Post-translational modifications, subcellular relocation and release in apoptotic microparticles: apoptosis turns nuclear proteins into autoantigens.

Abstract

Autoantibodies against particular nuclear components, such as chromatin and snRNPs, are a characteristic feature of the autoimmune disease systemic lupus erythematosus. The last decade, evidence has suggested that apoptotic cells are the main source of autoantigens in this disease. Therefore, it has been proposed that protein modifications occurring during apoptosis lead to the formation of neo-epitopes, which can break the tolerance when apoptotic cells are not properly cleared. Indeed, many lupus autoantigens are prone to apoptosis-associated post-translational modifications and/or cleavage by caspases. In addition, lupus autoantigens are relocated from the nucleus to apoptotic blebs on the cell surface of early apoptotic cells. Therefore, to understand why certain nuclear proteins become autoantigens during apoptosis, it is important to know the apoptotic processing of these proteins. This review summarizes the current knowledge of apoptotic processing of lupus autoantigens and the possible effects on their encounter with the immune system in normal and autoimmune situations.

Elevated Transglutaminase Activity Triggers Angiotensin Receptor Activating Autoantibody Production and Pathophysiology of Preeclampsia

“…One of the commonly accepted causes for autoantibody production is PTM of proteins to generate neoantigens . Celiac disease is the most common autoimmune disease caused by TG2‐mediated PTM.…”

“…However, this possibility was not supported by epidemiological data that failed to show a correlation between PE and prior parvovirus infection . A commonly considered mechanism for an autoimmune response is posttranslational modification (PTM), resulting in the creation of a neoantigen that is recognized as nonself by the immune system . A large percentage of proteins in the body are targets of PTM, and it is now clear that some of these modifications create new antigens that stimulate an autoimmune response .…”

“…20 A commonly considered mechanism for an autoimmune response is posttranslational modification (PTM), resulting in the creation of a neoantigen that is recognized as nonself by the immune system. [21][22][23][24][25][26] A large percentage of proteins in the body are targets of PTM, and it is now clear that some of these modifications create new antigens that stimulate an autoimmune response. [21][22][23][24][25][26] One of the best-studied autoimmune diseases associated with PTM is celiac disease, a condition affecting %1% of the population of developed countries.…”

“…[21][22][23][24][25][26] A large percentage of proteins in the body are targets of PTM, and it is now clear that some of these modifications create new antigens that stimulate an autoimmune response. [21][22][23][24][25][26] One of the best-studied autoimmune diseases associated with PTM is celiac disease, a condition affecting %1% of the population of developed countries. 27 Celiac disease is a chronic small bowel disorder caused by an abnormal immune response to a tissue transglutaminase (TG2)-modified dietary protein, termed gliadin (a component of glutens that are prominent in wheat).…”

Autoimmune Consequences of Histone Deimination during Neutrophil Activation

“…PTMs associated with apoptotic cell death increase the immunogenicity of self antigens and predispose to autoimmunity. Examples of apoptosis-related PTMs include phosphorylation, acetylation, ubiquitination and transgluamination of histones (68). Phosphorylation of small nuclear ribonucleoprotein (snRNP) (U1-70K) and acetylation of histone H4 (H4-8K) cause enhanced immunoreactivity with systemic lupus sera (69,70).…”