Impact and production of Non‐HLA‐specific antibodies in solid organ transplantation

Zhang, Xiaohai; Reinsmoen, Nancy L.

doi:10.1111/iji.12494

Cited by 10 publications

(6 citation statements)

References 78 publications

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“…In more recent years, preformed and de novo non-HLA specific DSA targeting G-protein coupled receptors expressed on graft glomerular endothelium have been the focus of intense research, as they may account for a significant proportion of HLA-DSA negative acute and chronic ABMR [ 115 , 116 , 117 ]. They include a wide range of autoantibodies against different antigens, all of which represent potential biomarkers for ABMR [ 118 ] ( Table 5 ).…”

Section: Armentioning

confidence: 99%

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Quaglia

Merlotti

Guglielmetti

et al. 2020

IJMS

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New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

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Section: Armentioning

confidence: 99%

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Quaglia

Merlotti

Guglielmetti

et al. 2020

IJMS

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“…Autoantibodies (auto-Abs) directed against AT 1 R acting as agonists or probably positive agonistic modulators inducing pathogenic conditions have been demonstrated several times ( 22 , 91 – 93 ) as in women with preeclampsia ( 21 ), or in patients with acute vascular graft rejection ( 19 , 94 , 95 ). AT 1 R auto-Abs association with clinical features has also been studied extensively in the context of transplantation ( 96 – 100 ), or their effects on angiogenesis in preeclampsia ( 101 – 103 ). Binding of activating AT 1 R-Abs promotes specific downstream signaling via activation of AT 1 R ( 19 , 20 ); however, while Ang II binding to the receptor has been already explored intensively ( 104 – 108 ), the binding mode(s) between auto-Abs and receptors have not yet been determined.…”

Section: Antibody Bindingmentioning

confidence: 99%

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting

et al. 2022

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In conjunction with the endothelin (ET) type A (ETAR) and type B (ETBR) receptors, angiotensin (AT) type 1 (AT1R) and type 2 (AT2R) receptors, are peptide-binding class A G-protein-coupled receptors (GPCRs) acting in a physiologically overlapping context. Angiotensin receptors (ATRs) are involved in regulating cell proliferation, as well as cardiovascular, renal, neurological, and endothelial functions. They are important therapeutic targets for several diseases or pathological conditions, such as hypertrophy, vascular inflammation, atherosclerosis, angiogenesis, and cancer. Endothelin receptors (ETRs) are expressed primarily in blood vessels, but also in the central nervous system or epithelial cells. They regulate blood pressure and cardiovascular homeostasis. Pathogenic conditions associated with ETR dysfunctions include cancer and pulmonary hypertension. While both receptor groups are activated by their respective peptide agonists, pathogenic autoantibodies (auto-Abs) can also activate the AT1R and ETAR accompanied by respective clinical conditions. To date, the exact mechanisms and differences in binding and receptor-activation mediated by auto-Abs as opposed to endogenous ligands are not well understood. Further, several questions regarding signaling regulation in these receptors remain open. In the last decade, several receptor structures in the apo- and ligand-bound states were determined with protein X-ray crystallography using conventional synchrotrons or X-ray Free-Electron Lasers (XFEL). These inactive and active complexes provide detailed information on ligand binding, signal induction or inhibition, as well as signal transduction, which is fundamental for understanding properties of different activity states. They are also supportive in the development of pharmacological strategies against dysfunctions at the receptors or in the associated signaling axis. Here, we summarize current structural information for the AT1R, AT2R, and ETBR to provide an improved molecular understanding.

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“…Auto-antibodies have been identified in patients with acute vascular graft rejection, triggering the pathogenic activation of Nuclear Factor of “κappa-light-chain-enhancer” of activated B-cells (NFκB) and Activator Protein 1 (AP1), contributing to obliterative vasculopathy [ 14 , 15 , 16 ]. The association of AT 1 R-Abs with clinical features has also been extensively studied and demonstrated in the context of transplantations [ 17 , 18 , 19 , 20 , 21 ], as well as in preeclampsia, where it affects angiogenesis [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation

Philippe

Kleinau

Gruner

et al. 2022

IJMS

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The angiotensin II (Ang II) type 1 receptor (AT1R) is involved in the regulation of blood pressure (through vasoconstriction) and water and ion homeostasis (mediated by interaction with the endogenous agonist). AT1R can also be activated by auto-antibodies (AT1R-Abs), which are associated with manifold diseases, such as obliterative vasculopathy, preeclampsia and systemic sclerosis. Knowledge of the molecular mechanisms related to AT1R-Abs binding and associated signaling cascade (dys-)regulation remains fragmentary. The goal of this study was, therefore, to investigate details of the effects of AT1R-Abs on G-protein signaling and subsequent cell proliferation, as well as the putative contribution of the three extracellular receptor loops (ELs) to Abs-AT1R signaling. AT1R-Abs induced nuclear factor of activated T-cells (NFAT) signaling, which reflects Gq/11 and Gi activation. The impact on cell proliferation was tested in different cell systems, as well as activation-triggered receptor internalization. Blockwise alanine substitutions were designed to potentially investigate the role of ELs in AT1R-Abs-mediated effects. First, we demonstrate that Ang II-mediated internalization of AT1R is impeded by binding of AT1R-Abs. Secondly, exclusive AT1R-Abs-induced Gq/11 activation is most significant for NFAT stimulation and mediates cell proliferation. Interestingly, our studies also reveal that ligand-independent, baseline AT1R activation of Gi signaling has, in turn, a negative effect on cell proliferation. Indeed, inhibition of Gi basal activity potentiates proliferation triggered by AT1R-Abs. Finally, although AT1R containing EL1 and EL3 blockwise alanine mutations were not expressed on the human embryonic kidney293T (HEK293T) cell surface, we at least confirmed that parts of EL2 are involved in interactions between AT1R and Abs. This current study thus provides extended insights into the molecular action of AT1R-Abs and associated mechanisms of interrelated pathogenesis.

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Impact and production of Non‐HLA‐specific antibodies in solid organ transplantation

Cited by 10 publications

References 78 publications

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Angiotensin and Endothelin Receptor Structures With Implications for Signaling Regulation and Pharmacological Targeting

Molecular Effects of Auto-Antibodies on Angiotensin II Type 1 Receptor Signaling and Cell Proliferation

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