Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression

https://doi.org/10.1016/j.jneuroim.2010.12.001Get rights and content

Abstract

The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (α-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to α-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5-year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers.

Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets.

Introduction

How the immune system protects Parkinson's disease (PD) sufferers from toxic misfolded proteins requires resolution. It has been shown that α-synuclein protein, as a major PD biomarker (Lees et al., 2009) may be present not only as monomeric but also oligomeric forms in the substantia nigra or as aggregates in Lewy bodies (Yu and Lyubchenko, 2009). It has also been demonstrated that prefibrillar aggregates of α-synuclein, as well as other amyloid protein species, constitute generic toxins in higher organisms including humans (Baglioni et al., 2006). Correspondingly, El-Agnaf et al. (2006) reported raised levels of oligomeric forms of α-synuclein in PD patient plasma confirming α-synuclein misfolding during neurodegeneration in vivo. Furthermore, as an accompaniment to neurodegenerative processes, natural autoimmunity may well be perturbed by generation of toxic protein species in humans (Orr et al., 2005, Gruden et al., 2007, Roodveldt et al., 2008). Previously we found that peripheral immune responses to amyloid structures are a sensitive indicator of the early onset of neurodegenerative diseases (Gruden et al., 2004, Gruden et al., 2007). We have also evaluated autoimmune reactions to insulin amyloidogenic species as an endocrine biomarker in PD (Wilhelm et al., 2007). Moreover, it is a distinct possibility that dopamine (DA) released from degenerating neurons may influence the process of protein misfolding in PD (Pham et al., 2000). Immunological consequences associated with inflammation and oxidative stress have been proposed from the etiological pathogenic factors involved in the initial degenerative stages of parkinsonism (Czionkowska et al., 2002). One of these crucial factors is raised neurotrophin expression and stimulated release from cells by activated microglia. As a result, substantially increased concentrations of neurotrophins, for instance S100B, concurrently with toxic oligomeric species of α-synuclein continue to promote apoptosis and subsequent phagocytosis of DA neurons (Yu and Lyubchenko, 2009, Nagatsu et al., 2000, Rothermundt et al., 2003). In connection with this, it is possible that synchronized autoimmune responses towards elevated DA and neutrotrophic factors, in parallel with autoimmune reactions to toxic α-synuclein species, may also limit α-synuclein cytotoxicity. Therefore, the aim of this study is to ascertain any potential interrelationship between autoimmune responses to selected PD biomarkers and a range of other immune system parkinsonian parameters.

Section snippets

Patients

PD patients (n = 32; 20 males and 12 females; 60.8 ± 2.0 years) were recruited from the Center of Neurology, RAMS. Patients underwent neurological examination and were diagnosed with PD according to disease severity by the UPDRS (Fahn and Elton, 1987). Patient scores ranged from 1 to 4, the majority being of grade 2 on the Hoehn and Yahr scale (Hoehn and Yahr, 1967). No opportunistic infections were observed either in PD patients or age-matched control subjects.

Both patient and control demographics

Characterization of α-synuclein oligomeric and fibrillar species

Oligomeric and fibrillar species of α-synuclein were characterized by the thioflavin-T binding assay and AFM analysis prior to ELISA. The formation of amyloid oligomers was accompanied by a 5 fold increase of thioflavin-T fluorescence (Fig. 1D), indicative of cross-β-sheet formation (Krebs et al., 2000). The oligomers were assessed by AFM as round-shapes (Fig. 1A) with heights 1.2–3.9 nm (Fig. 1B) and a maximal population centered around 1.8–2 nm corresponding to 20-mers [16]. The mature fibrils

Discussion

We simultaneously analyzed the spectrum of autoantibodies generated to native and amyloidogenic α-synuclein species, neurotrophic factor S100B and DA as major PD biomarkers in patient blood (Graeber, 2009) along with regulatory T- and B-cells. In altered conditions in vitro and in vivo, α-synuclein may self assemble forming ordered fibrils (Bertoncini et al., 2005) characterized by cross β-sheet structures similar to Lewy body aggregates (Foltynie et al., 2008). The initial phase of

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