scholarly journals Hydroxyl Radical Modification of Immunoglobulin G Generated Cross-Reactive Antibodies: Its Potential Role in Systemic Lupus Erythematosus

2011 ◽  
Vol 4 ◽  
pp. CMAMD.S6793 ◽  
Author(s):  
Hani A. Al-Shobaili ◽  
Ahmad A. Al Robaee ◽  
Abdullateef Alzolibani ◽  
Muhammad Ismail Khan ◽  
Zafar Rasheed
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Nucleic Acid ◽  
Immunoglobulin G ◽  
Lupus Erythematosus ◽  
Competitive Inhibition ◽  
Antigen Binding ◽  
Blood Proteins ◽  
Systemic Lupus ◽  
Human Igg ◽  
Binding Characteristics

Objective Role of reactive oxygen species (ROS) modified human Immunoglobulin G (IgG) in systemic lupus erythematosus (SLE) has been investigated. Methods Human IgG was modified by hydroxyl-radicals. Immunogenicity of native and modified human IgG was probed by inducing polyclonal antibodies in rabbits. Cross-reactions of induced antibodies with nucleic acid, chromatin, different blood proteins and their ROS modified conformers were determined by competitive inhibition ELISA. The binding characteristics of circulating autoantibodies in SLE patients (n = 72) against native and modified IgG were screened by direct binding and competition ELISA and the results were compared with healthy age-matched controls (n = 39). Results Induced antibodies against ROS-modified human IgG exhibited diverse antigen binding characteristics. Native DNA, native chromatin and their ROS-modified conformers were found to be effective inhibitors of induced antibody-immunogen interaction. Induced antibodies against native human IgG showed negligible binding to the above mentioned nucleic acid antigens. SLE sera (48.6%) showed strong binding to ROS-human IgG in comparison with its native analogue ( P < 0.01). Normal human sera (NHS) showed negligible binding with either antigen ( P > 0.05). Conclusion ROS-induced modifications in human IgG present neo-epitopes, and make it a potential immunogen. The induced antibodies against ROS-modified human IgG resembled the diverse antigen-binding characteristics of naturally occurring SLE anti-DNA autoantibodies. ROS-modified IgG may be one of the factors for the induction of circulating SLE autoantibodies.

scholarly journals THU0017 ATTEMPTS TO LINK EXONIC GENE POLYMORPHISMS TO SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)-ASSOCIATED PROTEIN MODIFIED FUNCTIONALITY: A STRUCTURAL BIOLOGY APPROACH

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 221.1-222
Author(s):  
E. Eliopoulos ◽  
G. Goulielmos ◽  
M. Matalliotakis ◽  
D. Vlachakis ◽  
T. Niewold ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Protein Structure ◽  
Molecular Modeling ◽  
Nucleic Acid ◽  
Molecular Mechanics ◽  
Lupus Erythematosus ◽  
Gene Polymorphisms ◽  
Association Studies ◽  
Systemic Lupus ◽  
Molecular Graphics

Background:Gene association studies and genome wide association studies (GWAS) have played a primary role in depicting genetic contributions to systemic lupus erythematosus (SLE) development, while accommodating the exonic polymorphisms on the protein structure level, when available, enhances our understanding of protein function modification or depletion. Linking human genetics with therapeutic targets requires the biological function of the causal gene and variant to be known.Objectives:To investigate recently identified SLE-associated functional gene polymorphisms, such asPARP1,ITGAM, TNFAIP3, NCF1, PON1, IFIH1, SH2B3andTYK2[1-4] by correlation to protein structure and function.Methods:Three-dimensional (3D) homology modeling and molecular mechanics/dynamics studies were applied for the localization of the polymorphisms under study on the respective proteins. The mutants were constructed using molecular modeling with the program Maestro (Schrodinger, LLC), which was also used to analyze the conformational changes caused by the mutation. All figures depicting 3D models were created using the molecular graphics program PyMOL V.2.2 [5].Results:Modeling revealed that rs1136410 SNP encodes the less common polymorphism Val762Ala onPARP1that reduces enzymatic activity of Poly(ADP-ribose) polymerase 1 (Figure 1),ITGAMpolymorphism rs1143679 (Arg77His) on Integrin alpha M, component of the macrophage-1 antigen complex affects protein surface recognition,TNFAIP3rs2230926 polymorphism encodes Cys instead of Phe at residue 127 of the ubiquitin editing A20 protein, while rs201802880 polymorphism of the neutrophil cytosolic factor 1 (NCF1) gene modifies the function of the cytosolic subunit of neutrophil NADPH oxidase with the mutation Arg90His.PON1is involved in the oxidative stress process that cause tissue damage observed in SLE and anti-phospholipid syndrome (APS). ThePON1Gln192Arg mutation (rs662 SNP) affects shape and recognition of the ligand recognition site as part of the evolutionary process, whileIFIH1(rs35667974) helicase C domain1 mutant I923V is located on an essential RNA beta loop interacting directly with the nucleic acid (Figure 2). Finally, the rs3184504 SNP ofSH2B3gene generates mutant Arg262Trp on SH2 adapter protein 3, acting as a signaling pathway involved in autoimmune disorders, while inTYK2 gene, one of the Janus kinases, the rs35018800 producing mutant Ala928Val modifies the ADP binding site.Figure 1.Details of the Val762 interaction where V762A mutation occurs in PARP1protein.Figure 2.Nucleic acid interacting IFIH1 helicase beta-loop where I923V mutation occurs (in purple).Conclusion:Based on several examples, we have tried to define a rational link from SLE-associated gene polymorphisms to structure and to modified function, including metagenomic analysis of SNPs, protein crystallography, protein molecular modeling, molecular mechanics and dynamics. Locating, shaping and understanding the target protein interaction interface plays a decisive role in most cases and provides clues for further pharmacological or medical actions [6].References:[1]Hur JW et al (2006). Rheumatology 45:711-7[2]Maiti AK et al (2014). Hum Mol Genet 23:4161-76[3]Shimane K et al (2010). Arthritis Rheum. 62:574-9[4]Linge P et al (2019). Ann Rheum Dis. 2019 Nov 8. pii: annrheumdis-2019-215820[5]Schrödinger LLC: The PyMOL Molecular Graphics System 2016 version 2.2. Available from: pymol.org/2/support.html[6]Plenge RM et al (2013). Nat Rev Drug Discov 12:581–94Disclosure of Interests:None declared

Electric charge and sugar chains of immunoglobulin G in systemic lupus erythematosus

2006 ◽  
Vol 10 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Koji Kinoshita ◽  
Sinya Ikoma ◽  
Toshiaki Yamagata ◽  
Yuji Nozaki ◽  
Masafumi Sugiyama ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Electric Charge ◽  
Immunoglobulin G ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Sugar Chains

scholarly journals Immunoglobulin G Levels as a Prognostic Factor for Autoimmune Hepatitis Combined With Systemic Lupus Erythematosus

2016 ◽  
Vol 68 (7) ◽  
pp. 995-1002 ◽  
Author(s):  
Doo-Ho Lim ◽  
Yong-Gil Kim ◽  
Danbi Lee ◽  
Soo Min Ahn ◽  
Seokchan Hong ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Prognostic Factor ◽  
Autoimmune Hepatitis ◽  
Immunoglobulin G ◽  
Lupus Erythematosus ◽  
Systemic Lupus

The Direct Embryotoxicity of Immunoglobulin G Fractions From Patients With Systemic Lupus Erythematosus

1995 ◽  
Vol 34 (6) ◽  
pp. 349-355 ◽  
Author(s):  
DAVID M. NADLER ◽  
NORMAN W. KLEIN ◽  
LILI A. ARAMLI ◽  
BENEDICT J. CHAMBERS ◽  
MARGARET MAVES ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immunoglobulin G ◽  
Lupus Erythematosus ◽  
Systemic Lupus

Urinary loss of immunoglobulin G anti-F(ab′)2 and anti-DNA antibody in systemic lupus erythematosus nephritis

1998 ◽  
Vol 132 (3) ◽  
pp. 210-222 ◽  
Author(s):  
Ralph C. Williams ◽  
Christine C. Malone ◽  
R.Tyler Miller ◽  
Francesco Silvestris
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Immunoglobulin G ◽  
Lupus Erythematosus ◽  
Systemic Lupus
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