-
Blood Transfusion = Trasfusione Del... Jul 2021Red blood cell (RBC) transfusion remains an essential part of sickle cell disease (SCD) management but it can lead to alloimmunisation, with an increased incidence in...
Complete RH and Kell matching related to low alloimmunisation risk in sickle cell disease: prevalence and risk factors of alloimmunisation in a Spanish Tertiary Care National Reference Centre.
BACKGROUND
Red blood cell (RBC) transfusion remains an essential part of sickle cell disease (SCD) management but it can lead to alloimmunisation, with an increased incidence in this population. Prevention is based on RBC antigen phenotype matching, with complete RH and Kell matching being a standard of care.
MATERIALS AND METHODS
We performed a retrospective, single-centre study analysing alloimmunisation prevalence and risk factors in a cohort of transfused SCD patients.
RESULTS
Eighty-seven patients (96.5% of paediatric age) received 1,781 RBC units (RBCu). Complete RH and Kell matched RBCu represented a median of 100% among total transfusions per patient. Of the 87 patients, 52 (59.8%) underwent chronic transfusion therapy, whereas 35 (40.2%) were only episodically transfused. Seven patients were alloimmunised (8.4%) and eleven antibodies were detected (alloimmunisation rate: 0.62/100 units transfused). 54.6% of these antibodies corresponded to RH-Kell despite the high accomplishment of the RH-Kell matching transfusion protocol. Alloimmunised patients had a median of 90.9% RH-Kell matched transfusions vs 100% in non-alloimmunised patients, but no statistical differences were observed (p=0.127). Number of transfused RBCu (19 vs 7; p=0.023), number of episodic RBCu (8 vs 2; p=0.006), episodic to chronic RBCu ratio (0.57 vs 0.09; p=0.045), number of vaso-occlusive crises (VOC) (4 vs 2; p=0.011), and autoantibody presence (57.1 vs 0%; p<0.001) were all statistically related to alloimmunisation.
DISCUSSION
We report a low alloimmunisation prevalence (8.4%) related to a high grade of RH-Kell matching. However, deviation from 100% translates into alloimmunisation, with >50% of alloantibodies corresponding to RH-Kell. Alloimmunisation risk increases with transfusion burden, particularly during acute complications, and in patients with a higher number of VOC, probably reflecting underlying inflammation and disease severity. Further studies will be needed to elucidate additional risk factors and help prevent alloimmunisation in these patients.
Topics: Anemia, Sickle Cell; Child; Erythrocytes; Humans; Isoantibodies; Prevalence; Retrospective Studies; Risk Factors; Tertiary Healthcare
PubMed: 33085598
DOI: 10.2450/2020.0096-20 -
Frontiers in Immunology 2020Autoimmune manifestations after allogeneic hematopoietic stem cell transplantation (AHSCT) are rare and poorly understood due to the complex interplay between the... (Review)
Review
Autoimmune manifestations after allogeneic hematopoietic stem cell transplantation (AHSCT) are rare and poorly understood due to the complex interplay between the reconstituting immune system and transplant-associated factors. While autoimmune manifestations following AHSCT have been observed in children with graft-versus-host disease (GvHD), an alloimmune process, they are distinct from the latter in that they are generally restricted to the hematopoietic compartment, i.e., autoimmune hemolytic anemia, thrombocytopenia, and/or neutropenia. Autoimmune cytopenias in the setting of ASHCT represent a donor against donor immune reaction. Non-hematologic autoimmune conditions in the post-AHSCT setting have been described and do not currently fall under the GvHD diagnostic criteria, but could represent alloimmunity since they arise from the donor immune attack on the antigens that are shared by the donor and host in the thyroid, peripheral and central nervous systems, integument, liver, and kidney. As in the non-transplant setting, autoimmune conditions are primarily antibody mediated. In this article we review the incidence, risk factors, potential pathophysiology, treatment, and prognosis of hematologic and non-hematologic autoimmune manifestations in children after AHSCT.
Topics: Anemia, Hemolytic, Autoimmune; Animals; Autoimmunity; Cell Self Renewal; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Transplantation Conditioning; Transplantation, Homologous
PubMed: 32983144
DOI: 10.3389/fimmu.2020.02017 -
International Journal of Molecular... Oct 2021The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a... (Review)
Review
The NOD, LRR, and pyrin domain-containing 3 (NLRP3) protein has been established as a central component of the inflammasome and regulates the inflammatory response to a myriad of environmental, microbial, and endogenous danger stimuli. Assembly of the NLRP3 inflammasome results in the cleavage and activation of caspase-1, in turn causing release of the pro-inflammatory interleukins 1-beta and 18. This activation response, while crucial to coordinated innate immune defense, can be aberrantly activated by the likes of cell-free DNA, and cause significant autoimmune pathology. Complications of autoimmunity induced by aberrant NLRP3 inflammasome activation have a great degree of mechanistic crossover with alloimmune injury in solid organ transplant, and stratagems to neutralize NLRP3 inflammasome activation may prove beneficial in solid organ transplant management. This article reviews NLRP3 inflammasome biology and the pathology associated with its hyperactivation, as well as the connections between NLRP3 inflammasome activation and allograft homeostasis.
Topics: Animals; Autoimmunity; DNA; Humans; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Neutrophils; Organ Specificity; Organ Transplantation; Protein Processing, Post-Translational
PubMed: 34639062
DOI: 10.3390/ijms221910721 -
Blood Reviews May 2023FNAIT is a pregnancy-associated condition caused by maternal alloantibodies against paternally-inherited platelet antigens, most frequently HPA-1a on integrin β3. The... (Review)
Review
FNAIT is a pregnancy-associated condition caused by maternal alloantibodies against paternally-inherited platelet antigens, most frequently HPA-1a on integrin β3. The clinical effects range from no symptoms to fatal intracranial hemorrhage, but underlying pathophysiological determinants are poorly understood. Accumulating evidence suggests that differential antibody-Fc-glycosylation, activation of complement/effector cells, and integrin function-blocking effects contribute to clinical outcome. Furthermore, some antibodies preferentially bind platelet integrin αIIbβ3, but others bind αvβ3 on endothelial cells and trophoblasts. Defects in endothelial cells and angiogenesis may therefore contribute to severe anti-HPA-1a associated FNAIT. Moreover, anti-HPA-1a antibodies may cause placental damage, leading to intrauterine growth restriction. We discuss current insights into diversity and actions of HPA-1a antibodies, gathered from clinical studies, in vitro studies, and mouse models. Assessment of all factors determining severity and progression of anti-HPA-1a-associated FNAIT may importantly improve risk stratification and potentially reveal novel treatment strategies, both for FNAIT and other immunohematological disorders.
Topics: Animals; Mice; Pregnancy; Female; Humans; Thrombocytopenia, Neonatal Alloimmune; Placenta; Endothelial Cells; Blood Platelets; Isoantibodies
PubMed: 36581513
DOI: 10.1016/j.blre.2022.101038 -
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 -
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 -
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 -
Journal of Clinical Medicine May 2020: Incompatibilities between the mother and unborn baby can cause complications that must be identified early to initiate the appropriate treatment. For example, neonatal... (Review)
Review
: Incompatibilities between the mother and unborn baby can cause complications that must be identified early to initiate the appropriate treatment. For example, neonatal alloimmune thrombocytopenia (NAIT), neonatal alloimmune neutropenia (NAIN), and morbus hemolyticus neonatorum affect children worldwide. : This literature review aims to depict the similarities and differences between these three disorders from a clinical and mechanistic point of view. : The current literature review entailed conducting a systematic search to locate articles on the three conditions. Different electronic databases, including PsycINFO, PubMed, Web of Science, and CINAHL, were searched using the search terms "neonatal alloimmune thrombocytopenia", "neonatal alloimmune neutropenia", "morbus hemolyticus neonatorum", "NAIT", "FNAIT", "fetal", "NAIN", and "hemolytic disease of the newborn". : This review shows that these three diseases are caused by incompatibilities between the maternal and fetal immune systems. Furthermore, these conditions can lead to severe complications that hinder fetal development and cause death if not well managed. Discussion: The current literature review shows that NAIT, NAIN, and morbus hemolyticus neonatorum are rare conditions that occur when the mother produces antibodies against the fetal immune system. Thus, there is a need for the early detection of these conditions to initiate appropriate treatment before the child experiences adverse effects. : The development of NAIT, NAIN, and morbus hemolyticus neonatorum is linked to the production of antibodies against the fetal immune system and fetal antigens. Further studies are required to determine potential interventions to reduce the risk of developing these three conditions.
PubMed: 32422924
DOI: 10.3390/jcm9051470 -
Frontiers in Immunology 2023Measurement of T cell receptor (TCR) or B cell receptor (BCR) gene utilization may be valuable in monitoring the dynamic changes in donor-reactive clonal populations... (Review)
Review
BACKGROUND
Measurement of T cell receptor (TCR) or B cell receptor (BCR) gene utilization may be valuable in monitoring the dynamic changes in donor-reactive clonal populations following transplantation and enabling adjustment in therapy to avoid the consequences of excess immune suppression or to prevent rejection with contingent graft damage and to indicate the development of tolerance.
OBJECTIVE
We performed a review of current literature to examine research in immune repertoire sequencing in organ transplantation and to assess the feasibility of this technology for clinical application in immune monitoring.
METHODS
We searched MEDLINE and PubMed Central for English-language studies published between 2010 and 2021 that examined T cell/B cell repertoire dynamics upon immune activation. Manual filtering of the search results was performed based on relevancy and predefined inclusion criteria. Data were extracted based on study and methodology characteristics.
RESULTS
Our initial search yielded 1933 articles of which 37 met the inclusion criteria; 16 of these were kidney transplant studies (43%) and 21 were other or general transplantation studies (57%). The predominant method for repertoire characterization was sequencing the CDR3 region of the TCR β chain. Repertoires of transplant recipients were found to have decreased diversity in both rejectors and non-rejectors when compared to healthy controls. Rejectors and those with opportunistic infections were more likely to have clonal expansion in T or B cell populations. Mixed lymphocyte culture followed by TCR sequencing was used in 6 studies to define an alloreactive repertoire and in specialized transplant settings to track tolerance.
CONCLUSION
Methodological approaches to immune repertoire sequencing are becoming established and offer considerable potential as a novel clinical tool for pre- and post-transplant immune monitoring.
Topics: B-Lymphocytes; Immune Tolerance; Kidney Transplantation; Organ Transplantation; Humans; T-Lymphocytes; Graft Rejection
PubMed: 36865546
DOI: 10.3389/fimmu.2023.1100479 -
Circulation Research Sep 2020Transplant arteriosclerosis is the major limitation to long-term survival of solid organ transplantation. Although both immune and nonimmune cells have been suggested to...
RATIONALE
Transplant arteriosclerosis is the major limitation to long-term survival of solid organ transplantation. Although both immune and nonimmune cells have been suggested to contribute to this process, the complex cellular heterogeneity within the grafts, and the underlying mechanisms regulating the disease progression remain largely uncharacterized.
OBJECTIVE
We aimed to delineate the cellular heterogeneity within the allografts, and to explore possible mechanisms underlying this process.
METHODS AND RESULTS
Here, we reported the transcriptional profiling of 11 868 cells in a mouse model of transplant arteriosclerosis by single-cell RNA sequencing. Unbiased clustering analyses identified 21 cell clusters at different stages of diseases, and focused analysis revealed several previously unknown subpopulations enriched in the allografts. Interestingly, we found evidence of the local formation of tertiary lymphoid tissues and suggested a possible local modulation of alloimmune responses within the grafts. Intercellular communication analyses uncovered a potential role of several ligands and receptors, including and , in regulating lymphatic endothelial cell-induced early chemotaxis and infiltration of immune cells. In vivo mouse experiments confirmed the therapeutic potential of CCL21 and CXCR3 neutralizing antibodies in transplant arteriosclerosis. Combinational use of genetic lineage tracing and single-cell techniques further indicate the infiltration of host-derived c-Kit stem cells as heterogeneous populations in the allografts. Finally, we compared the immune response between mouse allograft and atherosclerosis models in single-cell RNA-seq analysis. By analyzing susceptibility genes of disease traits, we also identified several cell clusters expressing genes associated with disease risk.
CONCLUSIONS
Our study provides a transcriptional and cellular landscape of transplant arteriosclerosis, which could be fundamental to understanding the initiation and progression of this disease. CCL21/CXCR3 was also identified as important regulators of immune response and may serve as potential therapeutic targets in disease treatment.
Topics: Animals; Aorta; Arteriosclerosis; Cell Lineage; Chemokine CCL21; Disease Models, Animal; Female; Gene Expression Profiling; Graft Survival; Immunity, Cellular; Immunity, Innate; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Proto-Oncogene Proteins c-kit; RNA-Seq; Receptors, CXCR3; Single-Cell Analysis; Time Factors; Transcriptome; Transplantation Tolerance
PubMed: 32689904
DOI: 10.1161/CIRCRESAHA.119.316470