Heat-Shock Proteins in Clinical Neurology

Heat-shock proteins (HSPs) are antigen-presenting proteinaggregation-preventing chaperones, induced by cellular stress in eukaryotic cells. In this review, we focus on recent HSP advances in neurological disorders. In myasthenia gravis, patients responding to immunosuppressive therapy have reduced serum HSP-71 antibodies. Generalized and ocular myasthenia gravis patients have elevated serum HSP-70 antibodies, indicating common pathogenic mechanisms. In Guillain-Barré syndrome, HSP-70 antibodies are elevated in serum and cerebrospinal fluid, and serum levels are higher than in myasthenia gravis and multiple sclerosis. In multiple sclerosis, serum HSP-27 antibodies are elevated during relapses providing disease activation marker, while  , crystallin expression in brain lesions indicates remission phase initiation. In acute stroke, serum HSP-27 antibodies are elevated irrespective of stroke type and duration. In epilepsy, HSP-27 is induced in patients’ astrocytes and cerebral blood vessel walls, and , -crystallin is expressed in epileptic foci. In neurodegenerative disorders such as Alzheimer dementia and Parkinson’s disease, HSPs are upregulated in brain tissue, and  , -crystallin modulates superoxide dismutase-1 (SOD-1) tissue accumulation in familial amyoReceived: February 17, 2011 Accepted: May 16, 2011 Published online: July 13, 2011 Fredrik Romi Department of Neurology, Haukeland University Hospital NO–5021 Bergen (Norway) Tel. +47 5597 5000 E-Mail fredrik.romi @ haukeland.no © 2011 S. Karger AG, Basel 0014–3022/11/0662–0065$38.00/0 Accessible online at: www.karger.com/ene D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 7 :0 8: 04 P M Romi /Helgeland /Gilhus Eur Neurol 2011;66:65–69 66 specific tolerance, which could also be adoptively transferred [10] . HSP-70 is believed to be involved in the pathogenesis of several autoimmune disorders, including Behçet’s disease [11] , Grave’s disease [12, 13] , and increased levels are found locally in experimental autoimmune neuritis [14] . Its ability to augment antigen presentation has been shown in experimentally induced diabetes mellitus [15] , HSP-70 therefore plays a role in antigen presentation and development of tolerance, and antibody-mediated interference with its function can alter immune responses. A pathogenic role of HSPs has been suggested for some neurological disorders, and advances have been made in understanding this role. HSPs may even have neuroprotective properties [16] . The aim of this paper is to review the field, focusing on possible current and future HSP implications for neurological disorders. HSPs in Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune disease with skeletal muscle weakness. Autoantibodies against acetylcholine receptor (AChR) in the postsynaptic membrane are present in 85% of generalized MG (GMG) patients and in half of ocular MG (OMG) patients [17, 18] . While 15% of OMG patients remain purely ocular, many patients develop GMG during the first 2 years of the disease [19] . Thymoma is present in 15% of MG patients [20] . AChR autoantibodies impair neuromuscular transmission by cross-linking AChR and increasing its degradation, and also by complement-mediated postsynaptic membrane damage, and direct blockade of ligand-receptor interaction [17, 21] . Antibodies to muscle-specific kinase (MuSK) are present in a proportion of AChR antibody-negative MG patients [22, 23] . MuSK is a signaling protein controlling AChR clustering and formation of the neuromuscular junction, triggered by agrin interaction with MuSK [24, 25] . MG without detectable antibodies to AChR and MuSK is called seronegative MG. Other antibodies are present in MG, such as antibodies to titin, ryanodine receptor, myosin, and -actin. These antibodies are associated with MG subtype and disease severity [26] . HSPs represent a novel autoimmune target in MG. MG patients who responded well to immunosuppressive therapy had significantly reduced HSP-71 antibody levels compared to those who did not respond to the same therapy [27] . Measuring HSP-71 antibodies in MG patients’ sera could therefore serve as a marker of therapy efficacy. Both GMG and OMG patients have higher HSP-70 antibody concentrations compared to healthy controls [28] , and irrespective of age, gender, or AChR antibody status. Higher levels of HSP-70 antibodies are likely to reflect increased exposure to HSP-70 antigens, current or previous, in the circulation or bound to cell membranes [28] . OMG affects a few small muscles only, and patients experience mild and focal symptoms. It is interesting that OMG patients still have significantly increased HSP-70 antibody levels in their sera, even though AChR antibodies are not detectable. This supports the notion that OMG, similarly to GMG, is a generalized autoimmune disease, and that common pathogenic mechanisms are implicated for these two disease entities. HSPs in Guillain-Barré Syndrome Increased HSP-70 antibody levels have been reported in the cerebrospinal fluid from patients with acute and untreated Guillain-Barré syndrome when compared to patients with motor neuron disease [29] . In a recent study [28] , it was demonstrated that Guillain-Barré syndrome patients had elevated serum HSP-70 antibody concentrations compared to healthy controls, MG patients, and multiple sclerosis (MS) patients. The previous study [29] did not find this difference in serum HSP-70 concentration – perhaps because only serum IgG levels were measured, whereas in the recent study, antibodies of all classes (IgG, IgA and IgM) were included. HSPs in Multiple Sclerosis An increased occurrence of T-cell lines recognizing HSP-70 antigen in MS patients was reported many years ago, indicating a role for HSP-70 in the pathogenesis of MS [30] . In the mean time, other HSP antigens and antibodies emerged in the pathogenesis of MS, such as the demonstration of a marked elevation of serum HSP-27 antibodies during the relapsing phase of MS [31] . HSP-27 antibodies may serve as a marker of disease activation if these results can be confirmed by others. Another HSP, , -crystallin, is present in the cerebrospinal fluid of MS patients [32] . However, antibodies to  , -crystallin are found in the serum of both MS patients and healthy controls [33] . The role of such antibodies is not clear. In tissue microarrays,  , -crystallin showed increased expression in MS brain tissue compared with controls independent of demyelination, indicating progressive , -crystallin D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 7 :0 8: 04 P M Heat-Shock Proteins in Clinical Neurology Eur Neurol 2011;66:65–69 67 upregulation of expression [34] . It has turned out that , -crystallin is a key regulatory molecule with inflammation-inhibiting properties in relapsing-remitting MS. The expression of this molecule in MS lesions indicates the initiation of the remission phase [35] .