Page 1945 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 113 Human Leukocyte Antigen and Human Neutrophil Antigen Systems 1725

in which the natural history of infectious diseases rarely correlates (CD1), transport of immunoglobulins (Fc receptor), and regulation
69
with HLA phenotype. An exception is the strong association between of iron metabolism (hemochromatosis gene product). Contrary to
HLA-B*5701 and lack of progression to acquired immunodeficiency classic MHC class I genes that are constitutively expressed, nonclassic
syndrome of individuals infected with human immunodeficiency MHC and MIC gene expression is dependent on stimulation by
55
70
virus (HIV). Associations have been observed between HLA phe- proinflammatory cytokines. In addition, two nonclassic MHC class
notype and predisposition for nasopharyngeal carcinoma. 56,57 This is II proteins (HLA-DM and HLA-DO) have been described as media-
of particular interest because nasopharyngeal carcinoma is a virally tors of peptide exchange by stabilizing empty MHC class II mol-
37
induced cancer against which T cells can mediate immune surveil- ecules. Finally, it is possible that several nonclassic MHC molecules
lance. HLA associations have also been described with less consistency whose function is to present peptides to lymphocytes may be present
58
than other virally driven tumors, such as cervical carcinoma, or throughout the genome. Because of their limited polymorphism,
immunogenic tumors, such as melanoma. 59,60 however, these genes may have evolved to serve specialized presenta-
The difficulty in demonstrating conclusive associations between tion functions. 71
infectious disease and HLA in humans could be caused by the suc- Characterized by low polymorphism, the regulation of HLA-G
cessful implementation of antigen presentation through a broad expression follows a nonclassic behavior. Aberrant cytokine-responsive
repertoire of HLA genes that could compensate for each other in regulatory sequences may be responsible for its predominant expres-
limitations in antigen presentation. Chickens carry a single MHC sion by trophoblasts that do not express other HLA proteins. 72–75 It
76
locus, and their susceptibility to infection appears to be clearly related may also account for its low levels in a variety of human tissues.
54
to MHC. For instance, Kaufman et al have shown that chickens Lack of responsiveness to common immunostimulatory pathways
carrying a particular Bf (the only MHC class I gene in chickens) allele (NF-κB, interferon-γ, or CIITA) is most pronounced in HLA-G cells
77
are fully protected from Rous virus-induced sarcomas, because this and is shared by other nonclassic MHC such as HLA-E. Also,
72
allele (B-f12) can bind several antigenic peptides from its proteins. HLA-G is expressed in a variety of cancers. It is hard to know what
On the contrary, chickens homozygous for B-f4 are killed by the same the relevance of HLA-G expression is, because it can occur in various
infection, because this allele cannot bind peptides from sarcoma virus membrane-bound or soluble isoforms with distinct functional char-
72
proteins. 54 acteristics. Functional isoforms that include the α-1 and α-2
78
HLA polymorphism is the basis of alloimmunization because domains bind and present peptides from cytoplasmic proteins.
most individuals are likely to have different HLA molecules on the Because of the minimal polymorphism, however, the repertoire of
surface of their cells. Hundreds of HLA alleles have been identified peptides presented is likely to be limited, suggesting that peptide
through high-resolution typing, making the chances of two individu- binding is necessary to stabilize the molecule rather than being
als having identical HLA phenotypes extremely low. Thus partial involved in antigen presentation.
mismatches are commonly accepted in transplantation cases and are Functionally, HLA-G is thought to modulate the function of NK
79
at the root of hyperacute, acute, and chronic rejections. Hyperacute cells through interactions with their inhibitory receptors. In addi-
rejection is caused by preformed antibodies against donor HLA alleles tion, the HLA-G leader sequence contains a peptide that can bind
61
in patients presensitized by multiple transfusions. Acute and chronic and stabilize the expression of HLA-E, which, in turn, inhibits NK
80
rejection result from a combination of humoral and cellular immune cells. Because the HLA-G–derived leader peptide has the strongest
reactivity toward HLA alleles of the donor. 62,63 In addition to allo- affinity for HLA-E (among all HLA class I molecules), it is likely that
sensitization, HLA alleles can mediate GVHD whereby hematopoietic HLA-G is a powerful direct and indirect inhibitor of NK cells,
cells derived from the grafted tissue recognize and reject the host reducing the risk for cardiac rejection or inducing immune escape of
tissues. They do this by identifying polymorphisms of intracellular cancer cells. 72,81 Although much has been published about the immu-
proteins of the host [minor histocompatibility antigens (mHags)] noregulatory role of HLA-G, its true function remains unknown,
presented in association with donor-recipient matched HLA alleles. principally because of discordant findings reported by various
74
groups. With the goal of achieving consensus, a workshop was
66
NONCLASSIC MHC AND MHC CLASS recently organized to standardize methods of analysis of HLA-G.
4
HLA-E is minimally polymorphic, binds hydrophobic peptides
I CHAIN-RELATED MOLECULES from other HLA class I leader sequences, and interacts with CD94/
NKG2 lectin-like receptors present predominately on NK and par-
+
Besides the three ubiquitously expressed highly polymorphic classic tially on CD8 T cells. 82–85 The peptide binding is highly specific and
HLA class I molecules, humans encode three relatively conserved stabilizes the HLA-E protein, allowing its migration to the cell
nonclassic, selectively expressed (HLA-E, HLA-F, and HLA-G) surface. Thus surface density of HLA-E is an indirect reflection of
86
MHC class I genes (also known as MHC-Ib). These evolved at dif- the number of HLA class I alleles expressed by a cell. The interac-
ferent rates in primates reflecting differential involvement in the tion of HLA-E with CD94/NKG2 protects HLA-E–expressing cells
modulation of immune responses. 4,64,65 In addition, these molecules from killing. Cells damaged by viral infection or neoplastic degenera-
are characterized by unique patterns of transcription, protein struc- tion may lose HLA class I expression. As a backup mechanism of
ture, and immunologic function. 66 protection, reduced HLA class I expression results in decreased
87
The MHC class I-related chain genes (MICA and MICB) are expression of HLA-E, leading to vulnerability to NK cells. Some
located within the MHC region and are characterized by high poly- viruses express mimic peptides that bind and stabilize HLA-E so that,
67
morphism (more than 50 alleles so far identified). The molecules although classic MHC molecules are downregulated, HLA-E expres-
encoded by these genes do not appear to bind peptides or associate sion is maintained, allowing the pathogen to simultaneously escape
+
with β 2 -microglobulin. Their polymorphic variants are not concen- CD8 T- and NK-cell killing. 88
trated around the peptide-binding groove, yet they seem to have The function of HLA-F remains enigmatic. Its transcriptional
functional significance, because most mutations are nonsynonymous, regulation is closest to classic HLA molecules in that it can be induced
89
suggesting selective pressure as a driving force. Their tissue distribu- by NF-κB, interferon regulatory factor-1, and class II trans-activator.
tion is restricted to epithelial and endothelial cells and fibroblasts. It However, contrary to classic HLA molecules, HLA-F is predomi-
+
appears that MIC genes modulate the function of NK and CD8 T nantly empty, mostly intracellular, with a restricted pattern of expres-
68
90
cells by binding the NKG2D stimulating receptor. Also, MIC genes sion. Its tissue distribution appears to be limited to B cells, therefore
90
have been implicated in transplant rejection because alloantibodies it is mostly found in lymphatic organs. Structural studies suggest
against them are often found in transplant recipients that may exert that HLA-F is a peptide-binding molecule and may reach the cell
91
complement-mediated cytotoxicity against endothelial cells from the surface under favorable conditions when a suitable peptide is present.
graft. Once on the cell surface, HLA-F may interact with the effector-cell
Other unusual MHC-like molecules are present in the genome receptors IL-T2 and IL-T4, as suggested by HLA-F tetrameric
91
and have disparate functions, including presentation of lipid antigens complexes-binding studies. Thus it is possible that in specific yet