rs660 polymorphism in Ro52 (SSA1; TRIM 21) is a marker for age-dependent tolerance induction and efficiency of alloimmunization in sickle cell disease☆

Tatari-Calderone, Zohreh; Minniti, Caterina P.; Kratovil, Tonya; Stojakovic, Milica; Vollmer, Alison; Barjaktarević, Igor; Zhang, Ed; Hoang, Albert; Luban, Naomi L.C.; Vukmanović, Stanislav

doi:10.1016/j.molimm.2008.12.027

Cited by 58 publications

(63 citation statements)

References 27 publications

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“…A polymorphism in the immunoregulatory TRIM21 gene, in close proximity to the ␤-globin locus, was recently shown to be associated with an increased rate of SCD alloimmunization, especially in early childhood. 60 In mice lacking TRIM21, no significant increases in alloimmunization frequency against RBC or platelets were observed, although the mouse model did not have SCD. 61 Genome-wide association studies and whole exome sequencing of large cohorts of patients with SCD receiving transfusions should facilitate the identification of genetic predictors of alloimmunization, but these studies will only be informative if performed in conjunction with an accurate laboratory phenotype, which requires routine and thorough testing for RBC alloantibodies.…”

Section: Scd-specific Susceptibility Factorsmentioning

confidence: 96%

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Yazdanbakhsh

Ware

Noizat‐Pirenne

2012

Blood

323

350

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Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication. (Blood. 2012;120(3):528-537) IntroductionBlood transfusion remains a cornerstone of treatment of patients with sickle cell disease (SCD). Despite improved patient outcomes with hydroxyurea administration, indications for chronic transfusions have increased in the last 10 years and are associated with considerable reduction in morbidity and mortality, most notably in preventing first stroke in children. [1][2][3] However, transfusions can lead to erythrocyte alloimmunization with serious complications for the patient. These antibodies are often directed against antigens expressed on RBCs of white persons, which represent the majority of donors in Western countries. 4 Finding compatible units lacking those antigens can sometimes be difficult, and identifying and characterizing the antibodies can be timeconsuming and laborious, causing transfusion delays. Genetic as well as acquired patient-related factors are likely to influence the process of alloimmunization.The most serious consequence of alloimmunization in SCD patients is the risk of developing a delayed hemolytic transfusion reaction (DHTR), which can be life-threatening. In many cases of DHTR in SCD, the patient's hemoglobin level falls below the pretransfusion level, suggesting that, in addition to hemolysis of the transfused RBCs, the patient's own RBCs are lysed, a condition known as hyperhemolysis. Additional transfusions may exacerbate the hemolysis and further worsen the degree of anemia. The destruction of the patient's own RBCs in DHTR of SCD is partly explained by the presence of autoantibodies 5 because alloimmunization is known to trigger autoantibody production. However, DHTR/hyperhemolysis cases have also been reported in the absence of detectable alloantibodies or autoantibodies.In this review, we discuss the known risk factors associated with alloimmunization, then emphasize possible mechanisms that can trigger autoimmunization and DHTR in SCD, and finally describe the challenges in transfusion management of these patients. We emphasize opportunities and emerging approaches for minimizing this life-threatening complication. RBC alloimmunization pathobiologyAlloimmunization to erythrocytes involves multiple steps, including RBC antigen recognition, processing, and presentation of antigen by HLA class II to TCR, activation of CD4 ...

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Section: Scd-specific Susceptibility Factorsmentioning

confidence: 96%

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Yazdanbakhsh

Ware

Noizat‐Pirenne

2012

Blood

323

350

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“…Tatari-Calderone et al [23] hypothesized that the incidence of RBC alloimmunization in SCD patients was influenced by linked inheritance of the hemoglobin beta S allele and a C/T single nucleotide polymorphism (SNP) (rs660) in the nearby Ro52 gene. 50% of T/T homozygous and 42.9% of C/T heterozygous patients had RBC alloantibodies.…”

Section: Rbc Alloimmunization: Genome-wide Analyses and Molecular Marmentioning

confidence: 99%

Red Blood Cell Alloimmunization in Sickle Cell Disease: Listen to Your Ancestors

Campbell‐Lee

Kittles²

2014

Transfus Med Hemother

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Red blood cell (RBC) alloimmunization occurs in approximately 30% of transfused sickle cell disease patients compared to 2-5% of all transfusion recipients. Because RBC transfusion is an important part of therapy in sickle cell disease, the need for additional antigen matching once alloimmunization occurs is problematic and leads to therapeutic limitations. Thus, identification of risk factors would benefit this patient population. Genome-wide analyses, in particular, methods which take into account genetic ancestry such as admixture mapping, could identify molecular markers which could be used to identify immune responders to transfusion.

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“…[6][7][8] In addition, genetic variants outside of HLA may regulate RBC alloimmunization. 9 Environmental differences between recipients also likely affect alloimmunization, as genetically identical animals still have variable alloantibody responses to transfused RBCs. 10,11 One such environmental variable may be the inflammatory status of the recipient, which has been shown to have a substantial effect upon alloimmunization to transfused RBCs in mice, 10,12,13 and potentially in humans.…”

Section: Introductionmentioning

confidence: 99%

Regulation of primary alloantibody response through antecedent exposure to a microbial T-cell epitope

Hudson

Lin

Hendrickson

et al. 2010

Blood

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Humoral alloimmunization to red blood cell (RBC) antigens is a clinically significant problem that can lead to transfusion reactions and difficulty in locating future compatible blood for transfusion. However, factors regulating responder/ nonresponder status are only partially understood. Herein, we identify a series of microbes with 100% identity in 8-to 9-amino acid peptides containing the variant amino acids in Kell, Kidd, and Duffy antigens. To test the hypothesis that infection with such a microbe could predispose to RBC alloimmunization, a mouse model was developed using murine polyoma virus expressing a defined CD4 ؉ Tcell epitope ovalbumin [323][324][325][326][327][328][329][330][331][332][333][334][335][336][337][338][339] IntroductionHumoral immunization to red blood cell (RBC) alloantigens can occur as a result of transfusion or pregnancy. Antibodies against clinically significant blood group alloantigens (ie, RhD, Kell, Kidd, etc) can lead to both hemolysis of transfused RBCs and/or to hemolytic disease of the newborn. 1,2 However, unlike humoral immunization to microbial infection, which approaches 100% in immunocompetent persons, exposure to RBC alloantigens induces a measurable antibody response in only a subset of recipients. Alloimmunization to the RhD antigen on RBCs ranges from 20% to 80%, with only 3% to 10% of recipients becoming immunized to the remaining RBC antigens (eg, Kell, Duffy, Kidd), despite chronic transfusion. [3][4][5] The reason why some transfused patients but not others become alloimmunized is unclear, and factors influencing alloimmunization have been only partially defined. Immunogenetics plays some role in variability of alloimmunization to blood products, as antibody responses to certain alloantigens are confined to distinct recipient human leukocyte antigen (HLA) types. [6][7][8] In addition, genetic variants outside of HLA may regulate RBC alloimmunization. 9 Environmental differences between recipients also likely affect alloimmunization, as genetically identical animals still have variable alloantibody responses to transfused RBCs. 10,11 One such environmental variable may be the inflammatory status of the recipient, which has been shown to have a substantial effect upon alloimmunization to transfused RBCs in mice, 10,12,13 and potentially in humans. 14 In the current report, we hypothesize that an additional potential factor is small peptide homology between microbial-derived peptides and blood group antigens.It has long been appreciated that alloimmunity can be induced through exposure to microbial antigens that mimic the 3-dimensional structure and epitopes of alloantigens (molecular mimicry); thus, antibodies generated against the microbial antigen can cross-react with alloantigens. This is a well-documented event with anti-ABO antibodies, where humans make antibodies against "non-self-" ABO antigens without any prior exposure through transfusion, because of immunization with gut microbes that express A and/or B antigens. 15 In the context of immunoglobulin G (...

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rs660 polymorphism in Ro52 (SSA1; TRIM 21) is a marker for age-dependent tolerance induction and efficiency of alloimmunization in sickle cell disease☆

Cited by 58 publications

References 27 publications

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Red Blood Cell Alloimmunization in Sickle Cell Disease: Listen to Your Ancestors

Regulation of primary alloantibody response through antecedent exposure to a microbial T-cell epitope

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