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Background Prolonged (val)ganciclovir [(V)GCV] exposure for ≥6 weeks is a known predisposing factor for cytomegalovirus (CMV) drug resistance. However, the selection of this threshold was based on limited data. In this study, we sought to reappraise the risk factors for the development of (V)GCV resistance through a specific focus on kidney transplant recipients (KTRs). Methods This single-center retrospective study included 313 consecutive KTRs treated for a first CMV episode. Adjusted Cox multivariate regression analysis was used for identifying independent risk factors. Results Antiviral drug resistance was identified in 20 (6%) KTRs. A cumulative (V)GCV exposure for more than 6 weeks (regardless of the viral load) was not associated with antiviral drug resistance (hazard ratio [HR] = 2.45, 95% confidence interval [CI] = 0.33–18.30, P =.38). In contrast, persistent CMV DNAemia requiring (V)GCV treatment for more than 8 weeks was the main independent risk factor for antiviral drug resistance (HR = 11.68, 95% CI = 2.62–52.01, P =.001). The (V)GCV treatment for more than 8 weeks was given to 9% and 18% of patients who had persistent or recurrent CMV DNAemia, respectively. These scenarios were associated with the occurrence of drug resistance in 39% and 12% of cases, respectively. Conclusions Cumulative (V)GCV exposure ≥6 weeks regardless of the viral load is not associated with antiviral drug resistance. In contrast, prolonged exposure to (V)GCV during CMV replication (with a cutoff ³8 weeks) seems to be a key factor. [ABSTRACT FROM AUTHOR]

HLA antibody detection with single antigen flow beads (SAFB) assays is impaired by complement interference whose frequency, predictability and distribution among HLA antigens have not been analyzed in large cohorts. We compared in two patients' cohorts the routine follow‐up SAFB profiles obtained in class I (n = 129) and class II (n = 85) with and without ethylenediaminetetraacetic acid (EDTA)‐treatment. The presence of complement interference was defined according to the reproducibility of the SAFB assays evaluated with our class I and II routine positive control sera. Interference occurred in 29.5% and 45.9% of patients in class I and II, respectively. In the untreated condition, at serum level, neither the number of positive beads, the highest bead mean fluorescence intensity (MFI) nor MFI at bead level, satisfactorily predicted interference. HLA‐C were the least affected among class I beads. HLA‐DQ beads were the most affected in class II. At least one antibody specificity was falsely negative without EDTA for about 3% of sera in class I and 9% in class II. EDTA‐treatment did not significantly modify the low‐MFI strengths (500‐3000 range). This study emphasizes the high frequency of complement interference and the importance and advantages of systematically pretreating sera with EDTA before performing SAFB assays. [ABSTRACT FROM AUTHOR]

HLA‐A*24:391 differs from HLA‐A*24:02:01:01 by one nucleotide substitution at position 33. [ABSTRACT FROM AUTHOR]

HLA‐C*16:116 differs from HLA‐C*16:01:01:01 by single‐nucleotide substitution at position 30. [ABSTRACT FROM AUTHOR]

HLA‐B*07:305 differs from HLA‐B*07:02:01:01 by one nucleotide substitution at position 255. [ABSTRACT FROM AUTHOR]

HLA-B*40:587 differs from HLA-B*40:02:01:01 by one nucleotide substitution in codon 275 in exon 5., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-C*07:01:126 differs from HLA-C*07:01:01:01 by one nucleotide substitution in codon 328 in exon 7., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DPA1*01:12:03 differs from HLA-DPA1*01:12:01 by one nucleotide substitution in codon 204 in exon 4., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*51:411 differs from HLA-B*51:01:01:01 by one nucleotide substitution in codon 235 in exon 4., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-A*26:247 differs from HLA-A*26:01:01:01 by one nucleotide substitution in codon 245 in exon 4., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Granulomatous disease is a serious complication of common variable immunodeficiency (CVID-GD) that occurs in 8-22% of these patients and can mimic sarcoidosis, with which it shares certain clinical, biological, and radiological features. However, few studies to date have compared the two pathologies immunologically and histologically. Therefore, we analyzed the immunological-histological findings for different tissue samples from ten patients with CVID-GD and compared them to those of biopsy-proven sarcoidosis. Specifically, we wanted to know whether or not the signaling abnormalities observed in sarcoidosis granulomas are also present in CVID-GD. Morphological differences were found between CVID-GD histology and classical sarcoidosis: mainly, the former's notable lymphoid hyperplasia associated with granulomas not observed in the latter. All CVID-GD involved organs contained several follicular helper-T (TFH) cells within the granulomatosis, while those cells were inconstantly and more weakly expressed in sarcoidosis. Moreover, CVID and sarcoidosis granulomas expressed the phosphorylated-signal transducer and activator of transcription (pSTAT)1 and pSTAT3 factors, regardless of the organ studied and without any significant difference between entities. Our results suggest that the macrophage-activation mechanism in CVID resembles that of sarcoidosis, thereby suggesting that Janus kinase (JAK)-STAT-pathway blockade might be useful in currently difficult-to-treat CVID-GD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

HLA-C*05:286 differs from HLA-C*05:01:01:02 by one nucleotide substitution in codon 283 in exon 5., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

T-cell mediated rejection (TCMR), de novo anti-HLA donor-specific antibodies (dnDSAs) and ensuing antibody-mediated rejection (ABMR) reduce kidney transplantation (KT) survival. The immunomodulatory effects of 25-hydroxyvitamin D [25(OH)D] could be beneficial for KT outcomes. We aimed to evaluating the association between 25(OH)D levels, the development of dnDSAs, clinical TCMR and ABMR, and graft survival. This single center retrospective study included 253 KT recipients (KTRs) transplanted without preformed DSA between 2010 and 2013. We measured 25(OH)D in successive serum samples: at KT (M0) and M12 for the entire cohort, and additionally at M24 and/or M36 when sera were available. We assessed graft outcomes up to 5 years post-KT. The proportion of KTRs having sufficient 25(OH)D at KT (M0) was high (81.4%) and then dropped at M12 (71.1%). KTRs with sufficient 25(OH)D at M0 experienced less clinical TCMR (HR, 0.41; 95% CI, 0.19-0.88 in multivariate analysis). A sufficient 25(OH)D at M12 was independently associated with a longer dnDSA-free survival (HR, 0.34; 95% CI, 0.17-0.69). There was no association between 25(OH)D and clinical AMBR. Studying the KTRs with 25(OH)D measurements at M12, M24 and M36 (n = 203), we showed that 25(OH)D sufficiency over the 3 first-years post-KT was associated with a longer graft survival in multivariate analyses (HR, 0.39; 95% CI, 0.22-0.70). To our knowledge, this study is the first showing an association between 25(OH)D sufficiency post-KT and dnDSA occurrence in KTRs. Moreover, we reinforce previously published data showing an association between 25(OH)D, TCMR and graft survival in KT., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-C*16:98:02 differs from HLA-C*16:98:01 by one nucleotide substitution in codon 132 in exon 3., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*40:539 differs from HLA-B*40:01:01 by one nucleotide substitution in codon 46 in exon 2., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DRB1*11:01:01:12N differs from HLA-DRB1*11:01:01:03 by one nucleotide substitution in intron 3 at position c.652+1G>C, hg19., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Our objective was to calculate an immunosuppressant possession ratio (IPR) to diagnose non-adherence at the time of antibody-mediated rejection (ABMR). IPR was defined as the ratio of number of pills collected at the pharmacy to the number of pills prescribed over a defined period. In a first cohort of 91 kidney transplant recipients (KTRs), those with an IPR < 90% had more frequently a tacrolimus through level coefficient of variation >30% than patients with an IPR = 100% (66.7% vs. 29.4%, p = 0.05). In a case-control study, 26 KTRs with ABMR had lower 6 months IPRs than 26 controls (76% vs. 99%, p < 0.001). In KTRs with ABMR, non-adherence was more often diagnosed by a 6 months IPR < 90% than by clinical suspicion (73.1% vs 30.8%, p = 0.02). In the multivariable analysis, only de novo DSA and 6 months IPR < 90% were independently associated with ABMR, whereas clinical suspicion was not (odds ratio, 4.73; 95% CI, 1.17-21.88; p = 0.03; and odds ratio, 6.34; 95% CI, 1.73-25.59; p = 0.007, respectively). In summary, IPR < 90% is a quantifiable tool to measure immunosuppressant non-adherence. It is better associated with ABMR than clinical suspicion of non-adherence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chambord, Chauveau, Djabarouti, Vignaud, Taton, Moreau, Visentin, Merville, Xuereb and Couzi.)

Given the risk of rejection, the presence of preformed donor specific antibodies (DSA) contraindicates transplantation in most allocation systems. However, HLA-Cw and -DP DSA escape this censorship. We performed a multicentric observational study, in which the objective was to determinate risk factors of acute antibody-mediated rejection (aABMR) in recipients transplanted with preformed isolated Cw- or DP-DSA. Between 2010 and 2019, 183 patients were transplanted with a preformed isolated Cw- or DP-DSA (92 Cw-DSA; 91 DP-DSA). At 2 years, the incidence of aABMR was 12% in the Cw-DSA group, versus 28% in the DP-DSA group. Using multivariable Cox regression model, the presence of a preformed DP-DSA was associated with an increased risk of aABMR (HR = 2.32 [1.21-4.45 ( p = 0.001)]) compared with Cw-DSA. We also observed a significant association between the DSA's MFI on the day of transplant and the risk of aABMR (HR = 1.09 [1.08-1.18], p = 0.032), whatever the DSA was. Interaction term analysis found an increased risk of aABMR in the DP-DSA group compared with Cw-DSA, but only for MFI below 3,000. These results may plead for taking these antibodies into account in the allocation algorithms, in the same way as other DSA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Laboux, Lenain, Visentin, Flahaut, Chamley, Provôt, Top, Kerleau, Labalette, Choukroun, Couzi, Blancho, Hazzan and Maanaoui.)

HLA-C*12:384 differs from HLA-C*12:03:01:02 by one nucleotide substitution in codon 42 in exon 2., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

HLA-DPA1*02:115 differs from HLA-DPA1*02:01:01:06 by one nucleotide substitution in codon 224 in exon 4., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*44:324:02 differs from HLA-B*44:324:01 by one nucleotide substitution in codon 99 in exon 3., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

HLA-A*24:587 differs from HLA-A*24:02:01:01 by one nucleotide substitution in codon 220 in exon 4., (© 2023 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

HLA-C*03:552 differs from HLA-C*03:04:01:01 by one nucleotide substitution in codon 72 in exon 2., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Alloreactivity can drive autoimmune syndromes. After allogeneic hematopoietic stem cell transplantation (allo-HCT), chronic graft-versus-host disease (cGVHD), a B cell-associated autoimmune-like syndrome, commonly occurs. Because donor-derived B cells continually develop under selective pressure from host alloantigens, aberrant B cell receptor (BCR) activation and IgG production can emerge and contribute to cGVHD pathobiology. To better understand molecular programing of B cells in allo-HCT, we performed scRNA-Seq analysis on high numbers of purified B cells from patients. An unsupervised analysis revealed 10 clusters, distinguishable by signature genes for maturation, activation, and memory. Within the memory B cell compartment, we found striking transcriptional differences in allo-HCT patients compared with healthy or infected individuals, including potentially pathogenic atypical B cells (ABCs) that were expanded in active cGVHD. To identify intrinsic alterations in potentially pathological B cells, we interrogated all clusters for differentially expressed genes (DEGs) in active cGVHD versus patients who never had signs of immune tolerance loss (no cGVHD). Active cGVHD DEGs occurred in both naive and BCR-activated B cell clusters. Remarkably, some DEGs occurred across most clusters, suggesting common molecular programs that may promote B cell plasticity. Our study of human allo-HCT and cGVHD provides understanding of altered B cell memory during chronic alloantigen stimulation.

HLA-C*17:01:18 differs from HLA-C*17:01:01:05 by one nucleotide substitution in codon 18 in exon 2., (© 2022 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

HLA-C*07:1023 differs from HLA-C*07:01:01:01 by one nucleotide substitution in codon 313 in exon 5., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-DQA1*01:89 differs from HLA-DQA1*01:01:01:01 by one nucleotide substitution in codon -5 in exon 1., (© 2022 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

HLA-A*01:419 differs from HLA-A*01:01:01:03 by one nucleotide substitution in codon 200 in exon 4., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-A*11:422 differs from HLA-A*11:01:01:01 by one nucleotide substitution in codon 285 in exon 5., (© 2022 The Authors. HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Defined by the Banff classification, its gold standard diagnosis remains a challenge, with limited inter-observer reproducibility of the histological scores and efficient immunomarker availability. We performed an immunohistochemical analysis of 3 interferon-related proteins, WARS1, TYMP and GBP1 in a cohort of kidney allograft biopsies including 17 ABMR cases and 37 other common graft injuries. Slides were interpreted, for an ABMR diagnosis, by four blinded nephropathologists and by a deep learning framework using convolutional neural networks. Pathologists identified a distinctive microcirculation staining pattern in ABMR with all three antibodies, displaying promising diagnostic performances and a substantial reproducibility. The deep learning analysis supported the microcirculation staining pattern and achieved similar diagnostic performance from internal validation, with a mean area under the receiver operating characteristic curve of 0.89 (± 0.02) for WARS1, 0.80 (± 0.04) for TYMP and 0.89 (± 0.04) for GBP1. The glomerulitis and peritubular capillaritis scores, the hallmarks of histological ABMR, were the most highly correlated Banff scores with the deep learning output, whatever the C4d status. These novel immunomarkers combined with a CNN framework could help mitigate current challenges in ABMR diagnosis and should be assessed in larger cohorts., (© 2022. The Author(s).)

Background: Fibrosis progression is a major prognosis factor in kidney transplantation. Its assessment requires an allograft biopsy, which remains an invasive procedure at risk of complications., Methods: We assessed renal stiffness by magnetic resonance elastography (MRE) as a surrogate marker of fibrosis in a prospective cohort of kidney transplant recipients compared with the histologic gold standard. Interstitial fibrosis was evaluated by three methods: the semi-quantitative Banff ci score, a visual quantitative evaluation by a pathologist, and a computer-assisted quantitative evaluation. MRE-derived stiffness was assessed at the superior, median, and inferior poles of the allograft., Results: We initially enrolled 73 patients, but only 55 had measurements of their allograft stiffness by MRE before an allograft biopsy. There was no significant correlation between MRE-derived stiffness at the biopsy site and the ci score ( ρ =-0.25, P =0.06) or with the two quantitative assessments (pathologist: ρ =-0.25, P =0.07; computer assisted: ρ =-0.21, P =0.12). We observed negative correlations between the stiffness of both the biopsy site and the whole allograft, with either the glomerulosclerosis percentage ( ρ =-0.32, P =0.02 and ρ =-0.31, P =0.02, respectively) and the overall nephron fibrosis percentage, defined as the mean of the percentages of glomerulosclerosis and interstitial fibrosis ( ρ =-0.30, P =0.02 and ρ =-0.28, P =0.04, respectively). At patient level, mean MRE-derived stiffness was similar across the three poles of the allograft (±0.25 kPa). However, a high variability of mean stiffness was found between patients, suggesting a strong influence of confounding factors. Finally, no significant correlation was found between mean MRE-derived stiffness and the slope of eGFR ( P =0.08)., Conclusions: MRE-derived stiffness does not directly reflect the extent of fibrosis in kidney transplantation., Competing Interests: L. Couzi reports consultancy for Astellas, Biotest, Hansa, Novartis, and Otsuka; and honoraria from Astellas, Biotest; Hansa, and Otsuka. P. Merville reports consultancy for Astellas and BMS; research funding from Astellas; honoraria from CSL Behring and Sanofi; and an advisory or leadership role for BMS and Novartis. J. Visentin reports being the inventor on a patent concerning a method to quantify anti-HLA antibodies in patient samples using surface plasmon resonance (WO 2017/168083). All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

HLA-B*44:03:62 differs from HLA-B*44:03:01:01 by one nucleotide substitution in codon 127 in exon 3., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-C*12:354 differs from HLA-C*12:03:01:01 by one nucleotide substitution in codon 240 in exon 4., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-B*44:544N differs from HLA-B*44:02:01:01 by one nucleotide substitution in codon 147 in exon 3., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

HLA-A*24:564 differs from HLA-A*24:02:01:01 by one nucleotide substitution in codon 240 in exon 4., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cytomegalovirus (CMV) persists as the most frequent opportunistic infection among solid organ transplant recipients. This multicenter trial aimed to test whether treatment with everolimus (EVR) could decrease the incidence of CMV DNAemia and disease. We randomized 186 CMV seropositive kidney transplant recipients in a 1:1 ratio to receive EVR or mycophenolic acid (MPA) in association with basiliximab, cyclosporin, and steroids and 87 in each group were analyzed. No universal prophylaxis was administered to either group. The composite primary endpoint was the presence of CMV DNAemia, CMV treatment, graft loss, death, and discontinuation of the study at 6 months posttransplant. In the modified intent-to-treat analysis, 42 (48.3%) and 70 (80.5%) patients in the EVR and MPA groups reached the primary endpoint (OR = 0.21, 95% CI: 0.11-0.43, p < .0001). Fewer patients of the EVR group received treatment for CMV (21.8% vs. 47.1%, p = .0007). EVR was discontinued in 31 (35.6%) patients. Among the 56 patients with ongoing EVR treatment, only 7.4% received treatment for CMV. In conclusion, EVR prevents CMV DNAemia requiring treatment in seropositive recipients as long as it is tolerated and maintained., (© 2022 The American Society of Transplantation and the American Society of Transplant Surgeons.)

HLA-A*30:02:28 differs from HLA-A*30:02:01:01 by one nucleotide substitution in codon 47 in exon 2., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Highly sensitized (HS) anti-HLA patients awaiting kidney transplantation benefit from specific allocation programs. Serological monitoring at 3-mo intervals is recommended to prevent unexpected positive crossmatch (XM), but this strategy is not evidence-based. Therefore, we assessed its relevance when using single-antigen flow bead (SAFB) and screening flow bead (SFB) assays., Methods: We included 166 HS patients awaiting a transplant and assessed their SAFB profile during the year preceding their inclusion. Anti-HLA antibodies were evaluated by SAFB assay and compared within patients as serum pairs at 3, 6, and 9 mo. We assessed the performance of SFB for detecting changes in SAFB profiles with 35 serum pairs., Results: On comparing 354, 218, and 107 serum pairs at 3, 6, and 9 mo, respectively, only 0.6%, 0.7%, and 1% of all antigens tested exceeded for the first time the unacceptable antigen threshold (mean fluorescence intensity ≥2000) in the most recent sample. Irrespective of the follow-up period, the calculated panel-reactive antibodies increased by a mean of 1%, and there was no significant increase in the proportion of donors at risk for positivity of flow- or complement-dependent cytotoxicity XM. The SFB did not accurately detect the variations of SAFB profiles., Conclusions: Changes in HS patient profiles are anecdotal and show little association with transplant access or risk for positive XM. Less-frequent monitoring in HS patients should be considered to improve cost-effectiveness without affecting transplant safety., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The pathogenicity of de novo donor-specific antibodies (dnDSA) varies according to their characteristics. While their MFI, complement-fixing ability, and IgG3 subclass are associated with ABMR occurrence and graft loss, they are not fully predictive of outcomes. We investigated the role of the Fc glycosylation of IgG3 dnDSA in ABMR occurrence using mass spectrometry after isolation by single HLA antigen beads. Between 2014 and 2018, we enrolled 54 patients who developed dnDSA (ABMR- n = 24; ABMR+ n = 30) in two French transplant centers. Fucosylation, galactosylation, GlcNAc bisection, and sialylation of IgG3 dnDSA were compared between ABMR+ and ABMR- patients. IgG3 dnDSA from ABMR+ patients exhibited significantly lower sialylation (7.5% vs. 10.5%, p < .001) and higher GlcNAc bisection (20.6% vs. 17.4%, p = .008). Fucosylation and galactosylation were similar in both groups. DSA glycosylation was not correlated with DSA MFI. In a multivariate analysis, low IgG3 sialylation, high IgG3%, time from transplantation to kidney biopsy, and tacrolimus-free regimen were independent predictive factors of ABMR. We conclude that a proinflammatory glycosylation profile of IgG3 dnDSA is associated with a risk of ABMR occurrence. Further studies are needed to confirm the clinical interest of DSA glycosylation and to clarify its role in determining the risk of ABMR and graft survival., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Antibody-mediated rejection (ABMR) is the leading cause of allograft failure in kidney transplantation. Its histological hallmark is represented by lesions of glomerulitis i.e., inflammatory cells within glomeruli. Current therapies for ABMR fail to prevent chronic allograft damage i.e., transplant glomerulopathy, leading to allograft loss. We used laser microdissection of glomeruli from formalin-fixed allograft biopsies combined with mass spectrometry-based proteomics to describe the proteome modification of 11 active and 10 chronic active ABMR cases compared to 8 stable graft controls. Of 1335 detected proteins, 77 were deregulated in glomerulitis compared to stable grafts, particularly involved in cellular stress mediated by interferons type I and II, leukocyte activation and microcirculation remodeling. Three proteins extracted from this protein profile, TYMP, WARS1 and GBP1, showed a consistent overexpression by immunohistochemistry in glomerular endothelial cells that may represent relevant markers of endothelial stress during active ABMR. In transplant glomerulopathy, 137 proteins were deregulated, which favor a complement-mediated mechanism, wound healing processes through coagulation activation and ultimately a remodeling of the glomerular extracellular matrix, as observed by light microscopy. This study brings novel information on glomerular proteomics of ABMR in kidney transplantation, and highlights potential targets of diagnostic and therapeutic interest.

HLA-DQB1*05:275 differs from DQB1*05:01 by one nucleotide substitution in codon 224 in exon 4., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)