# Oxidatively Modified Proteins: Cause and Control of Diseases
## 4 Use of oxPTMs as Disease Biomarkers  
Modified structures on the cell surface are characteristic footprints for some diseases and targets to trigger or block an immune response. Therefore, oxPTMs might be advantageous for disease diagnosis. For example, oxidation of low-density lipoprotein (LDL) has been proposed as a primary biomarker for diabetes [74] and cardiovascular diseases [75]. Furthermore, oxidation and chlorination of the extracellular matrix protein laminin were suggested as markers for cardiovascular disease and particularly atherosclerosis [73]. Just as LDL and laminin are anchored in the membrane and are accessible from outside, the major histocompatibility complex (MHC) is located on the cell surface to enable interaction with cells of the adaptive immune system. Each cell degrades intracellular proteins, loads the resulting fragments onto MHC, and presents it on the cell surface. Once a trafficking T cell recognizes the MHC structure, the receptor matches the MHC-bound protein fragment (epitope) as being of self- or non-self-origin. Epitopes of natural intracellular proteins are identified as \"self\", and no immune response is triggered. In contrast, PTMs on epitopes make them differ from their native forms and hence can generate foreign structures, allowing them to become a target of an immune response (Figure 2). \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Modification** & **Protein** & **Disease** & **References** \\ \hline carbamylation & several & aging & [58; 59] \\ carbonylation & E-FABP & diabetes & [62] \\ citrullination & Fibrinogen & RA & [63] \\ citrullination & Collagen & RA & [64; 65; 66] \\ deamination & Chromogranin A & Diabetes & [67] \\ hyperphosphorylation & Tau & Alzheimer’s & [68; 69] \\ oxidation & LDL & atherosclerosis & [70; 71; 72] \\ oxidation & laminin & Cardiovascular disease & [73] \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Protein post-translational modifications (PTMs) linked to the cause of disease. In some cases, such as cancers, PTMs on epitopes which differ from the current host proteins might even serve to amplify an immune response leading to the eradication of unwanted cells. However, in autoimmune diseases, immune cells falsely attack host structures because PTM epitopes are presented and can lead to a break of tolerance [76], as seen in diabetes type I [77]. Not only in diabetes but also in other autoimmune disorders, PTM epitopes are suspected. Since the direct detection of native and PTM epitopes is difficult due to the isolation and qualification, indirect evidence is usually provided. In RA, T cell activation is the consequence of PTMs, such as carbamylation, citrulination, deamidation, or acetylation [78; 79; 80; 81]. Moreover, B cells release autoantibodies that are specific for PTMs, leading to the attack of host proteins and structures [82; 83; 84; 64]. Targeting those antibodies with neutralizing citrulinated peptides became a pioneering therapy option [63; 85], suggesting a role of oxPTMs as therapeutics (Table 2). Intracellular proteins with putative PTMs are degraded and loaded onto MHC, where they can serve as an antigenic or tolerogenic peptide. It would, therefore, come as no surprise if epitopes with PTMs were also found in Alzheimer's patients since oxidatively modified proteins were identified in AD brains by proteomics analysis [95; 96]. Since epitopes are structures that are recognized by immune cells, there are different therapeutic approaches to induce effective stimulation or inhibition