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Hematology. American Society of... Dec 2016Red blood cell (RBC) transfusions are critical for treatment and prevention of complications of sickle cell disease (SCD), and most SCD patients will receive 1 or more... (Review)
Review
Red blood cell (RBC) transfusions are critical for treatment and prevention of complications of sickle cell disease (SCD), and most SCD patients will receive 1 or more transfusions by age 20. However, SCD alloimmunization remains a serious complication of transfusions that can lead to life-threatening acute and delayed transfusion reactions. Alloimmunization rates are higher in SCD patients most likely due to RBC antigenic differences between largely white donors vs mainly African-American recipients and frequency of transfusions. However, it remains unclear why some but not all SCD patients develop alloantibodies. Cellular immune responses that differ between alloimmunized and nonalloimmunized SCD patients are beginning to be characterized. Altered CD4 T helper cell responses, known to control immunoglobulin G production, have been identified in alloimmunized SCD patients, including abnormalities in regulatory T cells, as well as helper type 1 (T1), T17, and follicular helper T cells. Furthermore, heightened innate immune cell responses to cell free heme with cell polarization toward proinflammatory T cell profiles were recently reported in SCD antibody responders, suggesting that the ongoing hemolytic state in SCD may impair the ability of innate immune cells in these already alloimmunized patients to counter alloimmunization. Identification of molecular pathways in key cellular components that differ between alloimmunized and nonalloimmunized SCD patients is likely to lead to identification of biomarkers of alloimmunization and future design of targeted therapies to prevent or even dampen alloantibody responses in these highly susceptible patients.
Topics: Anemia, Sickle Cell; Animals; Erythrocyte Transfusion; Erythrocytes; Humans; Immunization; Isoantibodies; Isoantigens; Th1 Cells; Th17 Cells
PubMed: 27913516
DOI: 10.1182/asheducation-2016.1.457 -
Transfusion Medicine Reviews Oct 2020Despite significant advancements in the production of platelet products, storage, and transfusion, transfusion refractoriness remains a significant clinical problem,... (Review)
Review
Despite significant advancements in the production of platelet products, storage, and transfusion, transfusion refractoriness remains a significant clinical problem, affecting up to 14% of hematological patients receiving platelet transfusions. Human leukocyte antigen (HLA) alloimmunization is a major cause of immune platelet refractoriness, and its rate can be significantly reduced by implementation of leukoreduction. Despite promising preclinical results, pathogen reduction does not reduce HLA alloimmunization. Patients with HLA alloimmune refractoriness are usually managed with HLA-selected platelet transfusions. In this review, we describe the pathophysiology of HLA alloimmunization and alloimmune refractoriness, as well as options to prevent and treat these transfusion complications. We discuss the evidence supporting these options and point out the outstanding gaps. Finally, we review the possible future directions for prevention and treatment of alloimmune refractoriness.
Topics: Blood Platelets; HLA Antigens; Humans; Isoantibodies; Platelet Count; Platelet Transfusion; Thrombocytopenia; Treatment Failure
PubMed: 33127210
DOI: 10.1016/j.tmrv.2020.09.010 -
Frontiers in Immunology 2018
Topics: Endothelial Cells; Endothelium, Vascular; Graft Rejection; Histocompatibility; Humans; Inflammation; Isoantibodies; Organ Transplantation
PubMed: 30581438
DOI: 10.3389/fimmu.2018.02886 -
Current Opinion in Organ Transplantation Feb 2016The Notch signaling pathway is known to play a pivotal role in T- and B-cell development and fate, presenting it as an attractive therapeutic target in alloimmunity.... (Review)
Review
PURPOSE OF REVIEW
The Notch signaling pathway is known to play a pivotal role in T- and B-cell development and fate, presenting it as an attractive therapeutic target in alloimmunity. This review provides an overview of the mechanisms of Notch signaling, focusing on new insights into its diverse functions in T-cell activation, differentiation and memory subset formation, and the consequences thereof in transplantation.
RECENT FINDINGS
Recent evidence has shown that while not critical for early antigen-specific CD4 T-cell activation, Notch signaling regulates the survival of memory CD4 T cells via control of glycolytic metabolism; in contrast, Notch signaling is critical for the generation of short-lived CD8 effector T cells, but not memory CD8 cells. Transient, selective inhibition of various Notch receptors and ligands in models of solid organ transplantation has been shown to successfully modulate the alloimmune response, affecting the balance between effector and regulatory cells, with particular influence on the natural regulatory T-cell population.
SUMMARY
These studies reveal diverse roles for individual Notch receptors and ligands in peripheral immunity and indicate that selective targeting of the Notch pathway is a promising, novel approach for immune modulation in transplantation; the advent of therapeutic human antibodies to neutralize both the Notch ligands and the individual Notch receptors suggests that this approach could be efficiently developed.
Topics: Animals; Cell Differentiation; Humans; Ligands; Lymphocyte Activation; Receptors, Notch; Signal Transduction; T-Lymphocytes
PubMed: 26626420
DOI: 10.1097/MOT.0000000000000266 -
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 -
Transfusion Medicine and Hemotherapy :... Oct 2018Antibodies to human neutrophil antigens (HNAs) have been implicated in transfusion-related acute lung injury and allo- and autoimmune neutropenia. To date, five HNA... (Review)
Review
BACKGROUND AND OBJECTIVE
Antibodies to human neutrophil antigens (HNAs) have been implicated in transfusion-related acute lung injury and allo- and autoimmune neutropenia. To date, five HNA systems are assigned, and during the last decades enormous efforts have been undertaken to identify the underlying genes and to characterize the antigens. This review of the literature will provide the current genetic, molecular and functional information on HNAs.
RECENT FINDINGS
New information on alleles and antigens has been added to nearly each of the five HNA systems. HNA-1d has been added as the antithetical epitope to HNA-1c that is located on the glycoprotein encoded by but not by and now are included as new alleles. A substitution was demonstrated as the main reason for the HNA-2-negative phenotype on neutrophils. The target glycoprotein of HNA-3 antibodies could be identified as choline transporter-like protein 2 (CTL2) encoded by The conformation sensitive epitope discriminates between arginine and glutamine at position 152 resulting in HNA-3a and HNA-3b. An additional Leu151Phe substitution can impair HNA-3a antibody binding. Recently an alloantibody against HNA-4b which discriminates from HNA-4a by an Arg61His exchange of the glycoprotein encoded by the gene was reported in neonatal alloimmune neutropenia. An update of the current HNA nomenclature based on the new findings was provided in 2016 by the ISBT Granulocyte Immunobiology Working Party nomenclature subcommittee.
CONCLUSIONS
The molecular basis of each of the five HNA antigen systems has been decoded during the past decades. This enables reliable molecular typing strategies, antibody detection and specification as well as development of new assays based on recombinant antigens. However, research on HNA alleles, antigens, and antibodies is not finally terminated and also in the future will add new findings.
PubMed: 30498408
DOI: 10.1159/000491031 -
American Journal of Transplantation :... Nov 2023Biological sex affects immunity broadly, with recognized effects on the incidence and severity of autoimmune diseases, infections, and malignancies. Consequences of sex... (Review)
Review
Biological sex affects immunity broadly, with recognized effects on the incidence and severity of autoimmune diseases, infections, and malignancies. Consequences of sex on alloimmunity and outcomes in solid organ transplantation are less well defined. Clinical studies have shown that donor and recipient sex independently impact transplant outcomes, which are further modified by aging. Potential mechanisms have thus far not been detailed and may include hormonal, genetic, and epigenetic components. Here, we summarize relevant findings in immunity in addition to studies in clinical and experimental organ transplantation detailing the effects of biological sex on alloimmunity. Understanding both clinical impact and mechanisms is expected to provide critical insights on the complexity of alloimmune responses, with the potential to fine-tune treatment and allocation while providing a rationale to include both sexes in transplant research.
Topics: Male; Female; Humans; Clinical Relevance; Graft Rejection; Organ Transplantation; Tissue Donors
PubMed: 37543092
DOI: 10.1016/j.ajt.2023.07.022 -
Transfusion Medicine and Hemotherapy :... Feb 2023Antibodies to human neutrophil alloantigens (HNA) are involved in the pathophysiology of several clinical conditions including transfusion-related acute lung injury...
BACKGROUND
Antibodies to human neutrophil alloantigens (HNA) are involved in the pathophysiology of several clinical conditions including transfusion-related acute lung injury (TRALI), alloimmune and autoimmune neutropenia, and febrile nonhemolytic transfusion reactions leading to neutropenia. The cognate antigens are polymorphic structures expressed on several glycoproteins on the neutrophils, i.e., antigens HNA-1a, -1b, -1c, and -1d on Fc-γ-receptor IIIb; HNA-2 on CD177; HNA-3a and -3b on choline transporter-like protein 2; HNA-4a and -4b on CD11b/αM subunit of the αMβ2-integrin (CD11b/CD18, Mac-1, CR3); and HNA-5a and -5b on αL-subunit (CD11a) of the αLβ2 integrin (CD11a/CD18), leukocyte function associated molecule (LFA)-1. Currently, there is a lacuna of diagnostic methods for detection of HNA in India. This study aimed to determine the HNA frequencies in Indians, estimate the risk of alloimmunization, and prepare typed neutrophil panels, which can be used to detect HNA antibodies in neutropenia cases.
MATERIAL AND METHODS
EDTA blood samples were collected from random 1,054 blood donors. HNA-2 was phenotyped on fresh EDTA samples using FITC labelled monoclonal anti-CD177 by flowcytometry. HNA-1 () genotyping was carried out by DNA sequencing and PCR-RFLP. Antigens of HNA-3 () and HNA-5 () were genotyped by PCR-RFLP using and restriction enzymes, respectively, while HNA-4 () was genotyped by PCR-SSP.
RESULTS
Allele frequencies of *, *, and * were found to be 0.433, 0.444, and 0.087, respectively. FCGR3B*01+*02+*03- was the most common genotype (33.78%). Ten individuals showed deficiency of FCGR3B individuals, while 23 showed hyperexpression, i.e., ***. *and * occurred with a frequency of 0.002 and 0.024. HNA-2 was found to be a high frequency antigen occurring in 98.8% population. Four percent individuals showed atypical expression of CD177 on their neutrophils. Allele frequencies of * and *were 0.812 and 0.188, respectively, and that of *, *, *, and * were 0.9546, 0.0454, 0.2372, and 0.7628, respectively.
CONCLUSION
This is the first study in India to report the frequencies of HNA among blood donors. Typed neutrophil panels identified in the present study will enable us to investigate suspected cases of immune neutropenia in future.
PubMed: 36818775
DOI: 10.1159/000525654 -
Transfusion and Apheresis Science :... Dec 2021Transfusion is a lifesaving treatment for lots of patients. However, in chronic blood recipients such as thalassemia patients, there are high concerns about alloantibody...
BACKGROUND
Transfusion is a lifesaving treatment for lots of patients. However, in chronic blood recipients such as thalassemia patients, there are high concerns about alloantibody production that affects the quality of their life. Therefore, research on risk factors of alloimmunization has been started and followed. This study aimed at the determination of correlation probability between some HLADRB1 alleles and alloimmunization in Iranian thalassemia patients.
MATERIALS AND METHODS
The present study was conducted on 60 alloimmunized and 60 non-alloimmunized transfusion-dependent thalassemia patients. Antibody screening and identification tests were carried out using the tube method, and HLA-DRB1 genotyping was done using a single specific primer-polymerase chain reaction (PCRSSP).
RESULTS
The results of antibody screening showed that the most prevalent alloantibodies were Anti-K (46.7 %), and followed by Anti-E (32.5 %), Anti-C (15.8 %), Anti-D (13.3 %), Anti-e (8 %), and Anti-c (5.8 %), respectively. DRB1*07:01 was detected more in non-responder patients (28.3 %). However, data analysis showed that there is no significant relationship between DRB1*07:01, *10, *13:01 frequency among responder and non-responder groups (p = 0·195, 0.648, 0.402, respectively). There was not any significant correlation between HLA-DRB1*10 and *13:01 allele and alloimmunization. There was a significant association between HLA-DRB1*12 and alloimmunization (p < 0·05, OR = 2.071, CI: 1.716-2.501).
CONCLUSION
The findings of this study represented that there is a significant relationship between HLADRB1*12 and Kell and E alloantibodies. Although more developed studies on other HLA alleles are demanded, these findings can be valuable in determining important alloimmunization risk factors to better management of transfusion complications.
Topics: Alleles; Blood Transfusion; HLA-DRB1 Chains; Humans; Isoantibodies; Prognosis; Thalassemia
PubMed: 34535395
DOI: 10.1016/j.transci.2021.103271