A peptide mimic blocks the cross-reaction of anti-DNA antibodies with glomerular antigens

Xia, Yumin; Eryilmaz, Ertan; Der, Evan; Pawar, Rahul D.; Cowburn, David; Putterman, Chaim

doi:10.1111/cei.12734

Cited by 15 publications

(24 citation statements)

References 37 publications

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“…Downstream proinflammatory cytokines and profibrotic factors are upregulated in LN ( 53 ). In addition, ALW, which is a DNA-mimicking peptide with a sequence of ALWPPNLHAWVP, can restore SOCS1 expression by blocking the binding of anti-dsDNA IgG to antigens, thus further suppressing the JAK2/STAT1 pathway and attenuating LN ( 53 , 54 ). These findings suggest that SOCS1 is involved in the nephritogenicity of anti-dsDNA IgG and that SOCS1 upregulation can ameliorate LN.…”

Section: Socs1 Inhibition Is Pivotal In the Pathogenesis Of Lnmentioning

confidence: 99%

Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus

Wang

Xia

2017

Front. Immunol.

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving injuries in multiple organs and systems. Exaggerated inflammatory responses are characterized as end-organ damage in patients with SLE. Although the explicit pathogenesis of SLE remains unclear, increasing evidence suggests that dysregulation of cytokine signals contributes to the progression of SLE through the Janus kinase/signal transducer and activator of transcription (STAT) signaling pathway. Activated STAT proteins translocate to the cell nucleus and induce transcription of target genes, which regulate downstream cytokine production and inflammatory cell infiltration. The suppressor of cytokine signaling 1 (SOCS1) is considered as a classical inhibitor of cytokine signaling. Recent studies have demonstrated that SOCS1 expression is decreased in patients with SLE and in murine lupus models, and this negatively correlates with the magnitude of inflammation. Dysregulation of SOCS1 signals participates in various pathological processes of SLE such as hematologic abnormalities and autoantibody generation. Lupus nephritis is one of the most serious complications of SLE, and it correlates with suppressed SOCS1 signals in renal tissues. Moreover, SOCS1 insufficiency affects the function of several other organs, including skin, central nervous system, liver, and lungs. Therefore, SOCS1 aberrancy contributes to the development of both systemic and local inflammation in SLE patients. In this review, we discuss recent studies regarding the roles of SOCS1 in the pathogenesis of SLE and its therapeutic implications.

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Section: Socs1 Inhibition Is Pivotal In the Pathogenesis Of Lnmentioning

confidence: 99%

Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus

Wang

Xia

2017

Front. Immunol.

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“…Autoreactive B cells were subsequently identified in a mouse model of lupus and in the peripheral blood of patients with SLE after the injection of a fluorescent derivative of this peptide, allowing visualization, characterization, and isolation of dsDNA-reactive B cells [116,117]. Moreover, some unrelated sequences were described as mimotopes of DNA and used to block autoantibody aggregation in mice models [118,119], thus confirming the great heterogeneity displayed by peptide mimic ability. The potential of peptide replica to provide diagnostic tests of SLE and to investigate the origin of anti-DNA antibodies and their interaction with polynucleotides is indeed of tremendous interest.…”

Section: Nucleotide Mimicsmentioning

confidence: 80%

Glycoreplica peptides to investigate molecular mechanisms of immune-mediated physiological versus pathological conditions

Mazzoleni

Mallet

Rovero

et al. 2019

Archives of Biochemistry and Biophysics

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Investigation of the role of saccharides and glycoconjugates in mechanisms of immune-mediated physiological and pathological conditions is a hot topic. In fact, in many autoimmune diseases crossreactivity between sugar moieties exposed on exogenous pathogens and self-molecules has long been hinted. Several peptides have been reported as mimetics of glycans specifically interacting with sugar-binding antibodies. The seek for these glycoreplica peptides is instrumental in characterizing antigen mimicry pathways and their involvement in triggering autoimmunity. Therefore, peptides mimicking glycan-protein interactions are valuable molecular tools to overcome the difficulties of oligosaccharide preparations. The clinical impact of peptide-based probes for autoimmune diseases diagnosis and follow-up is emerging only recently as just the tip of the iceberg of an overlooked potential. Here we provide a brief overview of the relevance of the structural and functional aspects of peptide probes and their mimicry effect in autoimmunity mechanisms for promising applications in diagnostics and therapeutics.

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“…Binding affinities to DNA (current paper) and peptide (Xia et al, 2015) of the PL9-11 antibodies were relatively low, as was the in vitro catalytic rate. Nevertheless, these autoantibodies can still exert profound effects, considering in combination the pathogenic potential of antibodies with catalytic activity, potentially amplified effects via a contribution of antibody avidity in vivo, and the typical serum half-life of IgGs (2–3 weeks).…”

Section: Discussionmentioning

confidence: 95%

“…The binding affinity of PL9-11 IgGs to ALW was also measured by SPR, showing an order of IgG2b>IgG2a≥IgG3>IgG1 (Xia et al, 2015). However, the NMR analysis determined that PL9-11 IgG3 had less peptidase activity than that seen for the other isotypes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Two 12 amino acid peptides (ALWPPNLHAWVP, or “ALW”; AHSANNFNVKGI, or “AHS”) used in this study were identified by screening a Ph.D. ™ -12 phage display library (New England Biolabs, Ipswich, MA) with the PL9-11 mAb panel, and selecting a shared sequence bound by all isotypes (Xia et al, 2015). The 12-mer APNQHTPPWMLK peptide, which is specific for the murine non-DNA binding 3E5 mAb, served as a negative control.…”

Section: Methodsmentioning

confidence: 99%

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Anti-DNA antibody mediated catalysis is isotype dependent

Xia

Eryilmaz

Zhang

et al. 2016

Molecular Immunology

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Anti-DNA antibodies are the serological hallmark of systemic lupus erythematosus, and participate in the pathogenesis of lupus nephritis by cross-reacting with multiple renal antigens. Previously, using a panel of murine anti-DNA IgGs that share identical variable regions but that differ in the constant regions, we demonstrated that the cross-reaction and renal pathogenicity of anti-DNA antibodies are isotype dependent. In this study, we investigated the catalytic potential of this anti-DNA antibody panel, and determined its isotype dependency. The three isotype switch variants (IgG1, IgG2a, IgG2b) and the parent IgG3 PL9-11 anti-DNA antibodies were compared in their catalysis of 500 base pair linear double stranded DNA and a 12-mer peptide (ALWPPNLHAWVP), by gel analysis, MALDI-TOF mass spectrometry, and nuclear magnetic resonance spectroscopy. The binding affinity of anti-DNA antibodies to double stranded DNA and peptide antigens were assessed by ELISA and surface plasmon resonance. We found that the PL9-11 antibody isotypes vary significantly in their potential to catalyze the cleavage of both linear and double stranded DNA and the proteolysis of peptides. The degree of the cleavage and proteolysis increases with the incubation temperature and time. While different PL9-11 isotypes have the same initial attack sites within the ALWPPNLHAWVP peptide, there was no correlation between binding affinity to the peptide and proteolysis rates. In conclusion, the catalytic properties of anti-DNA antibodies are isotype dependent. This finding provides further evidence that antibodies that share the same variable region, but which have different constant regions, are functionally distinct. The catalytic effects modulated by antibody constant regions need to be considered in the design of therapeutic antibodies (abzymes) and peptides designed to block pathogenic autoantibodies.

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A peptide mimic blocks the cross-reaction of anti-DNA antibodies with glomerular antigens

Cited by 15 publications

References 37 publications

Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus

Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus

Glycoreplica peptides to investigate molecular mechanisms of immune-mediated physiological versus pathological conditions

Anti-DNA antibody mediated catalysis is isotype dependent

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