Non-HLA antibodies against endothelial targets bridging allo- and autoimmunity
2016; Elsevier BV; Volume: 90; Issue: 2 Linguagem: Inglês
10.1016/j.kint.2016.03.019
ISSN1523-1755
AutoresDuska Dragun, Rusan Catar, Aurélie Philippe,
Tópico(s)Transplantation: Methods and Outcomes
ResumoDetrimental 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. 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. Efforts to understand mechanisms of allorecognition and to modulate the effectors of cellular immunity dominated the field of transplantation medicine for a long period of time. Increasing importance of antibody (Ab)-mediated rejection (ABMR) shifted the attention of the transplant community toward allo- and autoantibody-mediated mechanisms of transplant damage during the past decade. ABMR is a major barrier to tolerance and a leading cause of kidney allograft loss.1Halloran P.F. Reeve J.P. Pereira A.B. et al.Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.Kidney Int. 2014; 85: 258-264Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar Lack of adequate therapies to effectively modulate or reverse Ab-mediated injury illustrates the pressing need to identify new diagnostic and therapeutic concepts beyond traditional targeting of the immune system effectors. Vascular endothelium comprises a critical interphase between parenchymal cells of the transplanted organ and the immune system of the recipient. Homeostatic functions of the endothelium are regulation of organ perfusion, regulation of nutrient/waste/gas exchange between blood and tissue, regulation of hemostasis, and participation in immune surveillance.2Abrahimi P. Liu R. Pober J.S. Blood vessels in allotransplantation.Am J Transplant. 2015; 15: 1748-1754Crossref PubMed Scopus (36) Google Scholar Injuries to macrovascular and microvascular endothelium disturb endothelial homeostasis in the transplanted kidney at multiple levels and the cardiovascular system of the recipient.3Loupy A. Vernerey D. Viglietti D. et al.Determinants and outcomes of accelerated arteriosclerosis: major impact of circulating antibodies.Circ Res. 2015; 117: 470-482Crossref PubMed Scopus (37) Google Scholar Prominent upregulation of endothelial transcripts indicative of endothelial stress and microscopic microcirculation changes also underscore importance of the endothelium as a primary target for the effectors of cellular and humoral immunity after kidney transplantation.4Sis B. Jhangri G.S. Bunnag S. et al.Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining.Am J Transplant. 2009; 9: 2312-2323Crossref PubMed Scopus (388) Google Scholar Repetitive microvascular endothelial injuries and repair attempts lead to impairment in intrarenal oxygen delivery, activating various vasoactive systems and eventually resulting in fibrosis of the allograft.5Jiang X. Sung Y.K. Tian W. et al.Graft microvascular disease in solid organ transplantation.J Mol Med. 2014; 92: 797-810Crossref PubMed Scopus (28) Google Scholar Although critically important, the endothelium remains an unfortunately largely untapped therapeutic target in kidney and other forms of solid organ transplantation. Discovery of several endothelial antigenic targets on macrovascular and microvascular endothelium including G protein–coupled receptors (GPCRs); first, the angiotensin type I receptor (AT1R) and later the endothelin type A receptor (ETAR), as well as the bioactive C-terminal fragment of perlecan (referred to as LG3) with consecutive diagnostic developments, sparked the interest of the transplant community in nonhuman leukocyte antigen (HLA) Ab responses and their actions on the endothelium. Protein array studies enabled an unbiased search for other targets. After providing a brief general overview of kidney endothelium with the pitfalls of older studies on antiendothelial cell Abs (AECAs), we focus on recent clinical and experimental studies investigating the impact of anti-GPCR and antiperlecan Abs, followed by discovery of proteomics-based developments. As ABMR is frequently C4d negative,6Haas M. Sis B. Racusen L.C. et al.Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant. 2014; 14: 272-283Crossref PubMed Scopus (1062) Google Scholar which underscores the potential relevance of complement-independent mechanisms, we further address similarities and dissimilarities of specific Ab-related intracellular signaling pathways elicited in endothelial cells. In order to address current critical gaps between HLA and non-HLA Ab responses, we attempted to identify potential leads and common targets for future therapeutic improvements. Endothelial heterogeneity evolved as a core feature of the endothelium, reflecting its role to meet the diverse needs in specific body tissues.7Aird W.C. Proximate and evolutionary causation of endothelial heterogeneity.Semin Thromb Hemost. 2010; 36: 276-285Crossref PubMed Scopus (11) Google Scholar In the kidney, endothelial cells display functional heterogeneity in specific vasculature subsets.8Aird W.C. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.Circ Res. 2007; 100: 174-190Crossref PubMed Scopus (778) Google Scholar, 9Aird W.C. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms.Circ Res. 2007; 100: 158-173Crossref PubMed Scopus (1202) Google Scholar An endothelial layer of renal arteries and veins is nonfenestrated and continuous.8Aird W.C. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds.Circ Res. 2007; 100: 174-190Crossref PubMed Scopus (778) Google Scholar Microvascular fenestrated endothelium of glomerular capillaries evolved at the site of increased filtration and fenestrated endothelium of peritubular capillaries to cope with increased transendothelial transport. Data on the expression of HLA class II antigens vary from reporting constitutively high levels on quiescent glomerular and peritubular microvascular endothelial cells10Muczynski K.A. Ekle D.M. Coder D.M. et al.Normal human kidney HLA-DR-expressing renal microvascular endothelial cells: characterization, isolation, and regulation of MHC class II expression.J Am Socf Nephrol. 2003; 14: 1336-1348Crossref PubMed Scopus (131) Google Scholar to opposing findings based on the traditional view that only HLA class I antigens but not HLA class II antigens are expressed on quiescent endothelium of different vascular beds.11Collins T. Korman A.J. Wake C.T. et al.Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts.Proc Natl Acad Sci U S A. 1984; 81: 4917-4921Crossref PubMed Scopus (436) Google Scholar, 12Geppert T.D. Lipsky P.E. Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression.J Immunol. 1985; 135: 3750-3762PubMed Google Scholar Quiescent glomerular endothelial cells express very low levels of AT1R.13Cresci B. Giannini S. Pala L. et al.AT1 and AT2 receptors in human glomerular endothelial cells at different passages.Microvasc Res. 2003; 66: 22-29Crossref PubMed Scopus (19) Google Scholar The endothelium of preglomerular vessels expresses ETAR.14Davenport A.P. Kuc R.E. Hoskins S.L. et al.[125I]-PD151242: a selective ligand for endothelin ETA receptors in human kidney which localizes to renal vasculature.Br J Pharmacol. 1994; 113: 1303-1310Crossref PubMed Scopus (33) Google Scholar Despite the mentioned specific features of the kidney endothelium, endothelial cell lines derived from the kidney micro- or macrovascular endothelium are only very rarely used in research, and the majority of the studies are generated in other cell systems such as human umbilical vein endothelial cells (HUVECs) or aortic macrovascular endothelium. Maintenance of functional specificity of macro- and microvascular endothelium is essential for the health of the transplanted kidney. Kidney allograft endothelium is, however, never quiescent and is prone to various injurious stimuli that disturb the homeostatic function of the endothelium. Endothelial activation leading to broad upregulation of both class I and II HLA antigens as well as non-HLA antigens such as AT1R and ETAR occurs already during brain death15Yamani M.H. Cook D.J. Tuzcu E.M. et al.Systemic up-regulation of angiotensin II type 1 receptor in cardiac donors with spontaneous intracerebral hemorrhage.Am J Transplant. 2004; 4: 1097-1102Crossref PubMed Scopus (23) Google Scholar and organ retrieval process. Processes associated with endothelial dysfunction continue during ischemia and reperfusion injury and can be augmented with calcineurin inhibitors, the mainstay immunosuppressants.16Remuzzi G. Perico N. Cyclosporine-induced renal dysfunction in experimental animals and humans.Kidney Int. 1995; 52: S70-S74Google Scholar Logically, AECAs represent a heterogeneous group of Abs directed against a variety of antigenic determinants on endothelial cells.17Praprotnik S. Blank M. Meroni P.L. et al.Classification of anti-endothelial cell antibodies into antibodies against microvascular and macrovascular endothelial cells: the pathogenic and diagnostic implications.Arthritis Rheum. 2001; 44: 1484-1494Crossref PubMed Scopus (119) Google Scholar The most significant barrier to the general acceptance of AECAs as causative of allograft injury is the lack of standardized assays to determine their presence for a long time period. During the past years, 2 different detection platforms emerged. One is an indirect immunofluorescence test on slides covered with HUVECs.4Sis B. Jhangri G.S. Bunnag S. et al.Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining.Am J Transplant. 2009; 9: 2312-2323Crossref PubMed Scopus (388) Google Scholar, 18Sun Q. Cheng Z. Cheng D. et al.De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection.Kidney Int. 2011; 79: 655-662Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Surface antigen expression in quiescent HUVECs may, however, differ from that in activated kidney allograft endothelium. Not surprisingly, de novo but not preexisting AECAs were associated with steroid refractory acute rejection.18Sun Q. Cheng Z. Cheng D. et al.De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection.Kidney Int. 2011; 79: 655-662Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The other modality is a flow cytometry–based endothelial crossmatch assay (ECXM) that relies on isolation of endothelial cell precursors positive for the angiopoietin receptor Tie-2 from the peripheral blood of organ donors.19Breimer M.E. Rydberg L. Jackson A.M. et al.Multicenter evaluation of a novel endothelial cell crossmatch test in kidney transplantation.Transplantation. 2009; 87: 549-556Crossref PubMed Scopus (98) Google Scholar An isolation procedure for ECXM largely relies on monocyte-rich hematopoietic progenitors with surface antigen expression that largely differs from patterns detected in activated endothelial cells. Accordingly, results of clinical studies showed a better correlation of positive ECXM results with cellular than with humoral rejection.20Jackson A.M. Sigdel T.K. Delville M. et al.Endothelial cell antibodies associated with novel targets and increased rejection.J Am Soc Nephrol. 2015; 26: 1161-1171Crossref PubMed Scopus (94) Google Scholar Donor-reactive AECAs detected on ECXM belonged to complement nonfixing IgG2 and IgG4 subclasses.20Jackson A.M. Sigdel T.K. Delville M. et al.Endothelial cell antibodies associated with novel targets and increased rejection.J Am Soc Nephrol. 2015; 26: 1161-1171Crossref PubMed Scopus (94) Google Scholar AECAs detected by ECXM may differ from AECAs detected by means of immunofluorescence on HUVEC coverslips. Neither of the mentioned test modalities are in broad clinical use. Development of experimental primary cultures of endothelial cells prospectively isolated from deceased transplant donors are probably biologically closest to a real-life transplant situation, yet technically tedious to become feasible for clinical routine use.21Canet E. Devalliere J. Gerard N. et al.Profiling posttransplant circulating antibodies in kidney transplantation using donor endothelial cells.Transplantation. 2012; 93: 257-264Crossref PubMed Scopus (16) Google Scholar It is likely that the targeted detection of Igs against relevant endothelial antigens involved in allograft pathology (Figure 1) will offer a more practical diagnostic approach compared with measurements of broad reactivity to the endothelium. So far, most of the clinically relevant discovered endothelial Abs are directed against variety of proteins that display prominent extracellular regions (Figure 1). Perlecan shows a spatial difference as it is contained within the endothelial basement membrane and may act as a neoantigen. G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors and the most important drug targets because >40% of currently used drugs are GPCR modulators.22Venkatakrishnan A.J. Deupi X. Lebon G. et al.Molecular signatures of G-protein-coupled receptors.Nature. 2013; 494: 185-194Crossref PubMed Scopus (1088) Google Scholar Structural organization of 7-transmembrane span GPCRs is complex, showing an extracellular region with an N terminus and 3 extracellular loops (ECL1–ECL3); the transmembrane (TM) regions (TM1–7), consisting of 7 α-helices, and the intracellular region, consisting of 3 intracellular loops, an intracellular amphipathic helix, and the C-terminus.22Venkatakrishnan A.J. Deupi X. Lebon G. et al.Molecular signatures of G-protein-coupled receptors.Nature. 2013; 494: 185-194Crossref PubMed Scopus (1088) Google Scholar AT1R belongs to class A of GPCRs and mediates most of the physiologic and pathophysiologic effects of angiotensin II (Ang II) by promoting vasoconstriction, inflammation, proliferation, and fibrosis.23Ruster C. Wolf G. Angiotensin II as a morphogenic cytokine stimulating renal fibrogenesis.J Am Soc Nephrol. 2011; 22: 1189-1199Crossref PubMed Scopus (148) Google Scholar Similar actions of endothelin-1 are exerted via ETAR.24Boesen E.I. Endothelin receptors, renal effects and blood pressure.Curr Opin Pharmacol. 2015; 21: 25-34Crossref PubMed Scopus (40) Google Scholar A low level of expression of both AT1R and ETAR has been detected on quiescent glomerular kidney allograft endothelium.13Cresci B. Giannini S. Pala L. et al.AT1 and AT2 receptors in human glomerular endothelial cells at different passages.Microvasc Res. 2003; 66: 22-29Crossref PubMed Scopus (19) Google Scholar, 14Davenport A.P. Kuc R.E. Hoskins S.L. et al.[125I]-PD151242: a selective ligand for endothelin ETA receptors in human kidney which localizes to renal vasculature.Br J Pharmacol. 1994; 113: 1303-1310Crossref PubMed Scopus (33) Google Scholar Increased expression of both receptors can be found in activated endothelium, implicating them as endothelial antigens. As illustrated in Figure 2, AT1R-Abs belong to the complement fixing IgG1 and IgG3 and appear to recognize antigens contained in the ECL2 of the AT1R, which differ from binding sites for Ang II or sartanes.25Dragun D. Muller D.N. Brasen J.H. et al.Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352: 558-569Crossref PubMed Scopus (679) Google Scholar In terms of molecular pharmacology, Ang II is considered to be an orthosteric AT1R ligand, whereas AT1R-Abs can be considered allosteric AT1R agonists. Among commonly used pharmacologic antagonists, only losartan binds within the Ang II orthosteric site in the TM5 of AT1R, whereas others such as candesartan or olmesartan bind within TM3, 5, and 6. Antigenic targets or dominant IgG subclasses of ETAR-Abs have not yet been characterized. A recently developed method of serial femtosecond crystallography helped to finally solve a long-awaited crystal structure of AT1R.26Zhang H. Unal H. Gati C. et al.Structure of the Angiotensin receptor revealed by serial femtosecond crystallography.Cell. 2015; 161: 833-844Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar Structural data were instrumental in better understanding our initial functional data obtained in bioassay of potential AT1R-Ab epitopes contained in ECL2, as ECL2 of AT1R is engaged in disulfide bonding and exhibits a β-hairpin secondary structure.25Dragun D. Muller D.N. Brasen J.H. et al.Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352: 558-569Crossref PubMed Scopus (679) Google Scholar, 26Zhang H. Unal H. Gati C. et al.Structure of the Angiotensin receptor revealed by serial femtosecond crystallography.Cell. 2015; 161: 833-844Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar This is a common motif among peptide GPCRs,22Venkatakrishnan A.J. Deupi X. Lebon G. et al.Molecular signatures of G-protein-coupled receptors.Nature. 2013; 494: 185-194Crossref PubMed Scopus (1088) Google Scholar with possible implications for future studies of ETAR-Abs and new GPCR candidates as Ab targets. Histologic features of AT1R-Abs–mediated injury range from microvascular inflammation to endarteritis, fibrinoid necrosis, and arteriolar and arterial thrombosis.27Dragun D. Catar R. Kusch A. et al.Non-HLA-antibodies targeting Angiotensin type 1 receptor and antibody mediated rejection.Hum Immunol. 2012; 73: 1282-1286Crossref PubMed Scopus (43) Google Scholar Biopsy specimens of AT1R-Ab–positive patients with acute or chronic kidney allograft dysfunction are frequently C4d negative, which adds AT1R-Ab–related injury to the complex spectrum of C4d-negative rejection phenotypes. The mentioned histologic features occurred in the presence of AT1R-Abs alone and sometimes in conjunction with HLA donor-specific antigen (DSA) Abs, needing a more precise definition of pathophysiologic differences among ABMR entities. Detection of intense tissue factor staining of arterial, arteriolar, and glomerular endothelial cells in renal transplant biopsy specimens obtained during the AT1R-Ab–mediated rejection episodes may offer an explanation for the severe vascular phenotypes in the absence of complement activation. Tissue factor staining could be attenuated after aggressive treatment based on Ab removal and a high-dose AT1R blocker, a combination that enabled allograft function rescue.25Dragun D. Muller D.N. Brasen J.H. et al.Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352: 558-569Crossref PubMed Scopus (679) Google Scholar Tissue factor is well established as a mediator of clotting abnormalities associated with experimental hyperacute and acute rejection in xenotransplants28Chen D. Weber M. McVey J.H. et al.Complete inhibition of acute humoral rejection using regulated expression of membrane-tethered anticoagulants on xenograft endothelium.Am J Transplant. 2004; 4: 1958-1963Crossref PubMed Scopus (92) Google Scholar and in antiphospholipid Ab syndrome in humans.29Branch D.W. Rodgers G.M. Induction of endothelial cell tissue factor activity by sera from patients with antiphospholipid syndrome: a possible mechanism of thrombosis.Am J Obstet Gynecol. 1993; 168: 206-210Abstract Full Text PDF PubMed Scopus (133) Google Scholar The phenotype of ETAR-Ab–related transplant injury has not yet been precisely defined. Given the striking similarities in vasculopathic lesions with diffuse concentric narrowing of the vessel lumen between allograft arteriosclerosis and systemic sclerosis lesions, it is likely that the renal transplant phenotypes will be soon unraveled. Bioassay in neonatal cardiomyocytes used in the proof-of-concept study that was developed to measure the chronotropic response to AT1R-IgG in studies of preeclampsia proved very time-consuming and labor intensive. In order to replace the bioassay, a cell membrane extract–based sandwich enzyme-linked immunosorbent assay quantitatively detecting AT1R-IgG has been successfully developed and used in numerous clinical studies. Using careful isolation of membrane extracts from AT1R-overexpressing cells and using them as a solid phase proved essential for optimal sensitivity and specificity compared with a classical peptide enzyme-linked immunosorbent assay based on an amino-acid sequence of the epitopes. An overview of the published studies related to kidney transplantation or other transplants as well as autoimmune and metabolic disease settings is provided in Table 1.20Jackson A.M. Sigdel T.K. Delville M. et al.Endothelial cell antibodies associated with novel targets and increased rejection.J Am Soc Nephrol. 2015; 26: 1161-1171Crossref PubMed Scopus (94) Google Scholar, 25Dragun D. Muller D.N. Brasen J.H. et al.Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection.N Engl J Med. 2005; 352: 558-569Crossref PubMed Scopus (679) Google Scholar, 30Reinsmoen N.L. Lai C.H. Heidecke H. et al.Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients.Transplantation. 2010; 90: 1473-1477Crossref PubMed Scopus (174) Google Scholar, 31Giral M. Foucher Y. 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