ABSTRACT
New biomarkers with improved sensitivity and specificity are required to improve disease diagnosis and prognosis. Furthermore, to realize the concept of personalized medicine, new challenges of patient stratification and development of companion diagnostics need to be addressed. Consequently, biomarkers with diagnostic and prognostic value for cancer and autoimmune diseases will become more and more important. Autoantibodies are a class of analytes that have attracted attention over the last years. They are directed against certain human proteins and induced by immune system activity in response to disease processes, e.g., in neurodegenerative diseases, cancer, or classical autoimmune diseases. Here we review the use of autoantibody/antigen interactions for diagnostic assays and drug development strategies, which overcomes the technical problems and limitations of other proteomic
markers found in the last decades. Different technology platforms are described enabling the discovery and validation of biomarkers as well as the development of diagnostic assays based on novel autoantibody/antigen interactions. 10.1 Autoantibodies as BiomarkersAutoantibodies are a class of biomarkers suitable for risk assessment, screening, prognosis, disease stratification, and therapy monitoring. Autoantibodies, i.e., antibodies directed against certain human proteins, are induced by immune system activity in response to a disease process. Autoantibody production reflects the immune response to a continuous remodeling of cells or tissues caused by protein turnover and chronic disease processes. In this context, the immune system fails to properly distinguish between self and nonself, and attacks its own cells and tissues. However, in so-called autoimmune diseases, the autoantibodies present in blood are indicative for the clinical symptoms and the state of the disease. Prominent examples of autoimmune diseases are rheumatoid arthritis, multiple sclerosis, coeliac disease, diabetes mellitus type 1, systemic lupus erythematosus (SLE), Sjogren’s syndrome, inflammatory bowel disease, and Hashimoto’s thyroiditis. Beyond classical autoimmune diseases, also in several cancer indications, the presence of autoantibodies has been shown and was correlated to the disease state. Autoantibodies against autologous tumor-associated antigens (TAAs) have been described (Anderson and LaBaer 2005). Most of them are altered, which renders them into an immunogenic form. They can be mutated (p53) (Soussi, 2000), overexpressed (NY-ESO-1) (Schubert et al., 2000), aberrantly degraded, or glycosylated (MUC-1) (von Mensdorff-Pouilly et al., 2000). Also aberrant localization as described for cyclin B1 may provoke an immune response (Suzuki et al., 2005). It is speculated that the humoral response against TAAs is triggered by aberrant tumor cell death due to defective apoptosis or necrosis leading to the release of intracellular modified proteins with immunogenic potential. Tumor cell death also releases proteases that would generate cryptic self-epitopes. Historically, the immune system was separated into two branches: humoral immunity and cellular immunity. The protective function of
humoral immunization could be found in cell-free bodily fluids or serum and is mediated by secreted antibodies produced by activated B-lymphocytes. In contrast, the cell-mediated immunity does not involve antibodies but requires the activation of macrophages, natural killer cells, antigen-specific cytotoxic T-lymphocytes, and the release of different cytokines in response to an antigen. However, both systems are linked together by the activation of naïve B-cells in a T-cell-dependent manner. During T-cell-dependent activation, an antigen-presenting cell such as a macrophage or dendritic cell has digested the immunogenic antigen to peptides and presents this processed antigen to a helper T-cell (Th-cell), which is then primed to this antigen. When a B-cell processes and presents the same antigen to the primed Th-cell, the T-cell secretes several cytokines, which trigger the B-cell to proliferation and differentiation into plasma cells. Up to now it has been quite difficult and time consuming to identify reliable serum markers, especially proteins and peptides, for the diagnosis of a certain disease. A particularly important reason is that such diagnostic markers are present in patient samples often only in minute and highly variable concentrations and have a limited stability. In contrast to this, the use of autoantibodies as diagnostic markers has proven to be highly effective. Such antibodies can be detected by presenting their corresponding autoantigens in well-established assay formats, e.g., enzyme-linked immunosorbent assay, western blot, protein arrays, etc. A particular feature is their specific structure and high stability. They are present in serum or plasma in high concentrations and are not subjected to circadian rhythms or other short-term changes in physiological states. This means that sampling can occur any time because results are not influenced by the time of day of sampling or nutritional status. Due to their specificity and high affinity binding to their corresponding autoantigen, no enrichment or elaborated sample preparation is required. Enrichment occurs automatically during analysis by the binding of the autoantibodies to the autoantigen. Potentially, autoantibodies can also be used for the development of prognostic tests. Studies with SLE patients in the USA have shown that certain autoantibodies could be detected as long as 10 years prior to the onset of the disease (Arbuckle et al., 2003). This highlights that assessing the immune response by measuring autoantibodies is the most stable and efficient way of analyzing biomarkers for diagnostics.
