Multispecificity of Immunoglobulin M Antibodies Raised against Advanced Glycation End Products

Chikazawa, Miho; Otaki, Noriko; Shibata, Takahiro; Miyashita, Hiroaki; Kawai, Yoshichika; Maruyama, Shoichi; Toyokuni, Shinya; Kitaura, Yasuyuki; Matsuda, Tsukasa; Uchida, Koji

doi:10.1074/jbc.m113.452177

Cited by 29 publications

(33 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IgM NA are often positively charged to facilitate interaction with negatively charged targets (53), and may have high levels of poly-reactivity (54). Murine B1 cells secreting NA are also TLR-responsive (11, 55) and have unique BCR construction (56), making them distinct from pathogenic antinuclear autoantibody producing cells (57).…”

Section: Discussionmentioning

confidence: 99%

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

Simchoni

Cunningham‐Rundles

2015

The Journal of Immunology

View full text Add to dashboard Cite

B cells activated by nucleic-acid sensing Toll-like receptor 7 and TLR9 proliferate and secrete immune globulins. Memory B cells are presumably more responsive due to higher TLR expression levels, but selectivity and differential outcomes remain largely unknown. In this study, peripheral blood human B cells were stimulated by TLR7 or TLR9 ligands, with or without IFNα, and compared to activators CD40L plus IL-21, to identify differentially responsive cell populations, defined phenotypically and by BCR characteristics. While all activators induced differentiation and antibody secretion, TLR stimulation expanded IgM+ memory and plasma cell lineage committed populations and favored secretion of IgM, unlike CD40L/IL-21 which drove IgM and IgG more evenly. Patterns of proliferation similarly differed, with CD40L/IL-21 inducing proliferation of most memory and naïve B cells, in contrast to TLRs which induced robust proliferation in a subset of these cells. On deep sequencing of the IgH locus, TLR responsive B cells shared patterns of IgHV and IgHJ usage, clustering apart from CD40L/IL-21 and control conditions. TLR activators, but not CD40L/IL-21, similarly promoted increased sharing of CDR3 sequences. TLR responsive B cells were characterized by more somatic hypermutation, shorter CDR3 segments, and less negative charges. TLR activation also induced long positively charged CDR3 segments, suggestive of autoreactive antibodies. Testing this, culture supernatants from TLR stimulated B cells were found to bind HEp-2 cells, while those from CD40L/IL-21 stimulated cells did not. Human B cells possess selective sensitivity to TLR stimulation, with distinctive phenotypic and genetic signatures.

show abstract

Section: Discussionmentioning

confidence: 99%

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

Simchoni

Cunningham‐Rundles

2015

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Miho Chikazawa suggested that the AGEs could be an endogenous source of innate epitopes recognized by natural IgM antibodies patients with systemic lupus erythematosus with significantly higher serum levels of the IgM titer against the AGEs when compared to the healthy individuals. It was suggested that the protein modification by the endogenous carbonyl compounds generates electronegative proteins that induce multi specific natural antibodies [64].…”

Section: Role Of Glyoxidation Modified Histones In Autoimmune Diseasesmentioning

confidence: 99%

Glycoxidation of histone proteins in autoimmune disorders

Mir

Moinuddin

2015

Clinica Chimica Acta

View full text Add to dashboard Cite

“…Cell images were recorded as described above. The anti-AGE mouse IgM (ab18400, Abcam), the same isotype with E06 mAb, served as a negative control (41). To inactivate E06 mAb, 20 g/ml phosphorylcholine salt (Fisher) was pre-mixed with antibody in L-15 medium before incubating with the cells.…”

Section: Methodsmentioning

confidence: 99%

“…Because phosphatidylcholine is a major component of the outer leaflet of the plasma membrane, it seemed reasonable that this antibody might be sufficient to display an effect (52). Cells were pretreated with E06 mAb (50 g/ml) or a control IgM monoclonal antibody not targeting oxidized lipids (its epitope are advanced glycation end products) (41). The phosphorylcholine salt (PC salt) was also optionally added to media, as this molecule inhibits the binding of E06 mAb to the polar head of Ox-PC (53).…”

Section: Identification Of Efficient Cpps and Robustmentioning

confidence: 99%

Membrane Oxidation Enables the Cytosolic Entry of Polyarginine Cell-penetrating Peptides

Wang

Sun

Muthukrishnan

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Arginine-rich peptides can penetrate cells and consequently be used as delivery agents in various cellular applications. The activity of these reagents is often context-dependent, and the parameters that impact cell entry are not fully understood, giving rise to variability and limiting progress toward their usage. Herein, we report that the cytosolic penetration of linear polyarginine peptides is dependent on the oxidation state of the cell. In particular, we find that hypoxia and cellular antioxidants inhibit cell penetration. In contrast, oxidants promote cytosolic cell entry with an efficiency proportional to the level of reactive oxygen species generated within membranes. Moreover, an antibody that binds to oxidized lipids inhibits cell penetration, whereas extracellularly administered pure oxidized lipids enhance peptide transport into cells. Overall, these data indicate that oxidized lipids are capable of mediating the transport of polyarginine peptides across membranes. These data may also explain variability in cell-penetrating peptide performance in different experimental conditions. These new findings therefore provide new opportunities for the rational design of future cell-permeable compounds and for the optimization of delivery protocols.

show abstract

Multispecificity of Immunoglobulin M Antibodies Raised against Advanced Glycation End Products

Cited by 29 publications

References 41 publications

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

TLR7- and TLR9-Responsive Human B Cells Share Phenotypic and Genetic Characteristics

Glycoxidation of histone proteins in autoimmune disorders

Membrane Oxidation Enables the Cytosolic Entry of Polyarginine Cell-penetrating Peptides

Contact Info

Product

Resources

About