The two other loci related to AAV code for a serine protease inhibitor (serpin), which appears to control key intracellular and extracellular pathways of the auto-antigen PR3.3 New research suggests free PR3 may be more antigenic than complexed PR3, signifying that its role in autoimmunity may be more complicated than originally believed. These nuances can be further explored, because researchers published the genomic atlas of the human plasma proteome, which has expanded the ability to use specific proteins to link genetic factors to diseases.4 The evolving analyses support patient stratification based on ANCA specificity.
Researchers have used the accumulated data to determine why MPO- and PR3-AAV have so many clinical similarities. One hypothesis is that the various forms of ANCA have a common target (neutrophils) and the damage to the neutrophils results in a common clinical manifestation. “It could be a sort of antigenic accident,” explained Dr. Smith. If this is true, then it may be that the balance between costimulatory and coinhibitory signals shape T cell exhaustion and determine whether the immune system becomes autoreactive.5