CHAPTER 137 HUMAN LEUKOCYTE AND PLATELET ANTIGENS

Question 1

Two major classes of HLA and their examples

Answer 1

class I (A, B, and C loci)
class II (DR, DQ, and DP loci)

Question 2

primarily expressed on B cells and other antigen-presenting cells such as dendritic cells, endothelial cells, and monocytes

Answer 2

class II (DR, DQ, and DP loci)

Question 3

human leukocyte antigens play key roles in: (3)

Answer 3

1) HSC transplantation acceptance/ rejection

2) allosensitization to non-leukoreduced blood transfusions leading to platelet transfusion refractoriness,

3) lesser, in solid- organ transplantation

Question 4

HLA are highly polymorphic glycoproteins encoded by a region of genes known as the major histocompatibility complex (MHC) located on

Answer 4

chromosome 6p21

Question 5

T/F: After ABO antigens, HLA antigens are the major barrier to transplantation.

Answer 5

True

Question 6

Are ubiquitous and present on most nucleated somatic cells

Answer 6

Class I antigens

Question 7

Exhibit more restricted distribution, with varying levels of expression on B cells, dendritic cells, monocytes, macrophages, and endothelial cells.

Answer 7

Class II antigens

Question 8

T/F: class II antigens can be induced on many cell types through activation.

Answer 8

True

Question 9

nonclassical class Ib antigens
- much less polymorphic
- function less understood

Answer 9

HLA-E, HLA-F, and HLA-G

Question 10

Antibodies recognizing platelet-specific alloantigens have been discovered in three clinical situations:

Answer 10

1. mothers who give birth to infants with FNAIT;
2. patients who develop dramatic thrombocytopenia after blood transfusion (PTP);
3. and patients who have received multiple transfusions.

Question 11

principal cause of immunologic platelet transfusion refractoriness

Answer 11

class I HLA antigens

Question 12

T/F: occasionally patients receiving multiple platelet transfusions will develop antibodies to platelet specific alloantigens.

Answer 12

True

Question 13

If platelet transfusion refractoriness does develop because of platelet- specific antibodies, compatible platelet products may be identified by: (2)

Answer 13

1) using either platelet crossmatching or
2) by accessing family member or other HPA-typed donors who are compatible with the patient’s antibodies

Question 14

T/F: Antibodies against some HPA-allelic determinants can inhibit platelet function.

Answer 14

True

Question 15

_____can inhibit clot retraction and platelet aggregation, presumably because they block the binding of GPIIb/IIIa (α β ) (CD41/CD61) to fibrinogen. –> identify the type of platelet function disease

Answer 15

• Anti–HPA-1 alloantibodies,
• GLANZMANN

Question 16

______, lack platelet GPIb-V-IX (CD 42a-c)

Answer 16

Bernard-Soulier syndrome

Question 17

_______ can completely inhibit aggregation of HPA-4 platelets that are homozygous for the allele recognized by the alloantibodies because the epitope is in close proximity to the RGD (arginine-glycine-aspartic acid peptide sequence)

Answer 17

Anti–HPA-4 alloantibodies

Question 18

T/F: other anti–HPA-alloantibodies, such as those specific for HPA-3, may not significantly interfere with platelet function but nonetheless can cause Fc-mediated platelet destruction and immune thrombocytopenia

Answer 18

TRUE

Question 19

result from transfusion of antibodies to recipient HPA

Answer 19

passive alloimmune thrombocytopenia

Question 20

Transfusion of blood components containing antibodies to ____ and _____ have been reported to result in significant thrombocytopenia for 1 to 2 weeks.

Answer 20

HPA-1a and -5b

Question 21

T/F: Many of the best-documented platelet-specific antibodies detected in such patients are directed against platelet antigens whose phenotypic frequencies are less than 30% in the blood-donor population.

Question 22

Matching Type:
1. Anti–HPA-1 alloantibodies
2. Anti–HPA-3 alloantibodies
3. Anti–HPA-4 alloantibodies
4. Anti–HPA-1a and 5b alloantibodies

a. inhibit aggregation of HPA-4 platelets that are homozygous for the allele recognized by the alloantibodies because the epitope is in close proximity to the RGD
b. result in significant thrombocytopenia for 1 to 2 weeks
c. can inhibit clot retraction and platelet aggregation, presumably because they block the binding of GPIIb/IIIa (α β ) (CD41/CD61)
d. can cause Fc-mediated platelet destruction and immune thrombocytopenia

Answer 22

1, c
2, d
3, a
4, b

Question 23

TESTING FOR PLATELET-SPECIFIC ANTIGENS AND ANTIBODIES

The earliest.
Involved mixing of patient serum with normal platelets and used platelet function-dependent end points such as α-granule release, aggregation, or agglutination.

Answer 23

Phase I

Question 24

TESTING FOR PLATELET-SPECIFIC ANTIGENS AND ANTIBODIES

the only major phase I assay remaining in wide use today

Answer 24

serotonin release assay

Question 25

TESTING FOR PLATELET-SPECIFIC ANTIGENS AND ANTIBODIES detect either surface or total platelet-associated immunoglobulin on patient platelets or on normal platelets after sensitization with patient serum

Answer 25

phase II tests

Question 26

TESTING FOR PLATELET-SPECIFIC ANTIGENS AND ANTIBODIES An example of a phase II assay in wide use today:

Answer 26

solid-phase red cell adherence test, used for platelet crossmatching

Question 27

TESTING FOR PLATELET-SPECIFIC ANTIGENS AND ANTIBODIES developed in which the binding of antibodies to isolated platelet surface GPs is detected.

Answer 27

Phase III assays

Question 28

TESTING FOR PLATELET-SPECIFIC ANTIGENS AND ANTIBODIES detect alloantibodies in the evaluation of suspected FNAIT and PTP, as well as autoantibodies in some cases of ITP

Answer 28

Phase III assays

Question 29

Examples of phase III assays (2)

Answer 29

1. monoclonal antibody immobilization of platelet antigens assay (MAIPA) 2. modified antigen capture ELISA (MACE)

Question 30

because of limited access to rare typing sera and the need to establish platelet typing in patients with very few platelets, they have been largely supplanted by _______

Answer 30

molecular typing using methods based on PCR

Question 31

Alleles present at gene frequencies greater than 2 percent within the population are designated as ____

Answer 31

public alleles

Question 32

These alleles are more likely to encode alloantigens involved in PTP.

Answer 32

public alleles

Question 33

HPA NOMENCLATURE _____ allele represents the more prevalent form of the protein, while the _____ allele represents the less-common form.

Answer 33

a, b

Question 34

HPA-lb is expressed on the platelets of approximately _____ percent of persons of European ancestry but of less than____ percent of persons of Asian ancestry

Answer 34

15, 1

Question 35

Type _____ CD36-deficient individuals can become immunized via transfusion or pregnancy and make isoantibodies against CD36 that have been implicated in cases of FNAIT, PTP, and platelet transfusion refractoriness.

Answer 35

I

Question 36

T/F CD36 deficiency is common in Asians and Africans, but is rare in white populations.

Answer 36

TRUE

Question 37

Platelet GPIV (CD36) is expressed on various human cells including (5)

Answer 37

platelets, macrophages, capillary endothelium, erythroblasts, and adipocytes

Question 38

Matching Type 1. ANN 2. AIN 3. TRALI a. anti–HNA-2 and anti–HNA-3a b. anti–HNA-1a, anti–HNA-1b and FcγRIIIb epitopes c. anti–HNA-1a, anti–HNA-1b, anti–HNA-2, anti-FcγRIIIb

Answer 38

1. c 2. b 3. a

Question 39

- neutropenia is detected in the first week of life when the neonate becomes febrile or develops an infection -neutrophil count are 0.1 to 0.2 × 109/L. - Total WBC , platelet count, and hemoglobin are usually normal, but eosinophilia or monocytosis may be present. - occasionally, infant is asymptomatic, but almost all affected 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 neutropenia is approximately 11 weeks.

Answer 39

Alloimmune Neonatal Neutropenia

Question 40

Pathophysiology of Alloimmune Neonatal Neutropenia

Answer 40

During pregnancy, mothers can become alloimmunized to fetal neutrophil antigens. Maternal IgG directed to neutrophils can cross the placenta and destroy the neonate’s neutrophils.

Question 41

T/F: (IVIG) and granulocyte colony-stimulating factor (G-CSF) have a limited role in the treatment of neonatal alloimmune neutropenia

Answer 41

TRUE

Question 42

In most cases, children presented with severe neutropenia, having neutrophil counts less than 0.5 × 109/L Monocytosis has been reported to occur in up to 38 percent of patients. Marrow biopsies in affected patients usually show normal to hypercellular marrow with a decreased number of mature neutrophils.

Answer 42

Autoimmune Neutropenia of Childhood

Question 43

In AIN, the onset of autoimmune neutropenia of children begins at ___months of age Most studies have found that neutrophil counts recover spontaneously by the age of ____ years, with a median duration of neutropenia of 13 to 20 months.

Answer 43

8, 5

Question 44

occurs within 6 hours of a transfusion when hypoxia and noncardiogenic pulmonary edema occur, as measured by a fall in hemoglobin oxygen saturation to less than 90 percent or a partial pressure of arterial oxygen (PaO2)-to-fraction of inspired oxygen (FIO2) ratio (PaO2:FIO2) of less than 300 torr

Answer 44

TRALI

Question 45

T/F Febrile nonhemolytic transfusion reactions occur within a few hours of a transfusion and can be associated with chills and rigors.

Answer 45

T

Question 46

Matching Type 1. are expressed only on neutrophils 2. expressed on neutrophils and subpopulations of neutrophils 3. neutrophils, lymphocytes, platelets, endothelial cells, kidney, spleen, and placental cells. a. HNA 2 b. HNA 1 c. HNA 3

Answer 46

1, b 2, a 3, c

Question 47

- previously known as Mart(a) - located on the αM chain (CD11b) of the C3bi receptor (CR3) - caused by a single nucleotide substitution of G-to-A at position 30283 (Arg->His 61) - significance unknown

Answer 47

HNA 4

Question 48

- first described as Ond(a) - ound to be expressed on the αL integrin unit, leukocyte function antigen-1 (CD11a), - result of a G-to-C single nucleotide substitution at position 2446 (Arg-> Thr at 766)

Answer 48

HNA 5

Question 49

result of a single nucleotide change in choline transporter-like protein-2 gene (SLC44A2) at nucleotide 455, which results in an amino acid change at position 152

Answer 49

HNA 3

Question 50

Role of NB1 Glycoprotein in Neutrophil Function (3)

Answer 50

binds to platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) and functions as a cell adhesion molecule. important in the migration of neutrophils through endothelial cells. involved with neutrophil–endothelial cell interaction

Question 51

T/F: CD177 mRNA is overexpressed by neutrophils from patients with polycythemia rubra vera and essential thrombocytosis, but the expression of HNA-2 is not.

Answer 51

TRUE

Question 52

gene encoding NB1 glycoprotein, ____, is located on chromosome ____

Answer 52

CD 177 19q13.31

Question 53

HNA 1 _____ of neutrophilic metamyelocytes, and on approximately ____ of neutrophilic myelocytes

Answer 53

one-half 10%

Question 54

T/F The four HNA-1 system antigens are encoded by three alleles.

Answer 54

True

Question 55

The antigen frequencies of three of the alleles vary widely among different racial groups. Among whites, _____ is the most common antigen, but in Japanese and Chinese populations ____ is most common.

Answer 55

HNA-1b HNA-1a

Question 56

Function of HNA-1 Antigens

Answer 56

Neutrophils that are homozygous for HNA-1b have a lower affinity for immunoglobulin (Ig) G3 than those homozygous for HNA-1a. Neutrophils from those who are homozygous for HNA-1b phagocytize erythrocytes sensitized with IgG1 and IgG3 anti-Rh monoclonal antibodies and bacteria opsonized with IgG1 at a lower level than neutrophils homozygous for HNA-1a.

Question 57

Patients requiring platelet transfusions may be broadly sensitized to _____ (i.e., have high PRA) through prior transfusions (particularly nonleukoreduced) or pregnancies.

Answer 57

HLA-A, and -B

Question 58

_____ ankylosing spondylitis _____ narcolepsy _____ associated with hypersensitivity to abacavir

Answer 58

HLA- B27 HLA-DQ2 HLA-B*5701

Question 59

The HLA antigens coded by the MHC play a central role in (3)

Answer 59

1. transplantation - most common application 2. regulation of immune responses, and 3. susceptibility to a variety of diseases.

Question 60

HLA typing for matching of kidneys and pancreas is performed at the ________ loci at low resolution (serologic or antigen level by DNA).

Answer 60

HLA-A, HLA-B, and HLA-DR

Question 61

T/F: HLA matching is not prospectively performed for hepatic or cardiac transplantation.

Answer 61

TRUE

Question 62

_____ and ______ prime importance for kidney and heart transplants where its existence could cause a hyperacute rejection and graft failure.

Answer 62

Detection of alloantibody by screening techniques and the donor specific crossmatch

Question 63

T/F In HSC, the graft may recognize the host tissue as foreign and mount an immune response resulting graft-versus-host disease (GVHD)

Answer 63

T

Question 64

HUMAN LEUKOCYTE ANTIGEN TYPING Tissue typing for HLA antigens can be performed by various methods using (3) technologies

Answer 64

serologic, cellular, and molecular

Question 65

common prior to the widespread adoption of DNA methods. are labor-intensive and require the use of radioisotopes; mainly used in research laboratories.

Answer 65

Cellular assays

Question 66

Cellular assays

Answer 66

mixed lymphocyte reaction and the primed lymphocyte test

Question 67

a suspension of lymphocytes is incubated with human alloantisera or monoclonal antibody in a microtiter tray.

Answer 67

CDC

Question 68

test has been a fundamental procedure for defining HLA antigens for more than 30 years

Answer 68

CDC

Question 69

Serology for class II (DR and DQ) antigens requires enrichment for B lymphocytes, which can be accomplished with antibody or _____

Answer 69

immunomagnetic bead reagents.

Question 70

involve amplification of genomic DNA from selected portions of HLA genes with oligonucleotide primer pairs

Answer 70

PCR

Question 71

primarily of clinical interest in marrow/blood stem cell transplantation.

Answer 71

Molecular HLA typing

Question 72

described as massively parallel allowing for many overlapping reads of the same sequence area

Answer 72

NGS

Question 73

This is very important for solid-organ transplantation where the presence of ______ can cause irreversible rejection upon transplantation.

Answer 73

detection of antibodies to HLA antigens.

Question 74

have become standard practice as they are more sensitive than the CDC method.

Answer 74

solid phase assays

Question 75

T/F The α chain of HLA-DR is constant for all HLA-DR molecules, whereas the β chain is polymorphic and determines specificity of the molecule.

Answer 75

T

Question 76

Class II molecules: extracellular regions of each chain contain only two domains. The two domains of the α chain are designated α1 and α2, and the two domains of the β-chain are called β1 and β2. In all class II antigens the______represents the most polymorphic region.

Answer 76

β1 domain

Question 77

Class I Antigens Antigenicity resides in the_____, the areas of highest polymorphism

Answer 77

α1 and α2 domains

Question 78

T/F Platelets express HLA-A antigens, but lack some HLA-B and most HLA-C antigens.

Answer 78

T

Question 79

Include genes that encode other proteins that participate in immune response such as complement, heat shock proteins, tumor necrosis factor, and other lymphocyte antigens.

Answer 79

class III genes

Question 80

Class____ genes are the most centromeric Telomeric are the class____ genes

Answer 80

II I