title: Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity.
abstract: Detrimental actions of donor-specific antibodies (DSAs) directed against both major histocompatibility antigens (human leukocyte antigen [HLA]) and specific non-HLA antigens expressed on the allograft endothelium are a flourishing research area in kidney transplantation. Newly developed solid-phase assays enabling detection of functional non-HLA antibodies targeting G protein-coupled receptors such as angiotensin type I receptor and endothelin type A receptor were instrumental in providing long-awaited confirmation of their broad clinical relevance. Numerous recent clinical studies implicate angiotensin type I receptor and endothelin type A receptor antibodies as prognostic biomarkers for earlier occurrence and severity of acute and chronic immunologic complications in solid organ transplantation, stem cell transplantation, and systemic autoimmune vascular disease. Angiotensin type 1 receptor and endothelin type A receptor antibodies exert their pathophysiologic effects alone and in synergy with HLA-DSA. Recently identified antiperlecan antibodies are also implicated in accelerated allograft vascular pathology. In parallel, protein array technology platforms enabled recognition of new endothelial surface antigens implicated in endothelial cell activation. Upon target antigen recognition, non-HLA antibodies act as powerful inducers of phenotypic perturbations in endothelial cells via activation of distinct intracellular cell-signaling cascades. Comprehensive diagnostic assessment strategies focusing on both HLA-DSA and non-HLA antibody responses could substantially improve immunologic risk stratification before transplantation, help to better define subphenotypes of antibody-mediated rejection, and lead to timely initiation of targeted therapies. Better understanding of similarities and dissimilarities in HLA-DSA and distinct non-HLA antibody-related mechanisms of endothelial damage should facilitate discovery of common downstream signaling targets and pave the way for the development of endothelium-centered therapeutic strategies to accompany intensified immunosuppression and/or mechanical removal of antibodies.
authors.affiliation: Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. Electronic address: duska.dragun@charite.de.
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.affiliation: Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany.
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.affiliation: Clinic for Nephrology and Critical Care Medicine, Campus Virchow-Klinikum and Center for Cardiovascular Research, Medical Faculty of the Charité Berlin, Berlin, Germany.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Philippe
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists / Q000627:therapeutic use; D006084:Graft Rejection / Q000276:immunology* / Q000628:therapy; D006085:Graft Survival / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D019812:Heparan Sulfate Proteoglycans / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D010956:Plasmapheresis; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology; D044022:Receptor, Endothelin A / Q000276:immunology; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D065130:Endothelin A Receptor Antagonists; D006680:HLA Antigens; D019812:Heparan Sulfate Proteoglycans; D007166:Immunosuppressive Agents; D044140:Receptor, Angiotensin, Type 1; D044022:Receptor, Endothelin A; C071927:perlecan
keywords: acute rejection; angiotensin; endothelium; renin angiotensin system; signaling