Page 1944 - Hematology_ Basic Principles and Practice ( PDFDrive )

1724 Part XI Transfusion Medicine

as macrophages and dendritic cells. HLA class II molecules are
assembled within the endosomal compartment where they are com-
posed of a heterotrimer. This includes the α- and β-chains plus a
short invariant chain that stabilizes the molecule by occupying its
groove while chaperoning its migration to the endosomal compart-
ment where exogenous antigen is processed. Upon uptake, the
exogenous antigen undergoes limited proteolysis in the membrane-
bound acidic endosomal compartment (MHC class II peptide-loading
compartment, MIIC). Upon entering the MIIC, the pre-HLA class
II complex is degraded, and antigenic peptides are loaded with the
help of the nonclassic HLA-DM molecule. 37

EXPRESSION OF HUMAN LEUKOCYTE
ANTIGEN MOLECULES

There are genetic and structural differences between the two classes
of HLA alleles. The most striking difference is functional, because
HLA class I molecules are expressed by most nucleated cells with the
N exception of germinal cells, whereas HLA class II molecules are
expressed mainly by specialized antigen-presenting cells. 38,39 HLA
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class I molecules are also expressed by platelets. They are responsible
for refractoriness after multiple transfusions and sufficiently, though
Fig. 113.5 SCHEME OF THE PEPTIDE GROOVE OF A HUMAN minimally, expressed by reticulocytes to be targets of alloantibodies
LEUKOCYTE ANTIGEN (HLA) CLASS I MOLECULE, FORMED BY during hemolytic transfusion reactions. 41–45 HLA class II proteins are
THE α 1 AND α 2 DOMAINS AT THE SIDE AND THE β-SHEETS AT expressed constitutively by cells associated with the initiation of the
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THE BOTTOM. The view is looking down on the vertically oriented immune response, such as monocytes, macrophages, and B cells, or
molecule: the T-cell receptor point of view. (From Bjorkman PJ, Saper MA, by immune cells activated by cytokines during inflammation. Thus
Samraoui B, et al: Structure of the human class I histocompatibility antigen, HLA-A2. HLA class I molecules instruct the host about the condition of
+
Nature 329:506, 1987.) individual cells as potential targets for CD8 cytotoxic T cells respon-
sible for clearing the organisms of altered cells. HLA class II molecules
initiate immune responses by taking up pathogen components and
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Beyond the interactive component of the HLA molecule with presenting them to CD4 helper T cells, which can in turn initiate
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TCR, other domains act as coreceptors for the TCR. CD8 cytotoxic humoral and facilitate cellular immune responses.
T cells bind to the α 3 -domain of HLA class I through CD8, whereas Expression of HLA alleles is sensitive to environmental condi-
+
CD4 T cells interact with HLA class II-specific domains. Although tions and can be modulated by cytokines among which interferons
47
the coreceptor-TCR interaction is not an absolute requirement in play a major role. This is particularly important for HLA-B and
most cases, it determines HLA class I or II restriction of individual HLA-C normally expressed at a lower density than HLA-A, but
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T cells. Specific to HLA class I is the assembly with β 2 -microglobulin are more sensitive to cytokine induction. 48,49 In addition, HLA
on stabilization in the presence of high-affinity peptides derived from class II molecules can be expressed by most cells following cyto-
the cleavage of intracellular proteins (endogenous pathway of antigen kine stimulation. 50,51 Thus the ability of cells to present antigen in
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presentation). Most peptides derive from degradation of self-protein association with HLA is strongly influenced by the surrounding
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in the cytosol by proteasomes (PSMB) and other proteases. Soluble environment. This might explain why chronic inflammation induced
peptides (9 to 10 amino acids long) are then chaperoned into the by alloreactions during graft-versus-host disease (GVHD) may
endosomal compartment by transporter molecules associated with facilitate the presentation of tumor-specific antigens by tumor cells
antigen processing (TAP1 and TAP2). Within this compartment, with consequent development of GVN effect. In addition, it might
they bind to heavy chains according to each individual’s HLA phe- explain how systemic administration of proinflammatory cytokines
notype. The binding and stability of the HLA-peptide complex such as interleukin (IL)-2 may stimulate immune responses by
depends on the affinity of each peptide for a particular allele. If the increasing the antigen-presenting ability of cells within the tumor
stability is sufficient, the peptide-loaded HLA migrates to the cell microenvironment. 52
surface. Intracellular pathogens produce proteins that are also
degraded by proteasomes into peptides that compete with self-
peptides for binding to HLA class I molecules. Thus the function of HUMAN LEUKOCYTE ANTIGEN POLYMORPHISM
the endogenous pathway of antigen presentation is to provide infor- AND ITS CLINICAL SIGNIFICANCE
mation to the extracellular compartment of intracellular events. In
physiologic conditions, only self-peptides are presented, and therefore A striking characteristic of the HLA system is its extreme polymor-
53
minimal interactions occur with circulating T cells. During infection, phism. By chance, most individuals are heterozygote and therefore
pathogen-derived peptides signal cellular infection to T cells, whereas carry two different alleles for each HLA gene that, being codominant,
antibodies that cannot cross the cell membrane remain insensitive to are equally expressed on the cell surface. Because everybody carries
intracellular pathogens. Several pathogens, such as cytomegalovirus three HLA class I (-A,-B, and -C) and three HLA class II (-DR, -DQ,
(CMV), can interfere with this process as well as with reduction of and -DP) genes, most individuals (with the exception of homozy-
HLA/peptide density on the cell surface and, consequently, dimin- gotes) express six different HLA class I and six different HLA class
ished T-cell recognition. 31,32 This escape mechanism can be counter- II molecules on the surface of their cells. This has important func-
acted by the host through increased susceptibility of virally infected tional implications, because HLA polymorphism is clustered in
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cells to NK cell-mediated cytolysis. Reciprocally, viruses can evade domains of the HLA molecule associated with peptide binding and
NK cells and escape recognition by modulating HLA expression. 34–36 interaction with the TCR. Thus most individuals have a broad rep-
HLA class II molecules bind to longer peptides derived from the ertoire of molecules capable of presenting different pathogen compo-
metabolism of molecules endocytosed from the extracellular com- nents to immune cells leading to the belief that HLA polymorphism
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partment (exogenous pathway of antigen presentation). This is a improves the chances of a given species of surviving infection. This
specialized process used by professional antigen-presenting cells such paradigm is difficult to demonstrate in human pathologic conditions