Although it is currently unclear

Although it is currently unclear if DNA methylation changes are the cause or the consequence of the disease, it is clear that DNA methylation changes occur early during disease pathogenesis and precede disease detection by histological and/or imaging methods. Several DNA methylation-based biomarkers are already commonly used in the clinic, such as the testing of the DNA methylation status of the promoter for the prediction of the response to chemotherapy using alkylating agents in glioblastoma or of for the diagnosis of Lynch Syndrome. Commercial products such as the Epi Colon test, analyzing methylation in the gene () for the population-wide screening for colorectal cancer and approved by the Chinese FDA in July 2015, and the Lung () test () are now available. Panels with multiple genes can further improve the specificity and sensitivity of DNA methylation signatures as recently demonstrated in a stool-based screening test for colorectal cancer ((), Cologuard, Exact Sciences), where DNA methylation alterations were combined with mutation detection and which received the first US-FDA approval for a DNA methylation-based diagnostic test in 2014.
The study by Thomas and co-workers in this issue of EBioMedicine provides detailed characteristics on the pathogenic properties of BTS supplier that develop in patients with acquired thrombotic thrombocytopenic purpura (TTP) (). It is now well-established that TTP is due to dysregulation of primary hemostasis. A crucial initial step in this process involves von Willebrand factor-mediated adhesion of blood platelets to a damaged vessel wall. The platelet-adhesive properties of VWF are dependent on its ability to assemble into large polymers which are released from Weibel–Palade bodies, unique storage organelles present in endothelial cells (). Upon their release, these polymers form extended parallel aligned strings that recruit platelets to sites of vascular perturbation. The VWF cleaving protease ADAMTS13 controls VWF multimer size by selectively cleaving a peptide bond in the A2 domain of VWF that becomes exposed under the influence of fluidic shear stress (). In the absence of ADAMTS13 processing of VWF polymers is incomplete, resulting in enhanced platelet adhesion at sites of vascular injury (A). For reasons that are so far poorly understood, autoantibodies directed against ADAMTS13 can develop in previously healthy individuals. Like many other autoimmune disorders the highly polymorphic MHC class II locus has been implicated in the pathogenesis of TTP. The frequency of HLA-DR11 was significantly increased in patients with acquired TTP (). Feeding of antigen presenting cells with ADAMTS13 revealed that a CUB2 domain derived peptide is preferentially presented on HLA-DR11 (). Based on this it was hypothesized that microbial peptides with sequence overlap to this peptide may contribute to the onset of acquired TTP (). While our knowledge on the underlying cause for development of acquired TTP is still in its infancy, an increasing number of studies have described the binding characteristics of pathogenic antibodies in patients with acquired TTP (for review see ). In the current study Thomas and co-workers take this approach a step further by elegantly integrating functional and binding studies in a well-characterized cohort of patients with acquired TTP (). Their study confirms that in the majority of patients antibodies are present that are directed towards the spacer domain (B). In a subset of patients antibodies directed towards the TSP2-8 and CUB1-2 domain were identified. Antibodies exclusively targeting the carboxy-terminal TSP2-8 and CUB1-2 domains were observed in 3 out of 92 patients analyzed. These results are in excellent agreement with previous studies on the domain specificity of anti-ADAMTS13 antibodies (). A major asset of the current study is provided by combining mapping studies and linking these to the inhibitory properties of IgG purified from patient plasma. Their results show that inhibitory antibodies primarily target the spacer domain of ADAMTS13. Unexpectedly, in about half of the patients only weakly inhibitory antibodies were detected suggesting that functional inhibition of ADAMTS13 alone cannot account for the severe deficiency of ADAMTS13 in patients with acquired TTP.