Carbamyl Adducts on Low-Density Lipoprotein Induce IgG Response in<i>LDLR</i><sup>−/−</sup>Mice and Bind Plasma Autoantibodies in Humans Under Enhanced Carbamylation

Kummu, Outi; Turunen, S.; Wang, Chunguang; Lehtimäki, Jaakko; Veneskoski, Marja; Kastarinen, Helena; Koivula, Marja Kaisa; Risteli, Juha; Kesäniemi, Y. Antero; Hörkkö, Sohvi

doi:10.1089/ars.2012.4535

Cited by 18 publications

(34 citation statements)

References 48 publications

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“…Protein carbamylation creates potential neoepitopes that induce multiple autoantibody responses. 93-96 Rheumatoid arthritis (RA) is a disease associated with multiple types of autoantibodies, and when investigators examined if anti-carbamylated protein antibody levels are elevated in RA patients, they found that anti-homocitrulline antibodies are present and at a higher level in individuals with RA and arthralgias compared to healthy controls. They also showed positive associations with joint damage and could predict disease development in “pre-RA” patients independent of established biomarkers.…”

Section: Pathogenesismentioning

confidence: 99%

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Kalim

Karumanchi

Thadhani

et al. 2014

American Journal of Kidney Diseases

107

101

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Carbamylation describes a non-enzymatic, posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally rises. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins, and have been directly implicated in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation’s relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances.

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Section: Pathogenesismentioning

confidence: 99%

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Kalim

Karumanchi

Thadhani

et al. 2014

American Journal of Kidney Diseases

107

101

View full text Add to dashboard Cite

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“…Carbamylated LDL are immunogenic inducing IgG autoantibodies in LDL-deficient receptor mice [147]. These antibodies are cross-reactive with oxidative-specific epitopes, especially with MDA-LDL [148] suggesting that carbamylated LDL are partially oxidized.…”

Section: Ldl Modificationsmentioning

confidence: 99%

Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease

Orekhov

Bobryshev

Sobenin

et al. 2014

IJMS

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In atherosclerosis; blood low-density lipoproteins (LDL) are subjected to multiple enzymatic and non-enzymatic modifications that increase their atherogenicity and induce immunogenicity. Modified LDL are capable of inducing vascular inflammation through activation of innate immunity; thus, contributing to the progression of atherogenesis. The immunogenicity of modified LDL results in induction of self-antibodies specific to a certain type of modified LDL. The antibodies react with modified LDL forming circulating immune complexes. Circulating immune complexes exhibit prominent immunomodulatory properties that influence atherosclerotic inflammation. Compared to freely circulating modified LDL; modified LDL associated with the immune complexes have a more robust atherogenic and proinflammatory potential. Various lipid components of the immune complexes may serve not only as diagnostic but also as essential predictive markers of cardiovascular events in atherosclerosis. Accumulating evidence indicates that LDL-containing immune complexes can also serve as biomarker for macrovascular disease in type 1 diabetes.

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“…11 MDA and phosphocholine (PC) epitopes in plasma apoB-containing particles were determined as described previously. 35 Rgp44 and Rgp15-27 are consecutive sequences at the hemagglutinin/adhesin domain of gingipain. 36 PC-BSA (PC-conjugated BSA) was purchased from Biosearch Technologies (#PC-1011; Novato, CA, USA).…”

Section: Chemiluminescence Immunoassaysmentioning

confidence: 99%

Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis

et al. 2014

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Periodontal infections increase the risk of atherosclerotic vascular disease via partly unresolved mechanisms. Of the natural IgM Abs that recognize molecular mimicry on bacterial epitopes and modified lipid and protein structures, IgM directed against oxidized low-density lipoprotein (LDL) is associated with atheroprotective properties. Here, the effect of natural immune responses to malondialdehyde-modified LDL (MDA-LDL) in conferring protection against atherosclerosis, which was accelerated by the major periodontopathogen Porphyromonas gingivalis, was investigated. LDL receptor-deficient (LDLR(-/-)) mice were immunized with mouse MDA-LDL without adjuvant before topical application challenge with live P. gingivalis. Atherosclerosis was analyzed after a high-fat diet, and plasma IgG and IgM Ab levels were measured throughout the study, and the secretion of IL-5, IL-10 and IFN-γ in splenocytes stimulated with MDA-LDL was determined. LDLR(-/-) mice immunized with MDA-LDL had elevated IgM and IgG levels to MDA-LDL compared with saline-treated controls. MDA-LDL immunization diminished aortic lipid depositions after challenge with P. gingivalis compared with mice receiving only P. gingivalis challenge. Immunization of LDLR(-/-) mice with homologous MDA-LDL stimulated the production of IL-5, implicating general activation of B-1 cells. Immune responses to MDA-LDL protected from the P. gingivalis-accelerated atherosclerosis. Thus, the linkage between bacterial infectious burden and atherogenesis is suggested to be modulated via natural IgM directed against cross-reactive epitopes on bacteria and modified LDL.

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Carbamyl Adducts on Low-Density Lipoprotein Induce IgG Response inLDLR^−/−Mice and Bind Plasma Autoantibodies in Humans Under Enhanced Carbamylation

Abstract: These data give insight into mechanisms of in vivo humoral recognition of post-translationally modified structures. Humoral IgG immune response to carbamylated proteins is suggested to play a role in conditions leading to enhanced carbamylation, such as uremia and smoking.

Cited by 18 publications

References 48 publications

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease

Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis

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Carbamyl Adducts on Low-Density Lipoprotein Induce IgG Response inLDLR−/−Mice and Bind Plasma Autoantibodies in Humans Under Enhanced Carbamylation

Abstract: These data give insight into mechanisms of in vivo humoral recognition of post-translationally modified structures. Humoral IgG immune response to carbamylated proteins is suggested to play a role in conditions leading to enhanced carbamylation, such as uremia and smoking.

Cited by 18 publications

References 48 publications

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Protein Carbamylation in Kidney Disease: Pathogenesis and Clinical Implications

Modified Low Density Lipoprotein and Lipoprotein-Containing Circulating Immune Complexes as Diagnostic and Prognostic Biomarkers of Atherosclerosis and Type 1 Diabetes Macrovascular Disease

Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis

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Carbamyl Adducts on Low-Density Lipoprotein Induce IgG Response inLDLR^−/−Mice and Bind Plasma Autoantibodies in Humans Under Enhanced Carbamylation