Sickle cell disease: old discoveries, new concepts, and future promise

Abstract

The discovery of the molecular basis of sickle cell disease was an important landmark in molecular medicine. The modern tools of molecular and cellular biology have refined our understanding of its pathophysiology and facilitated the development of new therapies. In this review, we discuss some of the important advances in this field and the impediments that limit the impact of these advances.

Figure 1. Sickle erythrocytes.

Peripheral blood smear from a patient with SCD obtained during a routine clinic visit. The smear shows classical sickle-shaped (arrows) and various other misshaped erythrocytes (arrowheads). The image was obtained from an air-dried smear using differential interference contrast (DIC) microscopy with an Olympus BX61WI work station equipped with a LUMPlanFI ×60 numerical aperture 0.90 ∞ objective (Olympus) and a CoolSnap HQ camera (6.6 μm² pixel, 1,392 × 1,040 pixel format) (Roper Scientific). Scale bar: 10 μm.

Figure 2. Chromosomal organization of the α- and β-globin gene clusters.

(A) The genes of the β-globin gene cluster (ε, Gγ, Aγ, δ, and β) are present on chromosome 11 in the same order in which they are expressed during development. The β–locus control region (β–LCR) is a major regulatory element located far upstream of the genes of the cluster that is necessary for the high level of expression of those genes. (B) The genes of the α-globin gene cluster (ζ, α₁, and α₂) are present on chromosome 16, also in the same order in which they are expressed during development. HS-40 is a major regulatory element located far upstream of the genes of the cluster that is necessary for their high level of expression. (C) During fetal life, Hb F (α₂γ₂) is the predominant type of hemoglobin. Hemoglobin switching refers to the developmental process that leads to the silencing of γ-globin gene expression and the reciprocal activation of adult β-globin gene expression. This results in the replacement of Hb F by Hb A (α₂β₂) as the predominant type of hemoglobin in adult life. Figure modified from ref. .

Figure 3. Alteration of the rbc membrane by polymers of sickle hemoglobin.

Deoxygenation of Hb S induces a change in conformation in which the mutant β chain binds to a complementary hydrophobic site resulting from a valine replacement, leading to the formation of a hemoglobin polymer (Hb polymer; lower right, inset). The hemoglobin polymers disrupt the rbc cytoskeleton and form protrusions, giving rise to the characteristic sickle appearance. Interruption of the attachment of the membrane to the protein cytoskeleton results in exposure of transmembrane protein epitopes and lipid exchanges, notably of phosphatidylserine (PS), between the inside and the outside of the cell (upper right, inset). Exposure of negatively charged glycolipids contributes to the proinflammatory and prothrombotic state of sickle cell blood. Adapted with permission from Blackwell Publishing (129).

Figure 4. Sickle cell vasoocclusion.

Abnormal, sickle rbc induce the expression of inflammatory and coagulation mediators, leading to the activation of the vascular endothelium. Sickle rbc themselves may also stimulate endothelial cells directly by adhesion. The stimulated endothelial cells are poised to recruit rolling and adherent leukocytes in venules by expressing chemokines and cell adhesion molecules such as the selectins and immunoglobulin family members. Activated, firmly adherent neutrophils capture circulating discoid and sickle-shaped rbc, leading to transient episodes of vascular occlusions that are initiated in the smallest postcapillary venules. Interactions between rbc and leukocytes tend to occur at vessel junctions, where leukocyte recruitment is the most active. In sickle mice, vasoocclusion can be prevented by the inhibition of leukocyte adhesion or the inflammatory response. The large arrow indicates the direction of blood flow.