Antibodies against "DANGER" in the dynamic of post-transplant circulation

Evidence that has accumulated about the impact of non-human leukocyte antigen (HLA) antibodies against tissue-restricted antigens supports the concept that humoral targets can be constantly altered by transplant-associated stresses such as ischemia-reperfusion (IR) injury, organ preservation, immunosuppressive drugs, and pre-existing diseases. This accounts for the growing interest in "danger" signals--in the form of damage-induced molecules--expanding our understanding of the humoral cause of allograft rejection and failure from thinking it is caused only by genetically determined HLA mismatches to seeing the role played by antibody recognition of antigens modified posttransplant. The heterogeneous repertoire of antibodies was evidenced by the recent protein microarray analysis that revealed increased posttransplant levels of heterogeneous antibodies against the targets localized in specific kidney compartments. Antibodies can also be developed against molecules dynamically generated in the circulation as damage-associated molecular patterns (DAMPs) that are the endogenous version of exogenous pathogen-associated molecular patterns (PAMPs). Antibodies against some DAMP molecules have been identified in many autoimmune diseases, but mostly have been elusive in transplant immunology. Those humoral DAMP targets include the well-studied high-mobility group box 1, IR injury-induced proteins, and oxidation-specific epitopes exposed on oxidized low-density lipoprotein. Moreover, understanding the intersection of endogenous DAMPs and exogenous PAMPs in transplant immunology may reveal a new aspect of humoral reactions. Recently reported cross-recognition by polyreactive antibodies of apoptotic cells may be one of many unidentified recognition patterns that indicate existence of an immune system strategy for defending against a number of stress-induced targets as a set of "danger." Given all these findings, the recent approach of identifying disease-specific panels of up-regulated proteins may help link them with pathogenic antibodies from the pool of heterogeneous antibodies whose pathological roles have remained unidentified, helping us understand the effect of those antibodies-and vice versa, helping us understand the impact of disease-specific antigens, not just up-regulated antigens, as a cause of humoral reactions.