Antibodies against Angiotensin II Type 1 and Endothelin A Receptors: Relevance and pathogenicity

Philogene, Mary Carmelle; Johnson, Tory P.; Vaught, Arthur J.; Zakaria, Sammy; Fedarko, Neal S.

doi:10.1016/j.humimm.2019.04.012

Cited by 49 publications

(64 citation statements)

References 74 publications

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“…The reason for this pattern remains unclear. It has been suggested that there may be different levels of expression of these receptors during different stages of allograft injury, 53 which may help explain the timing of antibody formation, but this hypothesis requires further investigation. Of the patients with ETAR-Ab post-transplant with pretransplant samples available, an approximately equal number of patients had the antibody before transplant, whereas the others developed it presumably de novo.…”

Section: Discussionmentioning

confidence: 99%

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation

Pearl

Chen

ElChaki

et al. 2020

Kidney International Reports

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Introduction: Autoantibody to angiotensin II type 1 receptor (AT1R-Ab) has been recognized as a non-human leukocyte antigen (HLA) antibody relevant in transplantation. Endothelin type A receptor antibody (ETAR-Ab) has been strongly associated with AT1R-Ab, but the data in kidney transplantation are scarce. Methods: We examined the relationship of ETAR-Ab and AT1R-Ab with clinical outcomes, biopsy findings, inflammatory cytokines, and HLA donor-specific antibody (DSA) in a cohort of pediatric renal transplant recipients. Sixty-five patients were longitudinally monitored for ETAR-Ab, AT1R-Ab, HLA DSA, interleukin (IL)-8, tumor necrosis factor-a, IL-1b, interferon-g, IL-17, IL-6, renal dysfunction, hypertension, rejection, and allograft loss during the first 2 years post-transplant. Results: Fifteen patients (23%) had AT1R-Ab alone, 1 (2%) had ETAR-Ab alone, 23 (35%) had both ETAR-Ab and AT1R-Ab, and 26 (40%) were negative for both antibodies at all timepoints. Having both ETAR-Ab and AT1R-Ab was associated with >30% decline in estimated glomerular filtration rate (P ¼ 0.024), arteritis (P ¼ 0.016), and elevated IL-8 levels (P ¼ 0.010), but not rejection, HLA DSA, or allograft loss. Having both antibodies resulted in greater increases in IL-8 compared with AT1R-Ab alone, even when controlled for additional clinical factors, including HLA DSA (P ¼ 0.012). Conclusion: Our study demonstrates that, in pediatric kidney transplantation, ETAR-Ab is highly associated with AT1R-Ab, but there are a subset of patients with AT1R-Ab alone. Having both antibodies is significantly associated with arteritis, elevated IL-8, and decline in renal function, and our results suggest possible interaction effects. Better understanding of this interaction may be informative in developing protocols for testing, treatment, and prevention of allograft injury.

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Section: Discussionmentioning

confidence: 99%

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation

Pearl

Chen

ElChaki

et al. 2020

Kidney International Reports

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“…Antibodies against angiotensin II type 1 receptor (AT1R) have been identified as endothelial cell antibodies in patients with acute rejection . AT1R is expressed on the endothelium and represents a G‐protein‐coupled receptor such that antibodies interacting with the receptor activate signaling pathways . A recent study reported an HLA‐DSA‐independent effect on allograft rejection with a distinct histopathological (endothelial activation) and clinical phenotype (hypertension) .…”

Section: Non‐hla Antibody Responsementioning

confidence: 99%

“…The endothelin receptor type A (ETAR) represents another G‐protein‐coupled receptor that has been identified as endothelial antigen. Interestingly, not all transplant recipients with AT1R and ETAR antibodies experience allograft dysfunction and a high variability in antibody titers was observed between studies .…”

Section: Non‐hla Antibody Responsementioning

confidence: 99%

“…Single nucleotide polymorphisms that were identified in both AT1R and ETAR were mainly associated with expression levels . Antibodies that activate G‐protein‐coupled receptors were also detected in patients without transplantation and showed an association with cardiovascular disease, preeclampsia, hypertension, aging, autoimmune diseases, and cancer . AT1R and ETAR are therefore mainly considered autoantibodies rather than alloantibodies directed against non‐self residues.…”

Section: Non‐hla Antibody Responsementioning

confidence: 99%

“…AT1R and ETAR are therefore mainly considered autoantibodies rather than alloantibodies directed against non‐self residues. For a more detailed discussion of G‐protein‐coupled receptors in transplantation, the reader is referred to a recent review by Philogene et al .…”

Section: Non‐hla Antibody Responsementioning

confidence: 99%

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Novel insights into non‐HLA alloimmunity in kidney transplantation

et al. 2019

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Recognition of non-self structures on donor cells represents the main immunological barrier in solid organ transplantation. The human leukocyte antigens (HLA) are considered the most important non-self (allo)antigens in transplantation. Long-term graft attrition is mainly caused by the formation of alloreactive antibodies that are directed against nonself structures (i.e., epitopes) on cell surface proteins. Recently published data provided evidence for a similar importance of non-HLA mismatches between donors and recipients in acute rejection as well as long-term kidney allograft survival. These data suggest a broader concept of immunological non-self that goes beyond HLA incompatibility and expands the current concept of polymorphic non-self epitopes on cell surface molecules from HLA to non-HLA targets. Amino acid substitutions caused by single nucleotide variants in protein-coding genes or complete loss of gene expression represent the basis for polymorphic residues in both HLA and non-HLA molecules. To better understand these novel insights in non-HLA alloimmunity, we will first review basic principles of the alloimmune response with a focus on the HLA epitope concept in donor-specific antibody formation before discussing key publications on non-HLA antibodies.

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Association between anti‐endothelial antigen antibodies and allograft rejection in kidney transplantation

Lee,

Shin,

Kim

et al. 2023

Clinical Laboratory Analysis

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BackgroundEndothelial cells are vital in the transplant immune system as semiprofessional antigen‐presenting cells. Few studies have investigated the importance of anti‐endothelin subtype A receptor (ETAR) antibodies in kidney transplantation. Here, we aimed to analyze the association between anti‐angiotensin II type I receptor (AT1R) and anti‐ETAR antibodies and the association between the presence of anti‐endothelial antibodies and the risk of allograft rejection in kidney transplantation.MethodsIn total, 252 patients who underwent kidney transplantation were enrolled in this study. Antibodies for human leukocyte antigens (HLAs) and non‐HLAs were analyzed immediately before transplantation. Patients were categorized based on the occurrence of antibody‐mediated rejection (AMR) or T‐cell‐mediated rejection (TCMR) by 2017 Banff classification. All p‐values were two‐tailed, and statistical significance was set at p < 0.05.ResultsPatients with anti‐AT1R antibodies had a 3.49‐fold higher risk of TCMR than those without anti‐AT1R antibodies. Patients with anti‐ETAR antibodies had a 5.84‐fold higher risk of AMR than those without anti‐ETAR antibodies. The hazard ratio of AMR in patients with both HLA DSAs and anti‐ETAR antibodies, relative to patients without anti‐ETAR antibodies and HLA DSAs, was 32.85 (95% CI = 1.82–592.91).ConclusionOur findings indicated that anti‐ETAR antibodies are associated with AMR, and patients with both anti‐ETAR antibodies and de novo HLA DSAs were at a high risk of AMR.

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Antibodies against Angiotensin II Type 1 and Endothelin A Receptors: Relevance and pathogenicity

Cited by 49 publications

References 74 publications

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation

Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation

Novel insights into non‐HLA alloimmunity in kidney transplantation

Association between anti‐endothelial antigen antibodies and allograft rejection in kidney transplantation

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