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Blood Reviews Jul 2021Red blood cell (RBC) alloimmunization is a serious complication of blood transfusions, challenging selection of compatible units for future transfusions. Genetic... (Meta-Analysis)
Meta-Analysis Review
Red blood cell (RBC) alloimmunization is a serious complication of blood transfusions, challenging selection of compatible units for future transfusions. Genetic characteristics may be associated with the risk of RBC alloimmunization and may therefore serve to identify high-risk patients. The aim of this systematic review was to summarize the available evidence on genetic risk factors for RBC alloimmunization. Electronic databases were searched up to April 2020 for studies (Search terms included transfusion, alloimmunization and genetic). A total of 2581 alloimmunized cases and 26,558 controls were derived from 24 studies. The alleles that were most frequently studied and that demonstrated significant associations in a meta-analysis with alloimmunization to the Duffy antigen were HLA-DRB1*04 (Odds Ratio 7.80 (95%CI 4.57-13.33)), HLA-DRB1*15 (OR 3.76 (95%CI 2.14-6.59)), and HLA-DRB1*03 (OR 0.12 (95%CI 0.05-0.29)). Furthermore, significant associations with anti-K formation was found for the alleles HLA-DRB1*10 (OR 2.64 (95%CI 1.41-4.95)), HLA*DRB1*11 (OR 2.11, (95%CI 1.34-3.32)), and HLA-DRB1*13 (OR 1.71 (95%CI 1.26-2.33)). Overall, the available evidence was of moderate to low quality, hampering interpretation of reported results. There is an urgent need for high quality evidence on genetic risk factors for RBC alloimmunization.
Topics: Alleles; Blood Group Antigens; Blood Transfusion; Erythrocytes; Genetic Predisposition to Disease; Humans; Immunization; Isoantibodies; Risk Assessment; Risk Factors
PubMed: 33451870
DOI: 10.1016/j.blre.2020.100794 -
Open Biology Nov 2019The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in... (Review)
Review
The evolutionarily conserved Notch signalling pathway regulates the differentiation and function of mature T lymphocytes with major context-dependent consequences in host defence, autoimmunity and alloimmunity. The emerging effects of Notch signalling in T cell responses build upon a more established role for Notch in T cell development. Here, we provide a critical review of this burgeoning literature to make sense of what has been learned so far and highlight the experimental strategies that have been most useful in gleaning physiologically relevant information. We outline the functional consequences of Notch signalling in mature T cells in addition to key specific Notch ligand-receptor interactions and downstream molecular signalling pathways. Our goal is to help clarify future directions for this expanding body of work and the best approaches to answer important open questions.
Topics: Animals; Autoimmunity; Cell Differentiation; Homeostasis; Humans; Infections; Receptors, Notch; Signal Transduction; T-Lymphocytes
PubMed: 31690218
DOI: 10.1098/rsob.190187 -
Transfusion Medicine Reviews Jan 2023RBC alloimmunization remains a significant barrier to ongoing transfusion therapy leading to morbidity, and in extreme cases mortality, due to delayed or insufficient... (Review)
Review
RBC alloimmunization remains a significant barrier to ongoing transfusion therapy leading to morbidity, and in extreme cases mortality, due to delayed or insufficient units of compatible RBCs. In addition, the monitoring and characterization of alloantibodies, often with multiple specificities in a single patient, consumes substantial health care resources. Extended phenotypic matching has mitigated, but not eliminated, RBC alloimmunization and is only logistically available for specialized populations. Thus, RBC alloimmunization remains a substantial problem. In recent decades it has become clear that mechanisms of RBC alloimmunization are distinct from other antigens and lack of mechanistic understanding likely contributes to the fact that there are no approved interventions to prevent RBC alloimmunization from transfusion. The combination of human studies and murine modeling have identified several key factors in RBC alloimmunization. In both humans and mice, immunogenicity is a function of alloantigen copy number on RBCs. Murine studies have further shown that copy number not only changes rates of immunization but the mechanisms of antibody formation. This review summarizes the current understanding of quantitative and qualitative effects of alloantigen copy number on RBC alloimmunization.
Topics: Humans; Mice; Animals; Isoantigens; DNA Copy Number Variations; Erythrocytes; Blood Transfusion; Isoantibodies
PubMed: 36725483
DOI: 10.1016/j.tmrv.2022.12.009 -
JCI Insight Feb 2024While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data...
While the function of many leukocytes in transplant biology has been well defined, the role of eosinophils is controversial and remains poorly explored. Conflicting data exist regarding eosinophils' role in alloimmunity. Due to their prevalence in the lung, and their defined role in other pulmonary pathologies such as asthma, we set out to explore the role of eosinophils in the long-term maintenance of the lung allograft. We noted that depletion of eosinophils results in the generation of donor-specific antibodies. Eosinophil depletion increased memory B cell, plasma cell, and antibody-secreting cell differentiation and resulted in de novo generation of follicular germinal centers. Germinal center formation depended on the expansion of CD4+Foxp3-Bcl6+CXCR5+PD-1+ T follicular helper (Tfh) cells, which increase in number after eosinophil depletion. Mechanistically, we demonstrate that eosinophils prevent Tfh cell generation by acting as the dominant source of IFN-γ in an established lung allograft, thus facilitating Th1 rather than Tfh polarization of naive CD4+ T cells. Our data thus describe what we believe is a unique and previously unknown role for eosinophils in maintaining allograft tolerance and suggest that indiscriminate administration of eosinophil-lytic corticosteroids for treatment of acute cellular rejection may inadvertently promote humoral alloimmunity.
Topics: Eosinophils; Germinal Center; Antibodies; Transplantation, Homologous; Lung Transplantation
PubMed: 38329123
DOI: 10.1172/jci.insight.168911 -
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 -
Children (Basel, Switzerland) Dec 2022We describe the case of a newborn with the antenatal onset of hepatic failure, which has been investigated for all etiologies that can cause liver damage: infectious,...
We describe the case of a newborn with the antenatal onset of hepatic failure, which has been investigated for all etiologies that can cause liver damage: infectious, metabolic, genetic, and immune. The lack of a clear answer regarding the etiology and the response to immunoglobulin therapy led us to the diagnosis of gestational alloimmune liver disease. Gestational alloimunne liver disease is an uncommon and very severe cause of neonatal acute liver failure (NALF). Initially, the therapeutic approach aimed at correcting the effects produced by iron loading, respectively, iron chelators and antioxidants. Since all aspects of this case indicated characteristic features typical for GALD, therapy with intravenous immunoglobulins (IVIG) was introduced. If such therapy alters the prognosis of newborns with GALD, the etiology and pathophysiology remain uncertain. However, in cases regarding severe hepatic failure with the perinatal onset and apparently unknown etiology, immunoglobulin or exchange transfusion therapy should be taken into account even before finalizing all the etiological investigations. The prognosis is uncertain and varies between clinical resolution, chronic hepatitis/cirrhosis, and the need for a hepatic transplant, and overall survival depends on prompt therapeutic intervention.
PubMed: 36670617
DOI: 10.3390/children10010066 -
Clinical Liver Disease Jul 2022Content available: Audio Recording. (Review)
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British Journal of Haematology Feb 2021Haemolytic disease of the fetus and newborn (HDFN) remains an important cause of fetal mortality with potential neonatal and longer-term morbidity. HDFN is caused by... (Review)
Review
Haemolytic disease of the fetus and newborn (HDFN) remains an important cause of fetal mortality with potential neonatal and longer-term morbidity. HDFN is caused by maternal red cell alloimmunisation, with IgG antibodies crossing the placenta to destroy fetal erythroid cells expressing the involved antigen. Intrauterine fetal blood transfusion is the therapy of choice for severe fetal anaemia. Despite a strong evidence base and technical advances, invasive fetal therapy carries risk of miscarriage and preterm birth. Procedure-related risks are increased when invasive, in utero transfusion is instituted prior to 22 weeks to treat severe early-onset fetal anaemia. This review focuses upon this cohort of HDFN and discusses intravenous immunoglobin (IVIg) and novel monoclonal antibody (M281, nipocalimab) treatments which, if started at the end of the first trimester, may attenuate the transplacental passage and fetal effects of IgG antibodies. Such therapy has the ability to improve fetal survival in this severe presentation of HDFN when early in utero transfusion may be required and may have wider implications for the perinatal management in general.
Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Blood Transfusion, Intrauterine; Female; Fetal Diseases; Humans; Immunoglobulins, Intravenous; Immunomodulation; Infant, Newborn; Infant, Newborn, Diseases; Plasma Exchange; Pregnancy
PubMed: 32794242
DOI: 10.1111/bjh.17041 -
Diagnostics (Basel, Switzerland) Aug 2020Maternal passage of immunoglobulin G (IgG) is an important passive mechanism for protecting the infant while the neonatal immune system is still immature and... (Review)
Review
Maternal passage of immunoglobulin G (IgG) is an important passive mechanism for protecting the infant while the neonatal immune system is still immature and ineffective. IgG is the only antibody class capable of crossing the histological layers of the placenta by attaching to the neonatal Fc receptor expressed at the level of syncytiotrophoblasts, and it offers protection against neonatal infectious pathogens. In pregnant women with autoimmune or alloimmune disorders, or in those requiring certain types of biological therapy, transplacental passage of abnormal antibodies may cause fetal or neonatal harm. In this review, we will discuss the physiological mechanisms and benefits of transplacental transfer of maternal antibodies as well as pathological maternal situations where this system is hijacked, potentially leading to adverse neonatal outcomes.
PubMed: 32806663
DOI: 10.3390/diagnostics10080583 -
Frontiers in Immunology 2019The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical... (Review)
Review
The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical problem. Greater understanding of the immunologic mechanisms that cause allograft failure are needed, as well as new treatment strategies for protecting transplanted organs. The complement cascade is an important part of the innate immune system. Studies have shown that complement activation contributes to allograft injury in several clinical settings, including ischemia/reperfusion injury and antibody mediated rejection. Furthermore, the complement system plays critical roles in modulating the responses of T cells and B cells to antigens. Therapeutic complement inhibitors, therefore, may be effective for protecting transplanted organs from several causes of inflammatory injury. Although several anti-complement drugs have shown promise in selected patients, the role of these drugs in transplantation medicine requires further study.
Topics: Adaptive Immunity; Complement Activation; Complement System Proteins; Graft Rejection; Humans; Organ Transplantation; Receptors, Complement; Reperfusion Injury; Transplantation, Heterologous
PubMed: 31636644
DOI: 10.3389/fimmu.2019.02380