Biochemical and immunological studies on glycated human IGG and its possible role in rheumatoid arthritis

Abstract

Non enzymatic glycation of proteins consists of a series of reactions between reducing sugars, such as glucose, and amino groups of proteins. Labile Schiff bases that are formed in the first step rearrange reversibly to the more stable Amadori products (ketoamines) which further undergo a series of reactions to form advanced glycation end products (AGEs). Generation of AGEs is an evitable process in vivo and can be accelerated under pathological conditions such as hyperglycemia and/or oxidative stress. Increased AGE formation has been correlated with oxidative stress at physiological glucose concentration. Oxygen free radicals play a significant role in acute and chronic inflammatory joint diseases causing significant tissue damage. Free radicals are one of the major contributors to inflammation in rheumatoid arthritis (RA). The antioxidant defense system is shown to be compromised in RA patients. The low antioxidant level is a risk factor resulting in constant oxidative stress in RA patients. Because oxidative stress and free radicals play an important role in tissue damage and inflammation in RA, and AGEs formation is accelerated by oxidative stress, AGEs are thought to be implicated in the disease of RA. These AGEs get deposited in joints and are thought to contribute directly to the joint pathology. It is well documented that AGEs alter unique three-dimensional structure of various plasma proteins, such as IgG, albumin, hemoglobin, transferrin, etc, which induce functional abnormalities and thereby lead to several pathophysiological conditions. The dominant factor in protein glycation is the half-life of individual proteins. The proteins with longer half-lives showed enhanced glycation. In view of the long circulating half-life (24 days) and predominant role in immune protection, IgG glycation has attracted greater attention. IgG is a major serum protein found in all body fluids. It is rich in lysine and arginine making it a good target for glycation.