Advances in plasma proteomics: Moving from technology to precision medicine

Blood is the central system that connects all the tissues and organs in the body. It executes functions through a diverse set of signaling proteins that play important roles in modulating immunity, inflammation, coagulation, and metabolism.[1] Because of this unique role, blood carries biomolecules from everywhere in the body, which can be viewed as markers of ongoing activities that provide a window through which we can assess countless aspects of the body's health status. Significant efforts had been devoted toward developing and applying proteomics technologies to analyze the plasma/serum proteome, elucidate disease mechanisms and identify biomarkers for diagnosing disease and monitoring the response to treatment.[2] To promote the development of plasma proteomics, we organized the special issue “Advances in plasma proteomics: moving from technology to precision medicine”, in which four research articles, one technical brief and two reviews were selected. He et al. reviewed the advances of proteomics technologies in analyzing the plasma proteomics and peptidomics, and their applications in studying Coronavirus disease (COVID-19) and cancer. In addition, the issues and potential solutions in the proteomics-based translational studies were discussed.[3] Juanes-Velasco et al. developed a microarray that surveys acute phase proteins in plasma. The procedure was deployed to study SARS-CoV-2 infected patients, in which changes in acute phase protein levels were detected between healthy and COVID-19 patients.[4] Li et al. determined proteome changes in the plasma of 20 HIV patients before and after antiretroviral therapy (ART) using mass spectrometry with tandem mass tag labeling. A total of 1398 protein groups (PGs) were identified, in which the upregulated proteins (n = 50) were enriched in gap junction signaling and actin cytoskeleton signaling, while downregulated proteins (n = 18) were enriched in IL-15 signaling pathway. The results from this study illustrated the underlying mechanistic pathways in response to ART and identified potential targets to prompt the immune reconstitution.[5] Zhang et al. explored the O-glycoproteome changes in the serum of 10 breast cancer patients using isobaric-TMT-labeling quantitative O-glycoproteomics. 299 O-glycopeptides corresponding to 83 O-glycosites and 66 O-glycoproteins were identified. 13 O-glycopeptides were found differentially abundant between breast cancer patients and controls. The latter group was prepared by mixing equal volume of plasma from ten healthy volunteers, including IgG1, IgG3, CO4, HP, ANT3, IC1 and FINC.[6] In addition to profiling changes in disease-related protein levels, there is growing interest in studying adaptive immunity to evaluate the effect of auto-reactive antibodies.[7] These circulating autoantibodies can provide opportunities for disease early risk assessment, diagnosis, and prediction of therapeutic responses.[8-11] Therefore, detecting autoantibodies is a critical complement to other omics data for elucidating the mechanism of autoimmunity. Due to their rigid structure, antibodies are ideal biomarker candidates for rapidly implementing reliable test systems in clinical practice. To address this need, Ren et al. developed a microarray platform to measure thousands of serological autoantibodies simultaneously with high sensitivity (pg/ml) and reproducibility (r correlation within the array is 1 and r correlation between arrays from different batches is 0.97–0.99). With this array, autoantibodies were found to associate with different physiological and pathological states. Unique autoantibody profiles were identified for the healthy control, systemic lupus erythematosus, rheumatoid arthritis and lung cancer.[12] Using protein microarray, Banerjee, et al. profiled the expression of autoantibodies in the serum of four healthy controls, four Acromegaly, three Cushing's and three Nonfunctional Pituitary Adenomas (NFPAs) patients. The results identified autoantibodies to five proteins in Acromegaly, five proteins in Cushing's patients, two proteins in NFPA patients.[13] All these results demonstrate the suitability of protein microarray in discovering circulating antibodies associated with humoral autoimmunity. This could be used to execute systematic studies of human diseases together with genomics, proteomics, and metabolomics.[14] Compared to protein microarrays, the number of yet-discovered autoantibodies that are detected could be significantly expanded by the phage display and next-generation sequencing. Qi et al. reviewed the technological advances in the field of autoantibody studies by proteome microarray and phage display, discussed their merits and limitations and the future directions of this field.[15] Following the advances of genomics, proteomics has had a growing influence on precision medicine by elucidating patient heterogeneity and finding biomarkers for more precise disease detection as well as the targets for developing more effective therapies.[16] Studying the circulating proteomics will represent the frontier of clinical proteomics. It will not only offer a window into health and disease, but also bring forward the technologies (i.e., multiplexed immunoassays) that are easier to translate into the clinical laboratory due to the ease of sample preparation, detection, and data processing. It is worth noting that the proteomics-driven precision medicine has to be pushed forward by extensive collaboration between research institutes, hospitals, policy makers, companies, public and private investment, etc.[17] At last, we extend our gratitude to the authors for their manuscripts and to the staff of Proteomics-Clinical Applications for their expeditious and efficient handling of the manuscripts. This work was supported by the National Key R&D Program of China (2020YFE0202200). In addition, we would like to acknowledge the support from Human Plasma Proteome Project, Chinese Human Proteome Organization (CNHUPO), and National Center for Protein Sciences-Beijing (PHOENIX Center). The authors have declared no conflict of interest.