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Immunologic Research May 2014H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the... (Review)
Review
H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.
Topics: Abortion, Habitual; Animals; B-Lymphocytes; Female; Graft Rejection; Graft vs Host Disease; H-Y Antigen; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Isoantibodies; Male; Organ Transplantation; Pregnancy; Sex Factors; T-Lymphocytes; Transplantation Immunology
PubMed: 24781195
DOI: 10.1007/s12026-014-8514-3 -
The Journal of Clinical Investigation Oct 2022Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis...
Bronchiolitis obliterans syndrome (BOS) is a major impediment to lung transplant survival and is generally resistant to medical therapy. Extracorporeal photophoresis (ECP) is an immunomodulatory therapy that shows promise in stabilizing BOS patients, but its mechanisms of action are unclear. In a mouse lung transplant model, we show that ECP blunts alloimmune responses and inhibits BOS through lowering airway TGF-β bioavailability without altering its expression. Surprisingly, ECP-treated leukocytes were primarily engulfed by alveolar macrophages (AMs), which were reprogrammed to become less responsive to TGF-β and reduce TGF-β bioavailability through secretion of the TGF-β antagonist decorin. In untreated recipients, high airway TGF-β activity stimulated AMs to express CCL2, leading to CCR2+ monocyte-driven BOS development. Moreover, we found TGF-β receptor 2-dependent differentiation of CCR2+ monocytes was required for the generation of monocyte-derived AMs, which in turn promoted BOS by expanding tissue-resident memory CD8+ T cells that inflicted airway injury through Blimp-1-mediated granzyme B expression. Thus, through studying the effects of ECP, we have identified an AM functional plasticity that controls a TGF-β-dependent network that couples CCR2+ monocyte recruitment and differentiation to alloimmunity and BOS.
Topics: Animals; Bronchiolitis Obliterans; Decorin; Granzymes; Lung Transplantation; Macrophages, Alveolar; Mice; Monocytes; Receptors, CCR2; Receptors, Transforming Growth Factor beta; Transforming Growth Factor beta
PubMed: 36189800
DOI: 10.1172/JCI159229 -
Frontiers in Pediatrics 2022Alloimmune events such as the development of donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary... (Review)
Review
Alloimmune events such as the development of donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary contributors to kidney transplant failure in children. For decades, a creatinine-based estimated glomerular filtration rate (eGFR) has been the non-invasive gold standard biomarker for detecting clinically significant alloimmune events, but it suffers from low sensitivity and specificity, especially in smaller children and older allografts. Many clinically "stable" children (based on creatinine) will have alloimmune events known as "subclinical acute rejection" (based on biopsy) that merely reflect the inadequacy of creatinine-based estimates for alloimmune injury rather than a distinct phenotype from clinical rejection with allograft dysfunction. The poor biomarker performance of creatinine leads to many unnecessary surveillance and for-cause biopsies that could be avoided by integrating non-invasive biomarkers with superior sensitivity and specificity into current clinical paradigms. In this review article, we will present and appraise the current state-of-the-art in monitoring for alloimmune events in pediatric kidney transplantation. We will first discuss the current clinical standards for assessing the presence of alloimmune injury and predicting long-term outcomes. We will review principles of biomarker medicine and the application of comprehensive metrics to assess the performance of a given biomarker against the current gold standard. We will then highlight novel blood- and urine-based biomarkers (with special emphasis on pediatric biomarker studies) that have shown superior diagnostic and prognostic performance to the current clinical standards including creatinine-based eGFR. Finally, we will review some of the barriers to translating this research and implementing emerging biomarkers into common clinical practice, and present a transformative approach to using multiple biomarker platforms at different times to optimize the detection and management of critical alloimmune events in pediatric kidney transplant recipients.
PubMed: 36741087
DOI: 10.3389/fped.2022.1087841 -
Hematology, Transfusion and Cell Therapy 2024Sickle cell disease (SCD) is the most important hemoglobinopathy worldwide. The treatment often requires phenotype-matched red blood cell (RBC) transfusions, but...
INTRODUCTION
Sickle cell disease (SCD) is the most important hemoglobinopathy worldwide. The treatment often requires phenotype-matched red blood cell (RBC) transfusions, but alloimmunization to non-ABO antigens may occur in a part of the SCD patients. The genotyping has been used for RBC antigen prediction, reducing the possibility of the alloimmunization.
OBJECTIVE AND METHOD
In this study we performed the genotyping for the Kell and RHCE blood groups in samples from 77 phenotyped Brazilian SCD patients, whose alloimmunization profiles were also assessed.
RESULTS
Discrepancies between genotyping and phenotyping for the RHCE and Kell blood groups systems were observed in 22.07% (17/77) of the SCD patients. We found C/c and E/e discrepancies in 11.68% and 9.09% of patients, respectively; one SCD patient (1.3%) presented a discrepancy in the Kell group. Two SCD patients with discrepancies between genotype and phenotype were alloimmunized. In total, twenty-eight patients (36.4%) developed alloantibodies, of which 55.17% were directed against antigens in the Rh system, 8.62% were directed against antigens in the Kell system and 36.20%, against other groups. Finally, the frequency of discrepancies is significantly higher in non-alloimmunized patients (30.61%), compared to alloimmunized patients (7.14%) (p = 0.0217).
CONCLUSION
In part, the alloimmunization of the SCD patients may have been triggered by these discrepancies, indicating that the integration of serological and molecular tests in the immunohematology routine could help to increase the transfusion safety. However, the higher number of alloimmunized patients without discrepancies showed that reasons other than the discrepancies appear to have influenced more strongly the alloimmunization in the SCD patients in this study.
PubMed: 37344342
DOI: 10.1016/j.htct.2023.05.004 -
Hematology. American Society of... Dec 2016In excess of 340 blood group antigens have now been described that vary between individuals. Thus, any unit of blood that is nonautologous represents a significant dose... (Review)
Review
In excess of 340 blood group antigens have now been described that vary between individuals. Thus, any unit of blood that is nonautologous represents a significant dose of alloantigen. Most blood group antigens are proteins, which differ by a single amino acid between donors and recipients. Approximately 1 out of every 70 individuals are transfused each year (in the United States alone), which leads to antibody responses to red blood cell (RBC) alloantigens in some transfusion recipients. When alloantibodies are formed, in many cases, RBCs expressing the antigen in question can no longer be safely transfused. However, despite chronic transfusion, only 3% to 10% of recipients (in general) mount an alloantibody response. In some disease states, rates of alloimmunization are much higher (eg, sickle cell disease). For patients who become alloimmunized to multiple antigens, ongoing transfusion therapy becomes increasingly difficult or, in some cases, impossible. While alloantibodies are the ultimate immune effector of humoral alloimmunization, the cellular underpinnings of the immune system that lead to ultimate alloantibody production are complex, including antigen consumption, antigen processing, antigen presentation, T-cell biology, and B-cell biology. Moreover, these cellular processes differ to some extent with regard to transfused RBCs as compared with other better-studied immune barriers (eg, infectious disease, vaccines, and solid organ transplantation). The current work focuses on illustrating the current paradigm of humoral immunity, with a specific focus on particulars of RBC alloimmunization and recent advances in the understanding thereof.
Topics: B-Lymphocytes; Blood Group Incompatibility; Erythrocyte Transfusion; Erythrocytes; Humans; Isoantigens; T-Lymphocytes
PubMed: 27913515
DOI: 10.1182/asheducation-2016.1.452 -
Oncotarget Jun 2015
Topics: Animals; Disease Models, Animal; Humans; Mice; Neovascularization, Pathologic; Thrombocytopenia, Neonatal Alloimmune
PubMed: 26164077
DOI: 10.18632/oncotarget.4757 -
Journal of Clinical Medicine May 2022Hemolytic disease of the fetus and newborn (HDFN), as well as fetal and neonatal alloimmune thrombocytopenia (FNAIT), represent two important disease entities that are... (Review)
Review
Hemolytic disease of the fetus and newborn (HDFN), as well as fetal and neonatal alloimmune thrombocytopenia (FNAIT), represent two important disease entities that are caused by maternal IgG antibodies directed against nonmaternally inherited antigens on the fetal blood cells. These antibodies are most frequently directed against the RhD antigen on red blood cells (RBCs) or the human platelet antigen 1a (HPA-1a) on platelets. For optimal management of pregnancies where HDFN or FNAIT is suspected, it is essential to determine the RhD or the HPA-1a type of the fetus. Noninvasive fetal RhD typing is also relevant for identifying which RhD-negative pregnant women should receive antenatal RhD prophylaxis. In this review, we will give an overview of the clinical indications and technical challenges related to the noninvasive analysis of fetal RBCs or platelet types. In addition, we will discuss the ethical implications associated with the routine administration of antenatal RhD to all pregnant RhD-negative women and likewise the ethical challenges related to making clinical decisions concerning the mother that have been based on samples collected from the (presumptive) father, which is a common practice when determining the risk of FNAIT.
PubMed: 35629001
DOI: 10.3390/jcm11102877 -
Archivum Immunologiae Et Therapiae... Aug 2016Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a relatively rare condition (1/1000-1/2000) that was granted orphan status by the European Medicines Agency in... (Review)
Review
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a relatively rare condition (1/1000-1/2000) that was granted orphan status by the European Medicines Agency in 2011. Clinical consequences of FNAIT, however, may be severe. A thrombocytopenic fetus or new-born is at risk of intracranial hemorrhage that may result in lifelong disability or death. Preventing such bleeding is thus vital and requires a solution. Anti-HPA1a antibodies are the most frequent cause of FNAIT in Caucasians. Its pathogenesis is similar to hemolytic disease of the newborn (HDN) due to anti-RhD antibodies, but is characterized by platelet destruction and is more often observed in the first pregnancy. In 75 % of these women, alloimmunization by HPA-1a antigens, however, occurs at delivery, which enables development of antibody-mediated immune suppression to prevent maternal immunization. As for HDN, the recurrence rate of FNAIT is high. For advancing diagnostic efforts and treatment, it is thereby crucial to understand the pathogenesis of FNAIT, including cellular immunity involvement. This review presents the current knowledge on FNAIT. Also described is a program for HPA-1a screening in identifying HPA-1a negative pregnant women at risk of immunization. This program is now performed at the Institute of Hematology and Transfusion Medicine in cooperation with the Department of Obstetrics and Gynecology of the Medical Centre of Postgraduate Education in Warsaw as well as the UiT The Arctic University of Norway.
Topics: Antigen Presentation; Antigens, Human Platelet; Blood Platelets; Europe; Female; Hemorrhage; Humans; Immunity, Cellular; Immunity, Humoral; Infant, Newborn; Integrin beta3; Isoantigens; Male; Neonatal Screening; Poland; Pregnancy; Rh-Hr Blood-Group System; Thrombocytopenia, Neonatal Alloimmune
PubMed: 26564154
DOI: 10.1007/s00005-015-0371-9 -
British Journal of Haematology Apr 2013Neonatal alloimmune thrombocytopenia, (NAIT) is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Although many cases are mild, NAIT... (Review)
Review
Neonatal alloimmune thrombocytopenia, (NAIT) is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Although many cases are mild, NAIT is a significant cause of morbidity and mortality in newborns and is the most common cause of intracranial haemorrhage in full-term infants. In this report, we review the pathogenesis, clinical presentation, laboratory diagnosis and prenatal and post-natal management of NAIT and highlight areas of controversy that deserve the attention of clinical and laboratory investigators.
Topics: Antigens, Human Platelet; Biomarkers; Female; Humans; Infant, Newborn; Perinatal Care; Platelet Transfusion; Pregnancy; Prenatal Care; Thrombocytopenia, Neonatal Alloimmune
PubMed: 23384054
DOI: 10.1111/bjh.12235 -
Texas Heart Institute Journal 2013Chronic rejection in the form of cardiac allograft vasculopathy is one of the major factors that affects long-term graft and patient survival after heart... (Review)
Review
Chronic rejection in the form of cardiac allograft vasculopathy is one of the major factors that affects long-term graft and patient survival after heart transplantation. Whereas multiple factors contribute to the development of cardiac allograft vasculopathy, immunologic mechanisms play the predominant role in the chronic rejection process, because both alloimmune and autoimmune responses are causal factors. In addition, many nonimmune donor and recipient factors also affect the development of cardiac allograft vasculopathy, including hyperlipidemia, cytomegalovirus infection, baseline coronary artery disease, and the mechanism of brain death in the donor. Modern immunosuppression maintenance therapies have the potential to limit the development of cardiac allograft vasculopathy in the long term. Further research initiatives are needed to identify patient-specific immunosuppressive drug regimens and to elucidate factors that contribute to the chronic rejection of cardiac transplant allografts.
Topics: Animals; Chronic Disease; Coronary Artery Disease; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Risk Factors; Time Factors; Treatment Outcome
PubMed: 24082367
DOI: No ID Found