Oxidative Modifications in Tissue Pathology and Autoimmune Disease

Abstract

Significance: Various autoimmune syndromes are characterized by abnormalities found at the level of tissues and cells, as well as by microenvironmental influences, such as reactive oxygen species (ROS), that alter intracellular metabolism and protein expression. Moreover, the convergence of genetic, epigenetic, and even environmental influences can result in B and T lymphocyte autoimmunity and tissue pathology. Recent Advances: This review describes how oxidative stress to cells and tissues may alter post-translational protein modifications, both directly and indirectly, as well as potentially lead to aberrant gene expression. For example, it has been clearly observed in many systems how oxidative stress directly amplifies carbonyl protein modifications. However, ROS also lead to a number of nonenzymatic spontaneous modifications including deamidation and isoaspartate modification as well as to enzyme-mediated citrullination of self-proteins. ROS have direct effects on DNA methylation, leading to influences in gene expression, chromosome inactivation, and the silencing of genetic elements. Finally, ROS can alter many other cellular pathways, including the initiation of apoptosis and NETosis, triggering the release of modified intracellular autoantigens.

Critical issues: This review will detail specific post-translational protein modifications, the pathways that control autoimmunity to modified self-proteins, and how products of ROS may be important biomarkers of tissue pathogenesis.

Future directions: A clear understanding of the many pathways affected by ROS will lead to potential therapeutic manipulations to alter the onset and/or progression of autoimmune disease.

Keywords: autoantigens; autoimmunity; carbonylation; citrullination; post-translational modification; type 1 diabetes.

FIG. 1.

Structures of common post-translational protein modifications in autoimmune disease. ^aThe majority of these modifications are mediated by specific enzymes that for the sake of clarity are omitted from this table. GlcNac, N-acetyl-D-glucosamine; GalNac, N-acetyl-D-galactosamine; Gal, D-galactose; Nan, N-acetyl-neruaminic acid.

FIG. 1.

Structures of common post-translational protein modifications in autoimmune disease. ^aThe majority of these modifications are mediated by specific enzymes that for the sake of clarity are omitted from this table. GlcNac, N-acetyl-D-glucosamine; GalNac, N-acetyl-D-galactosamine; Gal, D-galactose; Nan, N-acetyl-neruaminic acid.

FIG. 2.

ROS and inflammation initiate cycles of autoimmunity and epitope spreading. Post-translationally modified self proteins arise in tissues during cellular stress, including ROS, inflammatory cytokines, and/or infection. PTMs are released into the milieu and phagocytized by APCs (either macrophages, dendritic cells, or B cells). Neoantigenic PTM self-peptides are then presented to autoreactive T and B cells that have escaped negative selection in the thymus and bone marrow. This occurs because the modified peptide is typically not presented during selection in noninflamed secondary lymphoid organs. Subsequently, autoreactive T and B cells infiltrate host tissue where an autoimmune response develops, leading to a second round of PTM generation and/or altered DNA methylation. APC, antigen-presenting cell; PTM, post-translational modification; ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

ROS and inflammation induce carbonyl modification of the chaperone protein, P4Hb. The oxidative and cytokine stress in the pancreatic islet microenvironment induces carbonyl modification of beta cell proteins (see text) and P4Hb. P4Hb is one chaperone protein that is responsible for the accurate folding and processing of proinsulin to insulin in the beta cell. Carbonyl-modified P4Hb is a neoantigen that induces autoreactive B and T cells found in early onset human T1D and in the NOD mouse. In addition, carbonyl P4Hb fails to accurately process proinsulin, leading to reduced insulin secretion. NOD, nonobese diabetic; P4Hb, prolyl 4-hydroxylase beta polypeptide; T1D, type 1 diabetes. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Antigen processing is altered by PTMs. (A) Native isoforms of self-antigens are cleaved by intracellular proteases (as represented by “X”) into distinct peptides. Under most conditions, negative selection eliminates T and B cells that recognize these normal isoform peptides due to clonal deletion and anergy. (B) Post-translationally modified sites are often not accurately recognized or cleaved by proteases, thereby creating novel self-peptides to which immune tolerance does not exist. Novel peptide presentation by APCs primes T cells, which provide help to B cells in secreting autoantibodies. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

The generation of PTMs in pancreatic beta cells in T1D. Immune cell infiltration of pancreatic islets includes macrophages, CD4 and CD8 T cells, and NK cells. Direct attack to the beta cell from CD8 and NK cells occurs, whereas ROS is released from resident macrophages. Other inflammatory cytokines, including TNFα, IL-1β, IL6, and IFNγ, all contribute to PTMs generated inside of the beta cell. The response to ROS and cytokine stress includes various PTMs such as carbonylation, oxidation, citrullination, and protein methylation. In addition, DNMTs and TETs altered by the presence of ROS cause various defects in DNA methylation and subsequent downstream translational regulation. DNMT, DNA methyltransferase; IFN, interferon; TET, ten-eleven translocation. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

Overall pathway of ROS leading to autoimmune pathology. The origins of autoimmunity begin with a tissue microenvironment that is rich in ROS combined with weakened or overwhelmed antioxidant defenses. Various PTMs arise in surviving cells that alter several cellular pathways, including immunity (MHC binding and altered immunogenic self proteins) and changes in epigenetics, protein functions, or cellular pathways. The collective outcomes of these changes lead to tissue pathology. MHC, major histocompatibility complex. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars