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Blood Advances Jun 2024Rh phenotype matching reduces but does not eliminate alloimmunization in patients with sickle cell disease (SCD) due to RH genetic diversity that is not distinguishable...
Rh phenotype matching reduces but does not eliminate alloimmunization in patients with sickle cell disease (SCD) due to RH genetic diversity that is not distinguishable by serological typing. RH genotype matching can potentially mitigate Rh alloimmunization but comprehensive and accessible genotyping methods are needed. We developed RHtyper as an automated algorithm to predict RH genotypes using whole-genome sequencing (WGS) data with high accuracy. Here, we adapted RHtyper for whole-exome sequencing (WES) data, which are more affordable but challenged by uneven sequencing coverage and exacerbated sequencing read misalignment, resulting in uncertain predictions for (1) RHD zygosity and hybrid alleles, (2) RHCE∗C vs. RHCE∗c alleles, (3) RHD c.1136C>T zygosity, and (4) RHCE c.48G>C zygosity. We optimized RHtyper to accurately predict RHD and RHCE genotypes using WES data by leveraging machine learning models and improved the concordance of WES with WGS predictions from 90.8% to 97.2% for RHD and 96.3% to 98.2% for RHCE among 396 patients in the Sickle Cell Clinical Research and Intervention Program. In a second validation cohort of 3030 cancer survivors (15.2% Black or African Americans) from the St. Jude Lifetime Cohort Study, the optimized RHtyper reached concordance rates between WES and WGS predications to 96.3% for RHD and 94.6% for RHCE. Machine learning improved the accuracy of RH predication using WES data. RHtyper has the potential, once implemented, to provide a precision medicine-based approach to facilitate RH genotype-matched transfusion and improve transfusion safety for patients with SCD. This study used data from clinical trials registered at ClinicalTrials.gov as #NCT02098863 and NCT00760656.
Topics: Humans; Rh-Hr Blood-Group System; Machine Learning; Exome Sequencing; Genotype; Anemia, Sickle Cell; Genotyping Techniques; Alleles
PubMed: 38522094
DOI: 10.1182/bloodadvances.2023011660 -
American Journal of Transplantation :... Jun 2024The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and...
The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.
Topics: Humans; Graft Rejection; Liver Transplantation; Graft Survival; Allografts
PubMed: 38461883
DOI: 10.1016/j.ajt.2024.03.008 -
WMJ : Official Publication of the State... Feb 2024Rh D alloimmunization is the serologic response that occurs when Rh D-negative patients are exposed to Rh D-positive blood. Rh D blood typing is recommended in pregnancy...
INTRODUCTION
Rh D alloimmunization is the serologic response that occurs when Rh D-negative patients are exposed to Rh D-positive blood. Rh D blood typing is recommended in pregnancy to prevent alloimmunization.
CASE PRESENTATION
A 27-year-old gravida 3, para 2012 (G3P2012) previously Rh D-negative female presented with discordant and weakly positive Rh D blood typing results. Confirmatory genetic testing revealed weak D phenotype that can be treated clinically as Rh D-positive.
DISCUSSION
Genetic variants of Rh D can cause varied blood typing results depending on the hospital reporting protocol utilized. If labeled as Rh D-negative, this could lead to unnecessary administration of Rh D immunoglobulin in pregnancy. Genetic variants should be suspected when patients are noted to have blood typing results that are discordant or weakly positive.
CONCLUSIONS
Rh D genotyping should be considered when discordant or weakly positive Rh D blood type results are noted in order to confirm and classify genetic subtype.
Topics: Pregnancy; Humans; Female; Adult; Genetic Testing; Gravidity; Phenotype
PubMed: 38436642
DOI: No ID Found -
Hematology, Transfusion and Cell Therapy Feb 2024The clinical manifestation of foetal anaemia caused by maternal Kell alloantibodies differs from that caused by non-Kell alloantibodies. Severe anaemia develops in the... (Review)
Review
The role of measuring peak systolic velocity of the middle cerebral artery blood flow and anti-K1 titre during pregnancy to detect foetuses with severe anaemia, foetal hydrops, and the requirement of intrauterine transfusion: A systematic review and meta-analysis.
The clinical manifestation of foetal anaemia caused by maternal Kell alloantibodies differs from that caused by non-Kell alloantibodies. Severe anaemia develops in the foetus in the early weeks of gestation; therefore, proper management and early intervention are important. A systematic review and meta-analysis was performed to determine whether the anti-K1 titre can determine the sequelae of Kell alloimmunised pregnancies. Prospective and retrospective cohort studies were used to conduct a systematic review following a comprehensive literature search, in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Studies were screened based on a defined set of inclusion and exclusion criteria. A total of 5143 potential articles were identified. Ten studies were used in the meta-analysis of pregnancy outcomes for a specific anti-K1 titre cut-off. The meta-analysis identified statistical significance for intrauterine transfusion (ARD: 0.351; 95 % CI: 0.593-0.109; p-value = 0.004), hydrops (ARD: 0.808; 95 % CI: 1.145-0.472; p-value <0.001), intrauterine foetal death (ARD: 0.938; 95 % CI:1.344 to -0.533; p-value <0.001) and intrauterine transfusion for Doppler middle cerebral artery >1.5 MoM (ARD: 0.381; 95 % CI:1.079 to -0.317; p-value = 0.285). It was concluded that there is no correlation between anti-K1 titre and Kell sensitised pregnancy outcomes, but monitoring the anti-K1 titre is important to manage the pregnancy and it helps clinicians determine the need for intrauterine transfusions. Doppler middle cerebral artery peak systolic velocity is strongly correlated with foetal anaemia and is an efficient routine method for determining the need for intrauterine transfusions in pregnancies affected by anti-K1.
PubMed: 38429195
DOI: 10.1016/j.htct.2024.02.002 -
American Journal of Transplantation :... Feb 2024Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across...
Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across different patient populations are lacking. Using HLA-Matchmaker, HLA-EMMA and PIRCHE-II, this study reports on the association between molecular mismatch (MolMM) and de novo donor-specific antibody (dnDSA) in an ethnically diverse kidney transplant population receiving a steroid-sparing immunosuppression protocol. Of the 419 patients, 51 (12.2%) patients had dnDSA. De novo DSA were seen more frequently with males, primary transplants, patients receiving tacrolimus monotherapy, and unfavorably HLA-matched transplants. There was a strong correlation between MolMM load and antigen mismatch, although significant variation of MolMM load existed at each antigen mismatch. MolMM loads differed significantly by recipient ethnicity, although ethnicity alone was not associated with dnDSA. On multivariate analysis, increasing MolMM loads associated with dnDSA, whereas antigen mismatch did not. De novo DSA against 8 specific epitopes occurred at high frequency; of the 51 patients, 47 (92.1%) patients with dnDSA underwent a pretreatment biopsy, with 21 (44.7%) having evidence of alloimmune injury. MolMM has higher specificity than antigen mismatching at identifying recipients who are at low risk of dnDSA while receiving minimalist immunosuppression. Immunogenicity consideration is important, with more work needed on identification, especially across different ethnic groups.
PubMed: 38403189
DOI: 10.1016/j.ajt.2024.02.019 -
Current Opinion in Anaesthesiology Jun 2024The worldwide leading cause of maternal death is severe maternal hemorrhage. Maternal hemorrhage can be profound leading to an entire loss of blood volume. In the past... (Review)
Review
PURPOSE OF REVIEW
The worldwide leading cause of maternal death is severe maternal hemorrhage. Maternal hemorrhage can be profound leading to an entire loss of blood volume. In the past two decades, Patient Blood Management has evolved to improve patient's care and safety. In surgeries with increased blood loss exceeding 500 ml, the use of cell salvage is strongly recommended in order to preserve the patient's own blood volume and to minimize the need for allogeneic red blood cell (RBC) transfusion. In this review, recent evidence and controversies of the use of cell salvage in obstetrics are discussed.
RECENT FINDINGS
Numerous medical societies as well as national and international guidelines recommend the use of cell salvage during maternal hemorrhage.
SUMMARY
Intraoperative cell salvage is a strategy to maintain the patient's own blood volume and decrease the need for allogeneic RBC transfusion. Historically, cell salvage has been avoided in the obstetric population due to concerns of iatrogenic amniotic fluid embolism (AFE) or induction of maternal alloimmunization. However, no definite case of AFE has been reported so far. Cell salvage is strongly recommended and cost-effective in patients with predictably high rates of blood loss and RBC transfusion, such as women with placenta accreta spectrum disorder. However, in order to ensure sufficient practical experience in a multiprofessional obstetric setting, liberal use of cell salvage appears advisable.
Topics: Humans; Pregnancy; Female; Operative Blood Salvage; Postpartum Hemorrhage; Erythrocyte Transfusion; Blood Transfusion, Autologous; Blood Loss, Surgical; Embolism, Amniotic Fluid; Obstetrics
PubMed: 38391030
DOI: 10.1097/ACO.0000000000001337 -
Transplantation Direct Mar 2024The presence of anti-HLA donor-specific antibodies (DSAs) is associated with antibody-mediated rejection (AMR) and inferior graft survival. However, recent data suggest...
BACKGROUND
The presence of anti-HLA donor-specific antibodies (DSAs) is associated with antibody-mediated rejection (AMR) and inferior graft survival. However, recent data suggest that ~50% of AMR episodes are IgG DSA negative and possibly related to non-HLA DSAs. After the initial activation of B cells to alloantigen, IgM is the first immunoglobulin produced. In addition, both IgM and IgG isotopes can activate the classic complement pathway and induce complement-dependent cytotoxicity to allograft targets. Current practices focus on the assessment of IgG DSAs with little concern for the assessment of IgM DSAs.
METHODS
Here, we examined anti-HLA IgM in a cohort of 22 patients who developed de novo IgG DSAs by a modified single-antigen bead-based test.
RESULTS
We found IgM HLA DSAs developed before IgG DSAs. The median time from the detection of IgM DSAs to the appearance of de novo IgG DSAs was 461 d. Most patients had IgM DSAs against the same HLA-DQ antigens, for which IgG de novo DSAs were also later detected. IgM DSAs were detected in patients with biopsies suspected of AMR.
CONCLUSIONS
The detection of IgM DSAs could be an early indicator of alloimmune responses to allografts before IgG de novo DSAs appear.
PubMed: 38380350
DOI: 10.1097/TXD.0000000000001583 -
American Journal of Transplantation :... Mar 2024HLA donor-specific antibodies (DSA) elicit alloimmune responses against the graft vasculature, leading to endothelial cell (EC) activation and monocyte infiltration...
Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy.
HLA donor-specific antibodies (DSA) elicit alloimmune responses against the graft vasculature, leading to endothelial cell (EC) activation and monocyte infiltration during antibody-mediated rejection (AMR). AMR promotes chronic inflammation and remodeling, leading to thickening of the arterial intima termed transplant vasculopathy or cardiac allograft vasculopathy (CAV) in heart transplants. Intragraft-recipient macrophages serve as a diagnostic marker in AMR; however, their polarization and function remain unclear. In this study, we utilized an in vitro Transwell coculture system to explore the mechanisms of monocyte-to-macrophage polarization induced by HLA I DSA-activated ECs. Anti-HLA I (IgG or F(ab')) antibody-activated ECs induced the polarization of M2 macrophages with increased CD206 expression and MMP9 secretion. However, inhibition of TLR4 signaling or PSGL-1-P-selectin interactions significantly decreased both CD206 and MMP9. Monocyte adherence to Fc-P-selectin coated plates induced M2 macrophages with increased CD206 and MMP9. Moreover, Fc-receptor and IgG interactions synergistically enhanced active-MMP9 in conjunction with P-selectin. Transcriptomic analysis of arteries from DSA+CAV+ rejected cardiac allografts and multiplex-immunofluorescent staining illustrated the expression of CD68+CD206+CD163+MMP9+ M2 macrophages within the neointima of CAV-affected lesions. These findings reveal a novel mechanism linking HLA I antibody-activated endothelium to the generation of M2 macrophages which secrete vascular remodeling proteins contributing to AMR and CAV pathogenesis.
Topics: Humans; Toll-Like Receptor 4; Matrix Metalloproteinase 9; P-Selectin; Macrophages; Vascular Diseases; Endothelium; HLA Antigens; Allografts; Immunoglobulin G
PubMed: 38379280
DOI: 10.1016/j.ajt.2023.10.020 -
Scientific Reports Feb 2024Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte... (Observational Study)
Observational Study
Throughout pregnancy, the decidua is predominantly populated by NK lymphocytes expressing Killer immunoglobulin-like receptors (KIR) that recognize human leukocyte antigen-C (HLA-C) ligands from trophoblast cells. This study aims to investigate the association of KIR-HLA-C phenotypes in couples facing infertility, particularly recurrent pregnancy loss (RPL) and recurrent implantation failure (RIF), in comparison to a reference population and fertile controls. This observational, non-interventional retrospective case-control study included patients consecutively referred to our Reproductive Immunology Unit from 2015 to 2019. We analyzed the frequencies of KIR and HLA-C genes. As control groups, we analyzed a reference Spanish population for KIR analysis and 29 fertile controls and their male partners for KIR and HLA-C combinations. We studied 397 consecutively referred women with infertility and their male partners. Among women with unexplained RPL (133 women) and RIF (176 women), the centromeric (cen)AA KIR genotype was significantly more prevalent compared to the reference Spanish population (p = 0.001 and 0.02, respectively). Furthermore, cenAA was associated with a 1.51-fold risk of RPL and a 1.2-fold risk of RIF. Conversely, the presence of BB KIR showed a lower risk of reproductive failure compared to non-BB KIR (OR: 0.12, p < 0.001). Women and their partners with HLA-C1C1/C1C1 were significantly less common in the RPL-Group (p < 0.001) and RIF-Group (p = 0.002) compared to the control group. Moreover, the combination of cenAA/C1C1 in women with C1C1 partners was significantly higher in the control group than in the RPL (p = 0.009) and RIF (p = 0.04) groups, associated with a 5-fold increase in successful pregnancy outcomes. In our cohort, the cenAA KIR haplotype proved to be a more accurate biomarker than the classic AA KIR haplotype for assessing the risk of RPL and RIF, and might be particularly useful to identify women at increased risk among the heterogeneous KIR AB or Bx population. The classification of centromeric KIR haplotypes outperforms classical KIR haplotypes, making it a better indicator of potential maternal-fetal KIR-HLA-C mismatch in patients.
Topics: Pregnancy; Humans; Male; Female; HLA-C Antigens; Retrospective Studies; Amino Acid Motifs; Case-Control Studies; Abortion, Habitual; Receptors, KIR; Infertility; Biomarkers
PubMed: 38336826
DOI: 10.1038/s41598-024-53766-x -
Cells Jan 2024To improve outcomes following lung transplantation, it is essential to understand the immunological mechanisms that result in chronic graft failure. The associated...
To improve outcomes following lung transplantation, it is essential to understand the immunological mechanisms that result in chronic graft failure. The associated clinical syndrome is termed chronic lung allograft dysfunction (CLAD), which is known to be induced by alloimmune-dependent (i.e., rejection) and alloimmune-independent factors (e.g., infections, reflux and environmental factors). We aimed to explore the alloimmune-related mechanism, i.e., pulmonary rejection. In this study, we use a murine orthotopic left lung transplant model using isografts and allografts (C57BL/6 or BALB/c as donors to C57BL/6 recipients), with daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone). Serial sacrifice was performed at days 1, 7 and 35 post-transplantation ( = 6 at each time point for each group). Left transplanted lungs were harvested, a single-cell suspension was made and absolute numbers of immune cells were quantified using multicolor flow cytometry. The rejection process followed the principles of a classic immune response, including innate but mainly adaptive immune cells. At day 7 following transplantation, the numbers of interstitial macrophages, monocytes, dendritic cells, NK cells, NKT cells, CD4+ T cells and CD8+ T and B cells were increased in allografts compared with isografts. Only dendritic cells and CD4+ T cells remained elevated at day 35 in allografts. Our study provides insights into the immunological mechanisms of true pulmonary rejection after murine lung transplantation. These results might be important in further research on diagnostic evaluation and treatment for CLAD.
Topics: Mice; Animals; Mice, Inbred C57BL; Lung; Lung Transplantation; Transplantation, Homologous; Macrophages
PubMed: 38334633
DOI: 10.3390/cells13030241