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Best Practice & Research. Clinical... Jul 2019Foetal or neonatal thrombocytopenia results from alloimmunisation during pregnancy. Maternal alloantibodies can be formed following exposure to paternally derived human... (Review)
Review
Foetal or neonatal thrombocytopenia results from alloimmunisation during pregnancy. Maternal alloantibodies can be formed following exposure to paternally derived human platelet antigens (HPAs) on foetal platelets, in case of incompatible HPA type. These alloantibodies are of the immunoglobulin G subclass and can therefore enter the foetal circulation through active placental transport mediated by the neonatal Fc-receptor. After entering the foetal circulation, these alloantibodies can cause destruction of foetal platelets and potentially damage other foetal cells containing the specific antigen. Subsequent clinical presentation in foetuses or neonates can vary widely, from an asymptomatic thrombocytopenia to a broad spectrum of bleeding complications. Most frequently encountered are minor skin haemorrhages, such as hematomas or petechiae, but also more devastating haemorrhages can occur. Of these, an intracranial haemorrhage is the most feared complication because of its high risk of life-long major neurological handicaps or perinatal death.
Topics: Animals; Antigens, Human Platelet; Autoantibodies; Blood Transfusion, Intrauterine; Female; Fetal Diseases; Humans; Immunoglobulins, Intravenous; Infant, Newborn; Integrin beta3; Intracranial Hemorrhages; Pregnancy; Prenatal Care; Thrombocytopenia, Neonatal Alloimmune
PubMed: 30827816
DOI: 10.1016/j.bpobgyn.2019.01.017 -
Maedica Dec 2021RhD alloimmunization remains a severe problem worldwide, but its management has been revolutionized by two important discoveries: the possibility to establish fetal Rh...
RhD alloimmunization remains a severe problem worldwide, but its management has been revolutionized by two important discoveries: the possibility to establish fetal Rh genotype non-invasively by using a maternal blood sample, and using of Doppler velocimetry to monitor early signs of affected fetuses. We performed a literature review by searching PubMed for relevant information about diagnosis, prognosis, and management of secondary affected Rh alloimmunized pregnancies. The risk to develop fetal anemia and hydrops seems to increase with increasing concentrations of Rh antibodies, and studies show it is higher for subsequent pregnancies. Individuals presenting the DEL phenotype with the types 1, 2 or 3 can be considered RhD positive and anti-D immune globulin is not indicated. Medical algorithm involves previous pregnancy history together with serum parameters. Follow-up in a department of maternal fetal medicine is desired and encouraged in these cases. Depending on the severity and woman's previous pregnancy history, especially condition prior to 24 weeks of gestation, several therapies such as plasmaphereses, intravenous immune globulin or intrauterine transfusions can be conducted. Intrauterine transfusions have a better prognosis when performed earlier and on fetuses without hydrops. Although the incidence of hemolytic disease of the fetus and newborn has decreased and is no longer a major cause of perinatal mortality, vigilance is still required. There is a strong argument for reunite the management of these cases in dedicated maternal fetal medicine centers that perform invasive procedures in order to improve knowledge, gain skills and enhance clinical management.
PubMed: 35261671
DOI: 10.26574/maedica.2020.16.4.681 -
Nature Reviews. Nephrology Aug 2016The development of post-transplantation antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our... (Review)
Review
The development of post-transplantation antibodies against non-HLA autoantigens is associated with rejection and decreased long-term graft survival. Although our knowledge of non-HLA antibodies is incomplete, compelling experimental and clinical findings demonstrate that antibodies directed against autoantigens such as angiotensin type 1 receptor, perlecan and collagen, contribute to the process of antibody-mediated acute and chronic rejection. The mechanisms that underlie the production of autoantibodies in the setting of organ transplantation is an important area of ongoing investigation. Ischaemia-reperfusion injury, surgical trauma and/or alloimmune responses can result in the release of organ-derived autoantigens (such as soluble antigens, extracellular vesicles or apoptotic bodies) that are presented to B cells in the context of the transplant recipient's antigen presenting cells and stimulate autoantibody production. Type 17 T helper cells orchestrate autoantibody production by supporting the proliferation and maturation of autoreactive B cells within ectopic tertiary lymphoid tissue. Conversely, autoantibody-mediated graft damage can trigger alloimmunity and the development of donor-specific HLA antibodies that can act in synergy to promote allograft rejection. Identification of the immunologic phenotypes of transplant recipients at risk of non-HLA antibody-mediated rejection, and the development of targeted therapies to treat such rejection, are sorely needed to improve both graft and patient survival.
Topics: Autoantibodies; Autoantigens; Collagen; Heparan Sulfate Proteoglycans; Humans; Kidney Transplantation; Receptor, Angiotensin, Type 1; Transplantation Immunology
PubMed: 27345243
DOI: 10.1038/nrneph.2016.88 -
Journal of Immunological Methods Feb 2022Antibody-mediated rejection is a major cause of graft failure in organ transplantation. For this reason, B cell responses are of particular interest to transplantation...
Antibody-mediated rejection is a major cause of graft failure in organ transplantation. For this reason, B cell responses are of particular interest to transplantation research. Rats are important model organisms for transplant studies, but B cell alloimmune assays and B cell subset markers are poorly established in rats. We alloimmunized rats by donor blood injection using the high responder rat strain combination Brown Norway (donor) and Lewis (recipient) rats. Using splenocytes from alloimmunized and control rats, we established assays to assess allospecific B cell proliferation and the capacity to generate allospecific B memory cells and alloantibody-secreting cells after antigenic rechallenge in vitro using a mixed lymphocyte reaction. Furthermore, we defined a simple gating and sorting strategy for pre- and post-germinal center follicular B cells, as well as non-switched and switched plasmablasts. Our protocols for assessing B cell alloresponses and B cell subsets in rats may help to accelerate research into the role of B cells and manipulation of humoral alloresponses in transplant research.
Topics: Animals; B-Lymphocytes; Cell Proliferation; Cells, Cultured; Graft Rejection; Immunity, Humoral; Immunologic Memory; Isoantibodies; Isoantigens; Lymphocyte Activation; Male; Memory B Cells; Phenotype; Rats, Inbred BN; Rats, Inbred Lew; Rats
PubMed: 34971633
DOI: 10.1016/j.jim.2021.113212 -
Frontiers in Immunology 2023Acute myeloid leukemia (AML) is one of the commonest hematologic disorders. Due to the high frequency of disease- or treatment-related thrombocytopenia, AML requires...
INTRODUCTION
Acute myeloid leukemia (AML) is one of the commonest hematologic disorders. Due to the high frequency of disease- or treatment-related thrombocytopenia, AML requires treatment with multiple platelet transfusions, which can trigger a humoral response directed against platelets. Some, but not all, AML patients develop an anti-HLA immune response after multiple transfusions. We therefore hypothesized that different immune activation profiles might be associated with anti-HLA alloimmunization status.
METHODS
We tested this hypothesis, by analyzing CD4+ T lymphocyte (TL) subsets and their immune control molecules in flow cytometry and single-cell multi-omics.
RESULTS
A comparison of immunological status between anti-HLA alloimmunized and non-alloimmunized AML patients identified differences in the phenotype and function of CD4+ TLs. CD4+ TLs from alloimmunized patients displayed features of immune activation, with higher levels of CD40 and OX40 than the cells of healthy donors. However, the most notable differences were observed in non-alloimmunized patients. These patients had lower levels of CD40 and OX40 than alloimmunized patients and higher levels of PD1. Moreover, the Treg compartment of non-alloimmunized patients was larger and more functional than that in alloimmunized patients. These results were supported by a multi-omics analysis of immune response molecules in conventional CD4+ TLs, Tfh circulating cells, and Tregs.
DISCUSSION
Our results thus reveal divergent CD4+ TL characteristics correlated with anti-HLA alloimmunization status in transfused AML patients. These differences, characterizing CD4+ TLs independently of any specific antigen, should be taken into account when considering the immune responses of patients to infections, vaccinations, or transplantations.
Topics: Humans; Blood Platelets; T-Lymphocytes, Helper-Inducer; CD4-Positive T-Lymphocytes; Thrombocytopenia; Anemia, Hemolytic, Autoimmune; CD40 Antigens; Leukemia, Myeloid, Acute
PubMed: 37701444
DOI: 10.3389/fimmu.2023.1165973 -
Transfusion and Apheresis Science :... Feb 2020Non-invasive fetal HPA-1a typing is a valuable tool to identify the pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT). At present, prenatal... (Review)
Review
Non-invasive fetal HPA-1a typing is a valuable tool to identify the pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT). At present, prenatal determination of the fetus HPA-1a type is performed for diagnostic purposes in pregnancies of HPA-1 alloimmunized women with history of a previous fetus or child with FNAIT. Different approaches have been used to determine the fetal HPA-1a genotype from cell-free fetal DNA (cffDNA) in the mother's plasma, mainly based on real-time PCR. Due to the single nucleotide polymorphism (SNP) between the HPA-1a and HPA-1b allelic sequences, a robust and accurate detection of the fetal genotype is challenging, and the sensitivity of most assays is still limited early in pregnancy. Nowadays, the availability of technologies such as next generation sequencing (NGS) or digital PCR offers unprecedented possibilities of analyzing cell-free DNA (cfDNA)-amplified sequences with very high coverage and high sensitivity. In addition, other interesting approaches using variant sequence enrichment strategies have been recently described. In particular, coamplification at lower denaturation temperature PCR (COLD-PCR) offers a simple and sensitive strategy for noninvasive fetal HPA-1 typing. These novel approaches are explained in more detail in this review. Despite no population-based FNAIT screening programs have so far been implemented, the perspectives in terms of treatment and prevention are changing and less costly high-throughput maternal HPA-1a typing methods have been developed. Altogether, this may lead to the implementation of fetal HPA-1a typing with a broader scope in the future, playing a critical role within FNAIT screening programs.
Topics: Antigens, Human Platelet; Female; Fetus; Humans; Integrin beta3; Pregnancy; Thrombocytopenia, Neonatal Alloimmune
PubMed: 31953107
DOI: 10.1016/j.transci.2019.102708 -
Transfusion Clinique Et Biologique :... Nov 2022Post-transfusion alloimmunisation is the main complication of all those observed after one or more transfusion episodes. Alloimmunisation is observed after the... (Review)
Review
Post-transfusion alloimmunisation is the main complication of all those observed after one or more transfusion episodes. Alloimmunisation is observed after the transfusion of red blood cell concentrates but also of platelet concentrates. Besides alloimmunisation due to antigens carried almost exclusively by red blood cells such as those of the Rhesus-Kell system, alloimmunisation often raises against HLA antigens; the main responsibility for that, apart from platelet transfusions, lies with residual leukocytes in the products transfused, hence the central importance of effective leukoreduction right from the blood product preparation stage. Alloimmunization is not restricted to transfusion, but it is also observed during pregnancies, carrying out microtransfusions of blood from the fetus immunizing the mother through the placenta (in a retrograde way). Preexisting maternal-fetal immunization can complicate a transfusion program and intensify the creation of alloantibodies in several blood and tissue group systems. The occurrence of autoantibodies, created by several pathogenic reasons, can also interfere with the propensity of certain recipients of blood components to produce alloantibodies. The genetic condition of individuals is in fact strongly linked to the ability or not to recognize antigenic variants foreign to their own biological program and mount an alloimmune response. Some hemoglobin diseases, in carriers of which transfusions can be iterative and lifelong, are complicated by frequent alloimmunizations and amplification of the complications of these alloimmunizations, imposing even stricter transfusion rules. This review details the mechanisms favoring the occurrence of alloimmunization and the immunological principles for the production of molecular and cellular tools for alloimmunization. It concludes with the main preventive measures available to limit the occurrence of these frequent complications of varying severity but sometimes severe.
Topics: Humans; Isoantibodies; Erythrocytes; Blood Transfusion; Platelet Transfusion; Kell Blood-Group System
PubMed: 35970488
DOI: 10.1016/j.tracli.2022.08.140 -
Annual Review of Pathology Jan 2018Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation,... (Review)
Review
Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation, immune-mediated rejection mandates the use of prolonged global immunosuppression and limits the life span of transplanted allografts. After bone marrow transplantation, donor-derived immune cells can trigger life-threatening graft-versus-host disease. T cells are central mediators of alloimmune complications and the target of most existing therapeutic interventions. We review recent progress in identifying multiple cell types in addition to T cells and new molecular pathways that regulate pathogenic alloreactivity. Key discoveries include the cellular subsets that function as potential sources of alloantigens, the cross talk of innate lymphoid cells with damaged epithelia and with the recipient microbiome, the impact of the alarmin interleukin-33 on alloreactivity, and the role of Notch ligands expressed by fibroblastic stromal cells in alloimmunity. While refining our understanding of transplantation immunobiology, these findings identify new therapeutic targets and new areas of investigation.
Topics: Animals; Graft Rejection; Graft vs Host Disease; Humans; Transplantation Immunology; Transplantation, Homologous
PubMed: 29099650
DOI: 10.1146/annurev-pathol-020117-043720 -
Immunohematology Dec 2022Variant alleles are found mainly in Afro-descendant individuals, as well as in patients with sickle cell disease (SCD). The most common variants are related to the...
Variant alleles are found mainly in Afro-descendant individuals, as well as in patients with sickle cell disease (SCD). The most common variants are related to the allele, which can generate partial e and c antigens. Although variant alleles have been extensively studied, defining their clinical significance is a difficult task. We evaluated the risk of RhCE alloimmunization as a consequence of partial antigens in patients with a positive phenotype transfused with red blood cell (RBC) units with the corresponding antigen. A retrospective study was performed with Brazilian patients, evaluating the number of antigen-positive transfused RBC units (incompatible due to partial antigen) in 27 patients with SCD carrying variant alleles who did not develop antibodies as well as evaluating the variants present in 12 patients with partial phenotype and correlated antibody (one patient with SCD and 11 patients with other pathologies). Two patients showed variant alleles with molecular changes that had not yet been described. Variant alleles were identified in a previous study using molecular methods. was the most frequent allele found among the patients without antibodies. Six patients with partial c antigen had a mean of 3.8 c+ RBC units transfused, and 10 patients with partial e antigen were exposed for a mean of 7.2 e+ RBC units. Among the variant alleles found in alloimmunized patients, the most frequent was which was found in five patients; the antibodies developed were anti-hr and/or anti-c. Our results showed that is indeed the most frequent variant allele in our cohort of patients with SCD, but the partial antigens that were identified have low risk of alloimmunization. is the most impactful variant in the Brazilian population with high risk of alloimmunization and clinically significant anti-hr formation.
Topics: Humans; Rh-Hr Blood-Group System; Alleles; Brazil; Retrospective Studies; Anemia, Hemolytic, Autoimmune; Isoantibodies; Anemia, Sickle Cell
PubMed: 36789463
DOI: 10.21307/immunohematology-2022-054 -
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