D levels (1Y5). Recent epidemiologic data suggest a genetically determined susceptibility and indicate that the incidence of MS correlates with environmental factors that occur during childhood, which, after several years of latency, determine the onset of MS (6Y8). Therefore, the clinical, pathologic, and From the Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) Sez Biologia Cellulare ed 16 (GT, RT, GS, FG); and Dipartimento di Biomedicina Sperimentale e Neuroscienze Cliniche (BIONEC) (GS, PR), Palermo, Italy; Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, Georgia (AA); and Euro-Mediterranean Institute of Science and Technology, Palermo, Italy (AA, FG). Send correspondence and reprint requests to: Fabiana Geraci, PhD, Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF) Sez Biologia Cellulare ed 16 Viale delle Scienze 90128 Palermo, Italy; E-mail: Giuseppina Turturici and Rosaria Tinnirello contributed equally to this work. This work was supported by University funding FFR STEBICEF R2FFRAD15 + PNFK, progetto di ricerca per la sclerosi multipla R4D15 + P118 MERC. No competing financial interests exist. 1092 immunologic phenotypes of MS are highly heterogeneous, indicating that it may better be defined as a syndrome rather than a single disease. Multiple sclerosis is the most common chronic inflammatory central nervous system (CNS) disease of likely autoimmune etiology. It is thought to be caused by an inappropriate immune T cellYmediated response, that is, T-helper Type 1 and T-helper Type 17 (Th1, Th17), against CNS myelin or other antigens (9). This representation is called the outside-in model. However, a recent reinterpretation of the available experimental data suggested another hypothesis called the inside-out model (10). According to this model, MS is a primary neurodegenerative disease, and the inflammatory response is an epiphenomenon caused by the host’s aberrant immune response. Indeed, laboratory and clinical observations have shown some inconsistencies in the ‘‘outside-in’’ model, particularly in the initial stages of the disease during which the largest myelin abnormalities sometimes begin at the inner myelin sheath, which is not accessible to antibody- or immune cellYmediated attack (10). In autopsy material obtained from patients in early active stages of MS, no infiltration of T and B cells was observed in areas of demyelination and oligodendrocyte loss; only macrophage infiltration and microglial activation, markers of the innate immune response activation, were detected (11,12). Recent results from clinical trials in MS have confirmed that immunomodulatory drugs significantly attenuate the course of the disease (13). Demyelinating lesions are predominantly located in the white matter and contain clonally expanded CD8-positive/CD4-positive T cells (14Y17), FC T cells (18), and monocytes (19,20). It has additionally been demonstrated that the gray matter structures of the brain are also affected (21). Clinical symptoms and signs vary based on the site of the lesions. As a consequence of myelin sheath destruction, nerve action potentials are disrupted, resulting in neurologic disability. Pathologic hallmarks of MS include areas of focal demyelination characterized by gliosis and neuron and oligodendrocyte loss that are particularly common in the brain, spinal cord, and optic nerves (22). The majority of patients (nearly 85%Y90%) experience a sudden onset of symptoms, with subsequent episodes of acute attacks followed by partial or complete recovery and variable periods of remission. In the remaining 10% to 15% of patients, the course of MS is progressive from the onset, that is, primary progressive (PP) MS. Most patients with a relapsing-remitting (RR) disease course at onset eventually experience a change in the disease course to J Neuropathol Exp Neurol  Volume 73, Number 12, December 2014 Copyright © 2014 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited. J Neuropathol Exp Neurol  Volume 73, Number 12, December 2014 become progressive, that is, secondary progressive (SP) MS (23). Pathogenic studies have clearly indicated that axonal injury is a key feature of MS pathogenesis; the extent of axonal damage is also correlated to the degree of inflammation in the relapsing phases of the disease. A close relationship between inflammation and degeneration has also been described for all disease stages of MS. Nevertheless, the specific mechanisms of the interdependence between focal inflammation, diffuse inflammation, and neurodegeneration remain unclear. Unlike other neurologic diseases in which it is possible to define high-affinity antibodies that recognize self-antigens (24Y26), it is difficult to identify a single antigen specificity in MS patients that is responsible for the autoreactive response. The general idea is that, in MS pathogenesis, not one but several antigens are involved in the disease. It is likely that the initial autoreactivity is specific for a particular antigen but, in a second step of the disease, a process of epitope or antigen spreading may increase the pool of activated immune cells. Previous (...truncated)