Neo-epitopes on methylglyoxal modified human serum albumin lead to aggressive autoimmune response in diabetes

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• 作者：Jyoti^a ; Abdul Rouf Mir^b ; Safia Habib^a ; Sheelu Shafiq Siddiqui^c ; Asif Ali^a ; Moinuddin^a ; ^{moin_u@rediffmail.com" class="auth_mail" title="E-mail the corresponding author} ; ^{moinuddin.bh@amu.ac.in" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Methylglyoxal ; Human serum albumin ; Advance glycation end products (AGEs) ; Nε-(carboxyethyl)lysine ; Diabetes type 2 ; Autoimmunity
• 刊名：International Journal of Biological Macromolecules
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：86
• 期：Complete
• 页码：799-809
• 全文大小：2475 K

文摘

Glyco-oxidation of proteins has implications in the progression of diabetes type 2. Human serum albumin is prone to glyco-oxidative attack by sugars and methylglyoxal being a strong glycating agent may have severe impact on its structure and consequent role in diabetes. This study has probed the methylglyoxal mediated modifications of HSA, the alterations in its immunological characteristics and possible role in autoantibody induction. We observed an exposure of chromophoric groups, loss in the fluorescence intensity, generation of AGEs, formation of cross-linked products, decrease in α-helical content, increase in hydrophobic clusters, FTIR band shift, attachment of methylglyoxal to HSA and the formation of N^ε-(carboxyethyl) lysine in the modified HSA, when compared to the native albumin. MG-HSA was found to be highly immunogenic with additional immunogenicity invoking a highly specific immune response than its native counterpart. The binding characteristics of circulating autoantibodies in type 2 diabetes mellitus (DM) patients showed the generation of anti-MG-HSA auto-antibodies in the these patients, that are preferentially recognized by the modified albumin. We propose that MG induced structural perturbations in HSA, result in the generation of neo-epitopes leading to an aggressive auto-immune response and may contribute to the immunopathogenesis of diabetes type 2 associated complications.