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Chapter 113 Human Leukocyte Antigen and Human Neutrophil Antigen Systems 1735

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chemotactic peptide F-met-leu-phe. The administration of G-CSF HNA-4 AND HNA-5 ANTIGEN SYSTEMS
to healthy patients for several days increases the proportion of neu-
trophils expressing HNA-2 to near 90%. 244 HNA-4 and HNA-5 antigens are located in the β 2-integrins. Each
antigen system contains only a single antigen, HNA-4a and HNA-5a,
respectively. HNA-4a antigen was previously known as Mart(a).
CD177 Glycoprotein Biochemistry HNA-4a has a phenotype frequency of 99.1% in white patients.
HNA-4a has been located on the αM chain (CD11b) of the C3bi
The glycoprotein carrying HNA-2a, CD177, was previously known receptor (CR3) and is caused by a single nucleotide substitution of
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as the NB1 glycoprotein. It is located on neutrophil plasma mem- G to A at position 302 of the gene ITGAM. The substitution is
branes and secondary granules 240,245 and is linked to the plasma predicted to result in an arginine to histidine polymorphism at amino
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membrane via a GPI anchor. Although some GPI-anchored pro- acid 61.
teins are shed by F-met-leu-phe–treated neutrophils, CD177 is not, A second polymorphism of the β 2 -integrins, HNA-5a, was first
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nor is soluble CD177 glycoprotein present in plasma. The molecu- described as Ond(a). HNA-5a was found to be expressed on the αL
lar weight of CD177 is 58 to 64 kDa, and it contains N-linked integrin unit, leukocyte function-associated antigen-1 (LFA-1)
carbohydrate side chains. 240,245 (CD11a), and is caused by a G to C single nucleotide substitution
at position 2446 of the gene ITGAL. This change predicts an amino
acid change of arginine to threonine at amino acid 766. 260
Molecular Biology
The gene encoding CD177 is located on chromosome 19q13.31, and
its coding region consists of 1311 base pairs that code for a protein CLINICAL SIGNIFICANCE OF ANTIBODIES
of 416 and a signal peptide of 21 amino acids. 246,247 The predicted TO NEUTROPHIL ANTIGENS
protein has two cysteine-rich domains, three potential N-linked
glycosylation sites, and a potential ω-site for attachment of the GPI Alloimmune Neonatal Neutropenia
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anchor. This gene belongs to the Ly-6 snake toxin superfamily.
Other genes in this family include urokinase-type plasminogen During pregnancy, mothers can become alloimmunized to neutrophil
activator receptor (uPAR; CD87) and decay-accelerating factor antigens. Maternal IgG directed to neutrophils can cross the placenta
(CD59). and destroy the neonate’s neutrophils. Maternal alloimmunization to
neutrophil antigens can occur in utero and affect the first child. Most
neonates experience isolated neutropenia, but the cytopenias are
Polymorphisms self-limiting and resolve as the antibody is cleared. The alloimmu-
nized mothers produce and carry the antibodies; but the antibodies
HNA-2 is expressed in neutrophils by approximately 97% of whites, do not react with the mother’s blood cells or tissues, and they have
95% of African Americans, and 89% to 99% of Japanese. 241,248–250 normal neutrophil counts. Antibodies to neutrophil-specific antigens
HNA-2–negative neutrophil phenotype is caused by a CD177 HNA-1a, HNA-1b, and HNA-2 most commonly cause neonatal
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transcription defect. HNA-2 genes from two women with alloimmune neutropenia (Table 113.6). 255,261 Antibodies to HNA-1c
HNA-2–negative neutrophils who produced HNA-2a–specific allo- and HNA-3a rarely cause alloimmune neonatal neutropenia. Mothers
antibodies have been studied, and CD177 complementary DNA with FcγRIIIb deficiency have produced FcγRIIIb-specific antibodies
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(cDNA) sequences were present in both women. The HNA-2– that caused neonatal neutropenia. 233,255,261
negative phenotype was the result of different off-frame insertions at Newborns with alloimmune neutropenia are usually asymptom-
the RNA level, resulting in CD177 glycoprotein deficiency in atic. Most often, the neutropenia is detected in the first week of life
neutrophils. 251 when the neonate becomes febrile or develops an infection and a
neutrophil count is performed. Typically the counts are 0.100 to
9
0.200 × 10 /L. Some neonates have normal neutrophil counts the
Clinical Relevance of HNA-2 Antigens first day of life, but they become neutropenic on their second day.
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White blood cell count, platelet count, and hemoglobin level are
The rare women who produce HNA-2–specific alloantibodies and usually normal; but eosinophilia or monocytosis may be present. If
who lack NB1 glycoprotein are healthy. The expression of HNA-2 a bone marrow biopsy is performed, it often shows normal numbers
is reduced in neutrophils from people with paroxysmal nocturnal of erythroid progenitors and megakaryocytes with hyperplasia of
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hemoglobinuria and chronic myelogenous leukemia, but it is myeloid progenitors.
unknown whether this has any clinical significance. CD177 mRNA
is overexpressed by neutrophils from patients with polycythemia
rubra vera and essential thrombocytosis. 252,253 The role of CD177
in neutrophil function is unknown. In some studies HNA-2
may have a role in the adhesion of neutrophils to endothelial TABLE Specificities of Antibodies in Alloimmune Neonatal
cells. 254 113.6 Neutropenia
Antigen N = 18 211 (%) N = 48 253 (%)
HNA-3 ANTIGEN SYSTEMS HNA-1a 28 10
HNA-1b 22 8
The HNA-3 antigen system has one antigen, HNA-3a, which was
previously known as 5b. HNA-3a is expressed by neutrophils, lym- FcγRIIIb 0 8
phocytes, platelets, endothelial cells, kidney, spleen, and placental HNA-2a 11 2
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cells. HNA-3a has a gene frequency of 0.66. HNA-3a is located HNA-3a 0 2
on the Choline Transporter-like protein-2 (CTL-2) and is encoded
by SLC44A2. The HNA-3a phenotype is due to a nucleotide poly- Unknown 0 15
morphism that results in an arginine rather than a glutamine at HLA class I 251 11 54
position 154 of CTL-2. 256,257 Several cases of transfusion-related acute Negative 28 38
lung injury (TRALI) have been associated with transfusion of plasma HLA, Human leukocyte antigen; HNA, human neutrophil antigen.
containing anti-HNA-3a. 258,259