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Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells.

ABSTRACT: Serum amyloid A (SAA) is a sensitive inflammatory marker rapidly increased in response to infection, injury or trauma during the acute phase. Resolution of the acute phase and SAA reduction are well documented, however the exact mechanism remains elusive. Two inducible SAA proteins, SAA1 and SAA2, with their variants could contribute to systemic inflammation. While unconjugated human variant SAA1? is already commercially available, the variants of SAA2 are not. Antibodies against SAA have been identified in apparently healthy blood donors (HBDs) in smaller, preliminary studies. So, our objective was to detect anti-SAA and anti-SAA1? autoantibodies in the sera of 300 HBDs using ELISA, characterize their specificity and avidity. Additionally, we aimed to determine the presence of anti-SAA and anti-SAA1? autoantibodies in intravenous immunoglobulin (IVIg) preparations and examine their effects on released IL-6 from SAA/SAA1?-treated peripheral blood mononuclear cells (PBMCs). Autoantibodies against SAA and SAA1? had a median (IQR) absorbance OD (A450) of 0.655 (0.262-1.293) and 0.493 (0.284-0.713), respectively. Both anti-SAA and anti-SAA1? exhibited heterogeneous to high avidity and reached peak levels between 41-50 years, then diminished with age in the oldest group (51-67 years). Women consistently exhibited significantly higher levels than men. Good positive correlation was observed between anti-SAA and anti-SAA1?. Both anti-SAA and anti-SAA1? were detected in IVIg, their fractions subsequently isolated, and shown to decrease IL-6 protein levels released from SAA/SAA1?-treated PBMCs. In conclusion, naturally occurring antibodies against SAA and anti-SAA1? could play a physiological role in down-regulating their antigen and proinflammatory cytokines leading to the resolution of the acute phase and could be an important therapeutic option in patients with chronic inflammatory diseases.

SUBMITTER: Kuret T

PROVIDER: S-EPMC5884545 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells.

Kuret Tadeja T Lakota Katja K Mali Polonca P Čučnik Saša S Praprotnik Sonja S Tomšič Matija M Sodin-Semrl Snezna S

PloS one 20180404 4

Serum amyloid A (SAA) is a sensitive inflammatory marker rapidly increased in response to infection, injury or trauma during the acute phase. Resolution of the acute phase and SAA reduction are well documented, however the exact mechanism remains elusive. Two inducible SAA proteins, SAA1 and SAA2, with their variants could contribute to systemic inflammation. While unconjugated human variant SAA1α is already commercially available, the variants of SAA2 are not. Antibodies against SAA have been i ...[more]

PMID: 29617422

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Project description:BACKGROUND:Abnormal aggregation of proteins induces neuronal cell loss in neurodegenerative disorders such as Alzheimer's Disease, Creutzfeldt-Jakob Disease and Parkinson's Disease. Specific stimuli initialize conformational changes in physiological proteins, causing intra- or extracellular protein aggregation. We and other groups have identified naturally occurring autoantibodies (nAbs) as part of the human antibody pool that are able to prevent peptide fibrillation. These nAbs show a rescue effect following exposure of toxic aggregates on neurons, and they support microglial uptake of aggregated peptides. OBJECTIVE:Identification of a putative common epitope among the relevant proteins ?-Amyloid, ?-Synuclein and Prion Protein for the respective nAbs. MATERIAL AND METHODS:Binding affinity between the aforementioned proteins and nAbs was tested by Dot Blot, ELISA and SPR-technology. Furthermore, the functionality of the protein-nAbs-complexes was studied in Thioflavin-T assays and microglial uptake experiments to study dependent inhibition of protein aggregation and enhancement of Fc? mediated uptake by microglial cells. RESULTS:?-Amyloid and Prion Protein fragment showed considerable binding affinity and functional efficacy for all applied nAbs. Thereby, no significant difference within the different nAbs was detected. In contrast, ?-Synuclein was bound exclusively by nAbs-?-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with ?-Synuclein revealed no significant effect of nAbs in comparison to IVIg treatment. However, all applied nAbs as well as IVIg show a minimal functionality on the microglial uptake of ?-Synuclein. CONCLUSION:nAbs-A?, nAbs-PrP possibly display comparable affinity to the same structural epitope within A? and PrP106-126 A117V whereas the epitope recognized by nAbs-?-Syn is only present in ?-Syn. The structural similarity of A? and PrP fragment promotes the outline for an efficient antibody for the treatment of several neurodegenerative disorders and extend the functional characteristics of the investigated nAbs.

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Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells.

Publications

Naturally occurring antibodies against serum amyloid A reduce IL-6 release from peripheral blood mononuclear cells.

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