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2358 Part XIII: Transfusion Medicine Chapter 137: Human Leukocyte and Platelet Antigens 2359

65 percent 60–62 and is dependent on gender. The size of the HNA-2 posi- women with anti–HNA-4a showed evidence of neonatal alloimmune
tive subpopulation of neutrophils from women is approximately 60 per- neutropenia.
cent, compared with approximately 50 percent for men. 62,63 Neutrophil A second polymorphism of the β integrins, HNA-5a, was first
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expression of HNA-2 is greater in pregnant women than in healthy described as Ond(a). A chronically transfused man with aplastic anemia
female blood donors. 64 became alloimmunized to HNA-5a. HNA-5a was found to be expressed
on the α integrin unit, leukocyte function antigen-1 (CD11a), and
L
HNA-2 Molecular Biology is a result of a G-to-C single nucleotide substitution at position 2446
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The glycoprotein carrying HNA-2, NB1 glycoprotein, is located on neu- that results in a change of Arg to Thr at amino acid 766. The antigen
trophil plasma membranes and secondary granules 60,64 and is a GPI- frequency of HNA-5a is 78 to 96 percent. 81,82,84
anchored glycoprotein. The gene encoding NB1 glycoprotein, CD177, is
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located on chromosome 19q13.31 65,66 and belongs to the Ly-6 snake toxin ANTIBODIES TO NEUTROPHIL ANTIGENS
superfamily. Other genes in this family include urokinase-type plasmino-
gen activator receptor (CD87) and decay accelerating factor (CD59). Alloimmune Neonatal Neutropenia
HNA-2 is expressed on neutrophils by approximately 95 to 97 per- Neutrophil antibody tests are performed by agglutination or fluores-
cent of whites, 95 percent of African Americans, and 89 to 99 percent cent techniques, and these are not widely available because clinical
of Japanese. 62,67,68 SNPs have been identified in CD177. These SNPs have syndromes caused by these antibodies are uncommon. A commercial
been associated with the size of the HNA-2–positive population of neu- solid-phase assay that allows for the detection of antibodies directed
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trophils, but not the HNA-2–negative phenotype. The HNA-2–negative to HNA-1, HNA-2, HNA-3, HNA-4, and HNA-5 antigens is now avail-
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neutrophil phenotype is the result of a CD177 transcription defect. 70 able. During pregnancy, mothers can become alloimmunized to fetal
neutrophil antigens. Maternal IgG directed to neutrophils can cross the
Role of NB1 Glycoprotein in Neutrophil Function placenta and destroy the neonate’s neutrophils. Maternal alloimmuni-
NB1 glycoprotein binds to platelet endothelial cell adhesion molecule-1 zation to neutrophil antigens can affect the first child. Most neonates
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(PECAM-1, CD31) and functions as a cell adhesion molecule. experience isolated neutropenia, but the cytopenias are self-limit-
PECAM-1 is expressed on both neutrophils and endothelial cells and ing and resolve as the antibody is cleared. Antibodies to neutrophil-
PECAM-1–PECAM-1 interactions are important in the migration of specific antigens HNA-1a, HNA-1b, and HNA-2 most commonly cause
neutrophils through endothelial cells. Interactions between NB1 glyco- neonatal alloimmune neutropenia. 74,86 Mothers with FcγRIIIb defi-
protein and PECAM-1 are also involved with neutrophil–endothelial ciency have also produced antibodies to FcγRIIIb, causing neonatal
cell interactions, and mediate neutrophil transendothelial cell migra- neutropenia. 55,74,86
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tion. However, women who produce HNA-2 specific alloantibodies Most often the neutropenia is detected in the first week of life when
and who lack NB1 glycoprotein are healthy. the neonate becomes febrile or develops an infection and a neutrophil
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CD177 mRNA is overexpressed by neutrophils from patients with count is done. Typically, the counts are 0.1 to 0.2 × 10 /L. Total white
polycythemia rubra vera and essential thrombocytosis, but the expres- blood cell count, platelet count, and hemoglobin are usually normal, but
sion of HNA-2 is not. 72,73 The increased expression of CD177 mRNA in eosinophilia or monocytosis may be present. The clinical course is quite
neutrophils from these patients may be secondary to the constitutive variable. An occasional infant is asymptomatic, but almost all affected
activation of Janus kinase 2 (JAK2) by JAK2 V617F. children have an infection. The duration of the neutropenia may be
as short as a few days or as long as 28 weeks. The mean duration of
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neutropenia is approximately 11 weeks. Intravenous immunoglobulin
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THE HNA-3 ANTIGEN SYSTEM (IVIG) and granulocyte colony-stimulating factor (G-CSF) have a lim-
The HNA-3 antigen system has one antigen, HNA-3a, that was pre- ited role in the treatment of neonatal alloimmune neutropenia. 86
viously known as 5b. HNA-3a is expressed by neutrophils, lympho-
cytes, platelets, endothelial cells, kidney, spleen, and placental cells. Autoimmune Neutropenia of Childhood
HNA-3a has an antigen frequency of 89 to 92 percent and is located Autoimmune neutropenia is well described in children. 87–90 Typically,
on a 70- to 95-kDa neutrophil glycoprotein. HNA-3a is a result of a the onset of the autoimmune neutropenia of children begins at 8 months
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single nucleotide change in choline transporter-like protein-2 gene of age, but children between 1 and 36 months of age can be affected.
(SLC44A2) at nucleotide 455, which results in an amino acid change at Most studies have found that neutrophil counts recover spontaneously
position 152. 75,76 Several cases of transfusion-related acute lung injury by the age of 5 years, with a median duration of neutropenia of 13 to 20
(TRALI) have been associated with transfusion of plasma containing months. 87–90 In most cases, children presented with severe neutropenia,
anti–HNA-3a. 77–79 having neutrophil counts less than 0.5 × 10 /L. Monocytosis has been
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reported to occur in up to 38 percent of patients. Marrow biopsies in
affected patients usually show normal to hypercellular marrow with a
THE HNA-4 AND HNA-5 ANTIGEN SYSTEMS decreased number of mature neutrophils.
The HNA-4 and HNA-5 antigens are located on the β integrins. Each Antibodies to neutrophils can be detected in up to 98 percent of
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antigen system contains only a single antigen, HNA-4a and HNA-5a, affected patients. If an antibody specificity is identified, the antibodies
respectively. The HNA-4a antigen was previously known as Mart(a). are almost always specific to epitopes located on FcγRIIIb. The antibod-
HNA-4a was defined by an antibody in the sera of three nontrans- ies are directed to HNA-1a in 10 to 46 percent of patients, to HNA-1b
fused multiparous blood donors. This antigen has an autosomal dom- in 2 to 3 percent of patients, and rarely to FcγRIIIb epitopes expressed
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inant inheritance and an antigen frequency of 99 percent in whites by neutrophils from all donors. 88–89 Autoimmune neutropenia has been
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and Asians, and 97 percent in Brazilians. HNA-4a is located on the treated with glucocorticoids, IVIG, and G-CSF. 88
α chain (CD11b) of the C3bi receptor (CR3) and is caused by a sin-
M
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gle nucleotide substitution of G-to-A at position 302 that results in Transfusion Reactions
an Arg-to-His polymorphism at amino acid 61. The significance of the Antibodies to neutrophil and HLA antigens in transfused blood can
antibody is not known, and none of the infants of the three multiparous cause febrile nonhemolytic reactions. Febrile nonhemolytic transfusion

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