Autoantigenesis: the evolution of protein modifications in autoimmune disease

Abstract

Protein targets in autoimmune disease vary in location, originating within cells as in system lupus erythematosus (SLE), or found on cell surfaces or in extracellular spaces. The term 'autoantigenesis' is first defined here as the changes that arise in self-proteins as they break self-tolerance and trigger autoimmune B and/or T cell responses. As illustrated in many studies, between 50 and 90% of the proteins in the human body acquire post-translational modification. In some cases, it may be that these modifications are necessary for the biological functions of proteins of the cells in which they reside or as extracellular mediators. Summarized herein, it is clear that some post-translational modifications can create new self-antigens by altering immunologic processing and presentation. While many protein modifications exist, we will focus on those created, amplified, or altered in the context of inflammation or other immune system responses. Finally, we will address how post-translational modifications in self-antigens may affect the analyses of B and T cell specificity, current diagnostic techniques, and/or the development of immunotherapies for autoimmune diseases.

Figure 1

The multiple effects of posttranslational modifications. The effects of posttranslational modifications can be seen on multiple levels. Posttranslationally modified peptides become sources of altered self, and when in the context of proteins, can affect the tertiary structure of a protein and how it is processing by antigen processing cells. When significant amounts of certain posttranslational modifications accumulate in cells, they also have the potential to alter how the cell functions (i.e., proliferation rates, cell signaling). Finally, the culmination of all of these individual effects is the onset of autoimmune pathology in whole organisms and ultimately decreased survival.

Figure 2

Posttranslationally modified proteins initiate autoimmune responses. Posttranslational modifications can occur in self-proteins during cellular stress, such as inflammation, ageing or apoptosis. These PTM self-proteins are then released from necrotic or apoptotic cells, where they are phagocytosed by antigen presenting cells (APC), such as macrophages. Once inside the APC, the presence of these modifications can alter how proteases cleave the self-antigen, thereby generating new epitopes. These modified peptides are then presented in the context of MHC class II molecules to T and B cells that have escaped the thymus or bone marrow during negative selection because the modified peptide is not present in those organs. Finally, autoreactive T cells and B cells infiltrate host tissue and induce autoimmune pathology.

Figure 3

Antigen processing altered by the posttranslational modification of self-antigen. (A) Native forms of self-antigens are cleaved by proteases (as represented by the X) into distinct peptides. These peptides are not recognized by the immune system since functional T cells specific for the peptides generated do not exist in the normal immune repertoire due to mechanisms such as clonal deletion and anergy. (B) However, proteases involved in antigen processing may not be able to cleave after a modified amino acid, thereby creating a peptide in which no immune tolerance has developed. T cells in the periphery recognize this peptide, and provide T cell help to autoreactive B cells which then produce autoantibodies and promote disease.