Error message

Strict warning: Only variables should be passed by reference in find_menu_item() (line 334 of /home/sensproj/srf-sens/sites/srf.org/modules/srf_site_structure/srf_site_structure.module).
  • Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT, Solomon A, Walsh DM, O'Nuallain B. IgG Conformer's Binding to Amyloidogenic Aggregates. PLoS One. 2015 Sep 14;10(9):e0137344. doi: 10.1371/journal.pone.0137344. PubMed: 26367058. Categories: AmyloSENS

    IgG Conformer's Binding to Amyloidogenic Aggregates.

    PLoS One. 2015 Sep 14;10(9):e0137344. doi: 10.1371/journal.pone.0137344.

    IgG Conformer's Binding to Amyloidogenic Aggregates.

    Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT, Solomon A, Walsh DM, O'Nuallain B.

    Abstract

    Abstract:

    Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer's binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb's activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer's binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb's activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs.

  • Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231. PubMed: 24648510. Categories: AmyloSENS

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231.

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S.

    Abstract

    Abstract:

    Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function.

  • Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B. Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils. Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524. PubMed: 24164623. Categories: AmyloSENS

    Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.

    Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524.

    Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.

    Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B.

    Abstract

    Abstract:

    Amyloidosis involves the extracellular deposition of proteinaceous amyloid fibrils and accessory molecules in organ(s) and/or tissue(s), and is associated with a host of human diseases, including Alzheimer disease, diabetes, and heart disease. Unfortunately, the amyloidoses are currently incurable, and there is an urgent need for less invasive diagnostics. To address this, we have generated 22 monoclonal antibodies (mAbs) against aggregates formed by a blood transport protein, transthyretin (TTR), which primarily forms amyloid fibrils in a patient's heart and/or peripheral nerves. Four of the mAbs, 2T5C9, 2G9C, T1F11, and TB2H7, demonstrated diagnostic potential in enzyme-linked immunosorbent assays (ELISA) by their low to sub-nanomolar cross-reactivity with recombinant wild-type (WT) and mutant TTR aggregates and lack of binding to native TTR or amyloid fibrils formed by other peptides or proteins. Notably, in the presence of normal human sera, three of the four mAbs, 2T5C9, 2G9C, and T1F11, retained low nM binding to TTR amyloid fibrils derived from two patients with familial amyloidotic polyneuropathy (FAP). The two most promising mAbs, 2T5C9 and 2G9C, were also shown by immunohistochemistry to have low nM binding to TTR amyloid deposits in cardiac tissue sections from two FAP patients. Taken together, these findings strongly support further investigations on the diagnostic utility of TTR aggregate specific mAbs for patients with TTR amyloidoses.

  • Peto MV. Aluminium and iron in humans: bioaccumulation, pathology, and removal. Rejuvenation Res 2010 Oct;13(5):589-98. PubMed: 21142669. Categories: AmyloSENS, LysoSENS, OncoSENS

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Rejuvenation Res 2010 Oct;13(5):589-98.

    Aluminium and iron in humans: bioaccumulation, pathology, and removal.

    Peto MV.

    Abstract

    Abstract:

    It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.