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Immune reactivity towards insulin, its amyloid and protein S100B in blood sera of Parkinson's disease patients
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
P.K. Anokhin Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Show others and affiliations
2007 (English)In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 14, no 3, 327-334 p.Article in journal (Refereed) Published
Abstract [en]

Peripheral immune responses can be sensitive indicators of disease pathology. We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of 26 Parkinson's disease (PD) patients compared with controls by using ELISA. We found a statistically significant increase of the autoimmune responses to both antigens in PD patients compared with controls with a mean increase of 70% and 50% in the autoimmune reactions towards insulin and S100B, respectively. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in PD patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type, while sequential epitope of native insulin is hidden within the amyloid structures. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

Place, publisher, year, edition, pages
2007. Vol. 14, no 3, 327-334 p.
Keyword [en]
amyloid;immune reactivity;insulin;Parkinson's disease;S100B
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:umu:diva-25729DOI: 10.1111/j.1468-1331.2006.01667.xPubMedID: 17355556OAI: oai:DiVA.org:umu-25729DiVA: diva2:233410
Available from: 2009-09-01 Created: 2009-09-01 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Protein complexes: assembly, structure and function
Open this publication in new window or tab >>Protein complexes: assembly, structure and function
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

 Most proteins must fold into their native conformations to fulfil their biological functions. Failure of proteins to fold leads to cell pathology and a broad range of human diseases referred to as protein misfolding disease, e.g., Alzheimer’s disease, Parkinson’s disease, and type II diabetes. More than 40 proteins are known to be connected with misfolding diseases. These proteins share no sequence homology but all assemble into cross-b sheet containing insoluble fibrillar aggregates. Despite the pathological conditions that these proteins can induce, living organisms can take advantage of the inherent ability of these proteins to form such structures and to generate novel and diverse biological function, the functional amyloid.

 This thesis examines different aspects of cross-b sheet containing aggregates. The first paper describes the humoral response to aggregated structures of insulin and the astrocytical biomarker S100B in patients suffering from Parkinson’s disease. We show that the patients have an increased immunreactivity towards insulin and S100B in Parkinson’s disease patients compared to a control group.

 The second part of this work focuses on a functional amyloid. HAMLET (human a-lactalbumin made lethal for tumour cells) is a complex of a-lactalbumin and oleic acid, which kills tumour cells but not healthy differentiated cells. We wish to expand the concept of HAMLET to a structurally related protein and therefore create and characterize a complex of equine lysozyme and oleic acid (Paper II). We chose equine lysozyme because both proteins (equine lysozyme and a-lactalbumin) share common ancestors and are spatially related. The newly designed complex was named ELOA, for equine lysozyme with oleic acid. ELOA represents a functional oligomer due to its multimeric state and its ability to bind amyloid specific dyes. In the third paper, we investigate the interaction of the cytotoxic ELOA with live cells in real time to find a mechanistic model (Paper III).

 It is known that HAMLET is not only tumouricidal but is also toxic towards many bacteria. Therefore in the last part of the thesis, we investigated the effects of ELOA on different bacterial strains and focused on its interplay Streptococcus pneumoniae (Paper IV).

 These studies have added significantly to many aspects of protein folding and misfolding from its involvement in Parkinson’s disease to the newly gained functions and structural aspects of de novo produced ELOA.

Place, publisher, year, edition, pages
Umeå: Umeå university, 2009. 40 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1318
Keyword
HAMLET, ELOA, lysozyme, amyloid
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-29792 (URN)978-91-7264-913-2 (ISBN)
Public defence
2009-12-15, 3A9, KBC Huset, Umeå, 00:00 (English)
Opponent
Supervisors
Available from: 2009-11-25 Created: 2009-11-23 Last updated: 2009-11-25Bibliographically approved
2. Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
Open this publication in new window or tab >>Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av in vivo prostata amyloidos och autoimmunitet mot amyloida strukturer vid neurodegenerativa sjukdomar
Abstract [en]

By using multidisciplinary analysis of CA inclusions in prostate glands of patients diagnosed with prostate cancer, we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We have found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions. These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate.

We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of PD patients compared with healthy controls. Peripheral immune responses can be sensitive indicators of disease pathology. We found a statistically significant increase of the autoimmune responses to both antigens in patients compared with controls. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies - a-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance analyses. We found significantly higher antibody levels towards monomeric a-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards a-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression. Pooled IgGs from PD patients and controls interacted also with amyloid fibrils of Ab (1-40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to amyloid conformational epitope, though displaying higher specificity towards human amyloid species associated with neurodegeneration. The findings suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein - a-synuclein can be used in treatment strategies and in diagnostics, especially in identifying early disease.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2010. 40 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1386
Keyword
amyloid, amyloidosis, immune reactivity, S100A8/A9, insulin, α-synuclein
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-37561 (URN)978-91-7459-110-1 (ISBN)
Public defence
2010-12-01, KB3A9, Umeå University, Umeå, KBC building, 09:00 (English)
Opponent
Supervisors
Available from: 2010-11-12 Created: 2010-11-09 Last updated: 2012-08-15Bibliographically approved

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