Lack of Duffy antigen expression is associated with organ damage in patients with sickle cell disease

Afenyi‐Annan, Araba; Kail, Melanie E.; Combs, Martha Rae; Orringer, Eugene P.; Ashley-Koch, Allison E.; Telen, Marilyn J.

doi:10.1111/j.1537-2995.2007.01622.x

Cited by 69 publications

(64 citation statements)

References 49 publications

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“…The data of Afenyi-Annan et al 92 provide evidence that SCD patients with the Fy(aϪbϪ) phenotype are more susceptible to chronic organ damage and proteinuria than SCD patients of normal Fy phenotype and are consistent with such an hypothesis. Interpretation is likely also influenced by genetic differences of immune response and cytokine genes in African populations compared with other world populations, 93,94 but the genetic backgrounds of SCD patients with normal and Fy(aϪbϪ) phenotype may be sufficiently comparable to allow conclusions regarding alloimmunization and the role of Fy to be drawn.…”

Section: Org Frommentioning

confidence: 70%

The relationship between blood groups and disease

Anstee

2010

Blood

384

349

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The relative contribution of founder effects and natural selection to the observed distribution of human blood groups has been debated since blood group frequencies were shown to differ between populations almost a century ago. Advances in our understanding of the migration patterns of early humans from Africa to populate the rest of the world obtained through the use of Y chromosome and mtDNA markers do much to inform this debate. There are clear examples of protection against infectious diseases from inheritance of polymorphisms in genes encoding and regulating the expression of ABH and Lewis antigens in bodily secretions particularly in respect of Helicobacter pylori, norovirus, and cholera infections. However, available evidence suggests surviving malaria is the most significant selective force affecting the expression of blood groups. IntroductionHirszfeld and Hirszfeld 1 showed the frequencies of blood groups A and B differ between populations. Their observations raised fundamental questions regarding the causes of these differences, which were eloquently summarized by Mourant et al 2(p1) :Were the differences the result of random genetic drift and founder effects, in small populations which later multiplied and stabilized the original, fortuitous, frequencies, or were they the result of natural selection, arising from differences in fitness between the various blood groups, fitnesses which themselves depended upon locally determined features of the external environment?Mourant et al concluded that "most workers now agree that both processes are operative, but their relative importance remains in question." 2 We now have detailed information concerning almost all the genes giving rise to blood group polymorphisms, the structure of the gene products and the antigens themselves, and in many cases functional information sufficient to delineate mechanisms of interaction with external agents. [3][4][5] In addition, studies on the tracking of Y chromosome and mtDNA haplotypes in human populations provide us with unprecedented information concerning the significance of genetic drift and founder effects in determining the genetic background of different world populations. 6 Given this new information, it seems an appropriate time to revisit these questions and ask whether we are any nearer understanding the relative importance of natural selection and founder effects in determining the distribution of human blood groups. Infectious diseases and selection for ABO blood group antigensThe molecular basis of the ABO blood group system was elucidated in 1990. 7 The gene encodes a glycosyltransferase, which transfers N-acetyl D-galactosamine (group A) or D-galactose (group B) to the nonreducing ends of glycans on glycoproteins and glycolipids. The group O phenotype results from inactivation of the A1 glycosyltransferase gene, and the nonreducing ends of the corresponding glycans in group O subjects express the blood group H antigen ( Figure 1A). The ABH antigens are not confined to red cells but are widely expressed i...

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Section: Org Frommentioning

confidence: 70%

The relationship between blood groups and disease

Anstee

2010

Blood

384

349

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“…Conflicting results have been reported regarding the clinical relevance of DARC erythroid expression in the pathophysiology of SCA (15,30,32,33); Schnog et al (32), and more recently Nebor et al (15) failed to detect any association between DARC erythroid expression and the clinical severity of SCA. In contrast, Afenyi-Annan et al (33) suggested an association between the lack of this receptor and kidney dysfunction.…”

Section: Discussionmentioning

confidence: 73%

“…In contrast, Afenyi-Annan et al (33) suggested an association between the lack of this receptor and kidney dysfunction. Based on these observations and on our results showing IL8/RANTES-induced ␣4␤1 clustering on Duffy-positive SRes, we conclude that the presence of DARC, which modulates inflammatory processes, may determine the extent of inflammation in response to hypoxia in SCA.…”

Section: Discussionmentioning

confidence: 96%

Activation State of α4β1 Integrin on Sickle Red Blood Cells Is Linked to the Duffy Antigen Receptor for Chemokines (DARC) Expression

Durpès

Hardy‐Dessources

Nemer

et al. 2011

Journal of Biological Chemistry

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In sickle cell anemia, reticulocytes express enhanced levels of ␣4␤1 integrin that interact mainly with vascular cell adhesion molecule-1 and fibronectin, promoting vaso-occlusion. These interactions are known to be highly sensitive to the inflammatory chemokine IL-8. The Duffy antigen receptor for chemokines (DARC) modulates the function of inflammatory processes. However, the link between ␣4␤1 activation by chemokines and DARC erythroid expression is not or poorly explored. Therefore, the capacity of ␣4␤1 to mediate Duffy-negative and Duffy-positive sickle reticulocyte (SRe) adhesion to immobilized vascular cell adhesion molecule-1 and fibronectin was evaluated. Using static adhesion assays, we found that, under basal conditions, Duffypositive SRe adhesion was 2-fold higher than that of Duffynegative SRes. Incubating the cells with IL-8 or RANTES (regulated on activation normal T cell expressed and secreted) increased Duffy-positive SRe adhesion only, whereas Mn 2؉ increased cell adhesion independently of the Duffy phenotype. Flow cytometry analyses performed with anti-␤1 and anti-␣4 antibodies, including a conformationsensitive one, in the presence or absence of IL-8, revealed that Duffy-positive and Duffy-negative SRes displayed similar erythroid ␣4␤1 expression levels, but with distinct activation states. IL-8 did not affect ␣4␤1 affinity in Duffy-positive SRes but induced its clustering as corroborated by immunofluorescence microscopy. Our results indicate that in Duffy-negative SRes ␣4␤1 integrin is constitutively expressed in a low affinity state, whereas in Duffy-positive SRes ␣4␤1 is expressed in a higher chemokine-sensitive affinity state. This activation state associated with DARC RBC expression may influence the intensity of the inflammatory responses encountered in sickle cell anemia and participate in its interindividual clinical expression variability.␣4␤1 (CD49d/CD29, VLA4), the only integrin expressed on young SRes, 3 is a multifunctional adhesion protein mediating cell attachment via different ligands, the majors being VCAM-1 and FN (1, 2). In addition to reduced deformability of sickle erythrocytes, increased red cell adhesion to endothelium has been reported (3, 4). This abnormal adhesion may profoundly influence vaso-occlusive crises, by favoring cell contacts with the microvascular and venular endothelium via the ␣4␤1/VCAM-1 and/or the ␣4␤1/FN interactions (2, 5-7). As demonstrated previously, these interactions are highly sensitive to the inflammatory chemokine IL-8 in SCA (6, 7) as in other situations (8). In addition, the implication of IL-8 in the severity of vaso-occlusive episodes has been demonstrated (9). Together, these data suggest the importance of IL-8 in vasoocclusive crises through ␣4␤1 activation (5-7, 9, 10).Red blood cells (RBCs) express the Duffy blood group antigens (Fy) (11) carried by a glycoprotein identified as the Duffy antigen receptor for chemokines (DARC) of both the CC and the CXC classes, including . Four major Duffy phenotypes are serologically identified: Fy ...

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“…Provision of Duffy antigen by transfusion may attenuate the inflammatory response associated with ACS by binding chemokines, notably IL-8, via the Duffy antigen receptor for chemokines. 85,86 Duffy antigen is both an inflammatory modulator and the entry portal to the red cell by malarial parasites. 87 The latter role has made Duffy antigen positivity extremely rare in West Africa; approximately 70% of African Americans are Duffy antigen negative.…”

Section: Blood Is Thicker Than Water (Proverb)mentioning

confidence: 99%

“…87 The latter role has made Duffy antigen positivity extremely rare in West Africa; approximately 70% of African Americans are Duffy antigen negative. 86 White patients, who in most U.S. centers constitute the majority of blood donors, generally are positive for FYa and/or FYb, 86 and it is speculated that transfusion of Duffy-positive blood may favorably attenuate the course of ACS by its impact on chemokines. 85 Although no supportive clinical data are yet available, extended cross-matching to exclude Duffy incompatibility may be counterproductive, at least regarding treatment of ACS.…”

Section: Blood Is Thicker Than Water (Proverb)mentioning

confidence: 99%

How I treat acute chest syndrome in children with sickle cell disease

Miller

2011

Blood

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IntroductionAcute chest syndrome is (ACS) the second most common cause of hospitalization and challenges infection 1 as the leading cause of sickle cell-related mortality 2 in children. Still, management is largely determined by the experience of individual practitioners, and there are no conclusive randomized controlled clinical trials to guide therapy. What follows is a review of treatment options and related issues to assist in management; it will likely be especially useful to those who do not regularly encounter children with this potentially life-threatening complication.What is in a name? That which we call a rose by any other name would smell as sweet. (William Shakespeare)ACS is the term used to describe a new pulmonary infiltrate with respiratory findings in a person with sickle cell disease. 3 The etiology of these episodes is often multifactorial and difficult to discern. Although children may be more likely to have infectious etiologies for their chest syndrome and adults more likely sickle cell-related causes, 4,5 infection and inflammation may well induce sickling, and embolism/infarction may lead to superimposed infection. This is perhaps best illustrated by the fact that 2 common causes of ACS, Chlamydia pneumoniae and Mycoplasma pneumoniae, are associated with a severe clinical course in children with sickle cell disease 6-9 rather than the "walking pneumonia" that typifies infection in others. It thus makes no sense to try to differentiate between "pneumonia" and ACS.Chance is a word that does not make sense. Nothing happens without a cause. (Voltaire)The investigators of a multicenter National Acute Chest Syndrome Study (NACSS) 4 published in 2000 made aggressive attempts to identify etiology, including the performance of bronchoalveolar lavage (BAL) on consenting study enrollees; 72% of the 671 enrolled in the study had a lavage or sputum sample available. Despite these efforts, the authors only established potential causation in 38% overall and 70% of those with a complete assessment.The most common identifiable cause of ACS in this study was pulmonary fat embolism (PFE). 4 Originally described in trauma victims, PFE is a frequent complication of bone fracture and may progress to involve the lungs and CNS with multiorgan failure and death. 10,11 The NACSS made the diagnosis by using BAL to identify fat-laden macrophages; less-invasive means of making the diagnosis are not well established, and even the specificity of fat-laden macrophages in BAL specimens has been questioned. 12 Vichinsky et al, 13 in the first systematic, prospective search for PFE in sickle cell disease, found that 44% of patients with moderate-tosevere ACS had PFE as a probable etiology. These patients had longer, more severe hospital courses and a greater decrease in hemoglobin concentration and platelet count than those without fat emboli. Fat from bone marrow, which is typically infarcted during acute pain episodes, 14 embolizes to the lungs and, in its most extreme form, fat embolism syndrome may involve the brain, k...

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Lack of Duffy antigen expression is associated with organ damage in patients with sickle cell disease

Abstract: Duffy genotype may be a potential biomarker for the development of end-organ damage in SCD, particularly kidney dysfunction. The association of both WBC counts and hydroxyurea use with Duffy expression provides another avenue for investigation of the biologic role of this protein.

Cited by 69 publications

References 49 publications

The relationship between blood groups and disease

The relationship between blood groups and disease

Activation State of α4β1 Integrin on Sickle Red Blood Cells Is Linked to the Duffy Antigen Receptor for Chemokines (DARC) Expression

How I treat acute chest syndrome in children with sickle cell disease

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