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Current Opinion in Hematology Nov 2020The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC)... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC) transfusion, the formation of alloantibodies following RBC alloantigen exposure, and the development of hyperhemolysis in patients with sickle cell disease (SCD).
RECENT FINDINGS
Recent studies demonstrate that complement can accelerate alloantibody-mediated removal of target alloantigens from the RBC surface following incompatible transfusion. Complement also influences alloantigen availability during developing alloimmune responses and serves as a unique mediator of CD4 T-cell-independent alloantibody formation following RBC alloantigen exposure. Finally, alternative complement pathway activation appears to play a key role in the development of acute hemolytic episodes in patients with SCD, providing a potential druggable target to prevent acute complications in patients with this disease.
SUMMARY
Recent studies suggest that complement can regulate a wide variety of processes germane to hematology, from transfusion complications to baseline hemolysis in patients with SCD. As the role of complement in various disease processes becomes more fully understood, the ability to leverage recently developed complement modulating drugs will only continue to enhance providers' ability to favorably intervene in many hematological diseases.
Topics: Anemia, Hemolytic, Autoimmune; Animals; Blood Group Incompatibility; Complement System Proteins; Erythrocyte Transfusion; Erythrocytes; Hemolysis; Humans; Isoantibodies; Isoantigens
PubMed: 32889827
DOI: 10.1097/MOH.0000000000000610 -
Transfusion Clinique Et Biologique :... Aug 2015Red blood cell (RBC) alloimmunization can be a life-threatening complication for patients with sickle cell disease (SCD) receiving therapeutic transfusions. Despite... (Review)
Review
Red blood cell (RBC) alloimmunization can be a life-threatening complication for patients with sickle cell disease (SCD) receiving therapeutic transfusions. Despite provision of extended antigen-matched donor RBCs, patients continue to develop antibodies due to high degree of polymorphisms in the immunogenic antigens in individuals of African ancestry. Identification of biomarkers of alloimmunization in this patient population is therefore of great interest and will help to identify in advance patients most likely to make antibodies in response to transfusion. We have recently identified altered T cell responses and innate immune abnormalities in alloimmunized SCD patients. In this paper, we summarize this work and propose our working model of how innate immune abnormalities can contribute to pathogenic T cell responses in alloimmunized SCD patients. We believe that unravelling the basis of such altered interactions at the cellular and molecular level will help future identification of biomarkers of alloimmunization with the goal that this information will ultimately help guide therapy in these patients.
Topics: Anemia, Sickle Cell; B-Lymphocytes; Biomarkers; Blood Group Incompatibility; Erythrocyte Transfusion; Erythrocytes; Heme; Heme Oxygenase-1; Hemin; Humans; Interleukin-10; Interleukin-12; Isoantibodies; Lymphocyte Cooperation; Membrane Proteins; Models, Immunological; Monocytes; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Transfusion Reaction
PubMed: 26056038
DOI: 10.1016/j.tracli.2015.05.005 -
Current Opinion in Nephrology and... Nov 2016The present review aims to highlight the major recent advances in transplantation with regards to basic, translational, and clinical research. (Review)
Review
PURPOSE OF REVIEW
The present review aims to highlight the major recent advances in transplantation with regards to basic, translational, and clinical research.
RECENT FINDINGS
We describe new concepts in understanding allorecognition and allospecificity of T cells, and discuss current challenges in targeting memory T cells, including the limitation of rodent disease models. From a clinical perspective, we highlight the advances in molecular biopsy characterization, which have expanded our knowledge of potential drivers of injury and may provide better parameters for patient risk stratification. We also highlight the dual role of innate immunity in both stimulating and regulating adaptive immunity, as well as novel insights into environmental exposures that may affect immune regulation, such as high-salt diet. Finally, we discuss advances in understanding humoral response and novel technologies, such as chimeric antigen receptors-engineered T cells, microparticle-based drug delivery, and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) gene editing, that may provide intriguing and promising approaches to restrain alloimmunity.
SUMMARY
Current advances in our understanding of the basic mechanisms of alloimmunity and their potential translation to clinical applications will permit the development of novel diagnostic and therapeutic strategies to improve long-term graft survival.
Topics: CRISPR-Cas Systems; Gene Editing; Graft Rejection; Humans; Immunity, Cellular; Immunity, Humoral; Immunity, Innate; Kidney Transplantation; Transplantation, Homologous
PubMed: 27584931
DOI: 10.1097/MNH.0000000000000267 -
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 -
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 -
Frontiers in Immunology 2016Transfusion of blood cell components is frequent in the therapeutic arsenal; it is globally safe or even very safe. At present, residual clinical manifestations are... (Review)
Review
Transfusion of blood cell components is frequent in the therapeutic arsenal; it is globally safe or even very safe. At present, residual clinical manifestations are principally inflammatory in nature. If some rare clinical hazards manifest as acute inflammation symptoms of various origin, most of them linked with conflicting and undesirable biological material accompanying the therapeutic component (infectious pathogen, pathogenic antibody, unwanted antigen, or allergen), the general feature is subtler and less visible, and essentially consists of alloimmunization or febrile non-hemolytic transfusion reaction. The present essay aims to present updates in hematology and immunology that help understand how, when, and why subclinical inflammation underlies alloimmunization and circumstances characteristic of red blood cells and - even more frequently - platelets that contribute inflammatory mediators. Modern transfusion medicine makes sustained efforts to limit such inflammatory hazards; efforts can be successful only if one has a clear view of each element's role.
PubMed: 27965664
DOI: 10.3389/fimmu.2016.00534 -
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 :... 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 -
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