Antibodies against small heat-shock proteins in Alzheimer’s disease as a part of natural human immune repertoire or activation of humoral response? (pdf)

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Antibodies against small heat-shock proteins in Alzheimer’s disease as a part of natural human immune repertoire or activation of humoral response?

J Neural Transm (2016) 123:455–461 DOI 10.1007/s00702-015-1477-2 NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - ORIGINAL ARTICLE Antibodies against small heat-shock proteins in Alzheimer’s disease as a part of natural human immune repertoire or activation of humoral response? Ewa Papuć1 • Witold Krupski2 • Ewa Kurys-Denis2 • Konrad Rejdak1 Received: 17 May 2015 / Accepted: 20 October 2015 / Published online: 14 November 2015 The Author(s) 2015. This article is published with open access at Springerlink.com Abstract Characterization of autoantibodies specific for some disease-related proteins, would allow to better assess their role as diagnostic and prognostic markers. In the light of increasing evidence for both humoral and cellular adaptive immune responses in the pathophysiology of Alzheimer’s disease (AD), and data on the increased small heat-shock proteins (sHSP) expression in this disease, it seemed justified to assess humoral response against sHSP in AD patients. The aim of the study was to check whether AD has the ability to elicit immune response against small HSP, which could also serve as disease biomarkers. IgG and IgM autoantibodies against alpha B-crystallin and antiHSP 60 IgG autoantibodies were assessed in 59 AD patients and 59 healthy subjects. Both IgM and IgG autoantibodies against alpha B-crystallin in AD patients were significantly higher compared to healthy controls (p \ 0.05). No statistically significant differences were found between AD patients and healthy subjects were found in anti-HSP60 IgG autoantibody titers (p = 0.29). Anti-HSP60 antibodies present in AD patients may indeed belong to natural human immune repertoire, and chronic neurodegenerative process does not have significant inducing effect on the systemic immunoreactivity against HSP60. Increased titers of IgM and IgG autoantibodies against alpha B-crystallin in AD patients may reflect activation of humoral immune response in the course of this chronic disease, probably secondary to its increased & Ewa Papuć 1 Department of Neurology, Medical University of Lublin, 8 Jaczewskiego Str., 20-954 Lublin, Poland 2 Second Department of Radiology, Medical University of Lublin, Lublin, Poland expression. Further prospective studies, on larger group of AD patients and measuring a change in antibodies titers with disease progression are necessary to assess the exact role of these antibodies in AD. Keywords Alzheimer disease Small heat-shock proteins HSP60 Alpha B-crystallin Autoantibodies Humoral response Immune system Introduction Identification of disease-specific diagnostic and prognostic biomarkers which would allow for an early detection and clinical follow-up of Alzheimer’s disease (AD) patients is very important. As there is increasing evidence for both humoral and cellular adaptive immune responses in the pathophysiology of AD, assessment of disease-related B and T cell responses may constitute a promising source of potential early biomarkers specific for certain disorders. Characterization of autoantibodies specific for some disease-related proteins, would allow to better decipher their role as early diagnostic and prognostic markers in AD. In the light of previously emerging hypotheses on the activation of the adaptive immune system against amyloid b (Ab) aiming to decrease the accumulation of this peptide in the brain (Solomon et al. 1997; Schenk et al. 1999), it seemed justified to assess humoral response against other peptides which are overexpressed in AD. Heat-shock proteins (HSPs) are functionally and immunologically highly conserved molecules present in almost all living organisms (Ellis 2007). HSPs are upregulated in response to cellular stress to protect the cell from a variety of stresses (Kelly and Yenari 2002). This increased HSP expression takes place in cells exposed to 123 456 mild stress and protects them against subsequent stress. However, in cells subjected to severe stress, HSP promote apoptosis. In AD, HSPs expression is associated with deposition of Ab and neurofibrillary tangles, and recent findings suggest that HSPs prevent the accumulation of Ab (Abdul et al. 2006; Evans et al. 2006; Shimura et al. 2004). In the light of evidence for increased expression of some HSPs in brain tissues in patients with AD (Björkdahl et al. 2008) and also in brains of patients with mild cognitive impairment (MCI) (Di Domenico et al. 2010), we decided to assess humoral response against sHSP in AD, and to look for potential biomarkers of the disease. To test this hypothesis, we assessed the presence of autoantibodies against small HSP, like alpha B-crystallin and HSP 60 in sera of patients suffering from AD. We assessed all measurements from AD patients in relation to autoantibody levels in healthy control subjects. Alpha B-crystallin Alpha B-crystallin is a small heat-shock protein (sHSP), which occurs at increased levels in brains of Alzheimer’s disease patients, and co-localizes with amyloid b (Ab) (Renkawek et al. 1994). AD pathology involves not only aggregation of abnormal proteins, but also their decreased degradation, and cytoskeletal disruption. Small HSPs take part in protein degradation and protection against protein aggregation, and they interact with several cytoskeletal components such as microtubules (MT) and neurofilaments (NF). There is evidence that some small heat-shock proteins (sHSPs), like Hsp27 and alpha B-crystallin, are up-regulated in AD, especially in the regions commonly affected by AD but its consequences are still largely unknown (Björkdahl et al. 2008; Mao et al. 2001). The presence and increased sHsps expression in AD brains may indeed reflect a defensive response to prevent amyloid fibril formation and its toxicity (Renkawek and Bosman 1995). HSP 60 and related autoantibodies Anti-60 kD heat-shock protein (Hsp60) antibodies are present in sera of healthy human subjects (Varbiro et al. 2010), also in sera of patients with inflammatory and autoimmune disorders (Yokota and Fujii 2010; Mayr et al. 1999). In the light of evidence for inflammatory process present in human brains of patients with AD, as well as data on increased expression of different sHSP in neurodegenerative disorders, it may be hypothesized that AD may be also accompanied by the presence of anti-HSP antibodies. Thus, we decided to assess the humoral response against sHSP in sera of AD patients in comparison to healthy 123 E. Papuć et al. controls, to assess the presence of adaptive immune response in AD and to look for early biomarkers of the disease. Materials and methods 59 AD patients in different clinical stages of the disease [on Clinical Dementia Rating (CDR) grade 0.5–3] treated in the Department of Neurology of Medical University of Lublin, Poland were enrolled. All AD patients fulfilled NINCDS–ADRDA criteria for probable Alzheimer’s disease diagnosis (McKhann et al. 1984). AD patients were divided into three subgroups: mild AD (CDR 0.5–1 (...truncated)