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86 PARt oNE Principles of Immune Response

class II–peptide complex and become activated. This event triggers HLA molecules that bind peptides from molecules expressed
adaptive immunity. Eventually CD8 T cells recognize target cells in sites favoring autoimmune recognition by T cells. These
infected with the pathogen by interacting with the HLA class molecules become the target of the adaptive immune response.
I–peptide complex on their cell surface and the targets are Together, features specific to certain sets of self peptides and to
eliminated, thus containing the infection (Chapter 6). certain self HLA molecules can contribute to the progressive
In response, pathogens have evolved mechanisms to overcome development of autoimmunity and, ultimately, autoimmune
the specific attack by the host’s immune cells. The first of these disease (Chapter 50).
mechanisms is “antigenic drift” or “antigen shift,” whereby the
pathogen, through minor (drift) or more substantive changes HLA in Cancer
(shift), evades both humoral and cellular responses. These changes Immune evasion is a critical process in tumor biology. It is enabled
make the pathogen unrecognizable, as some of these new peptides by several mechanisms that include immune editing, downregula-
do not form recognizable complexes with the HLA molecules tion of HLA expression, secretion of immunosuppressive
of the host and therefore evade the T-cell responses. Another mediators, and expression of proteins that modulate immune
mechanism frequently adopted by viruses is to persist in vivo checkpoints. Most recently, somatic mutation of HLA genes was
by not replicating until the immunity of the host is compromised. revealed to be a significantly frequent process in some tumor
By not replicating, they avoid detection and exist in a dormant types. The strategies of immune evasion by cancer cells also
state (latency). It therefore becomes evident that the infectivity include the silencing or aberrant expression of HLA class I and
of a microorganism reflects the interplay between several complex class II molecules, events that have often been associated with
processes. These include the ability of the pathogen to create high-grade malignancy and metastatic potential in a variety of
new molecular forms unrecognizable by the host and thus evade human cancers. 19
detection. These efforts by the pathogen to avoid immunity are In patients with solid tumors, HLA-G can contribute to a
then counterbalanced by molecular polymorphisms between tumor-escape mechanism that favors cancer progression, and
HLA molecules that enable recognition of new molecular forms blocking strategies have been proposed to counteract it. Con-
of the pathogen. 17 versely, HLA-G can inhibit proliferation of malignant B cells as
a result of the interaction between HLA-G and its receptor ILT2,
HLA in Transplantation which mediates negative signaling on B-cell proliferation. Thus
The large number of different HLA alleles greatly reduces the treatment of some malignancies can benefit by blocking HLA-G,
probability that two unrelated individuals will inherit an identical whereas in others HLA-G induction can counteract tumor
set of HLA alleles. Two basic mechanisms of responses in progression. 20
transplantation have been described. The first involves the “direct” The concept of developing cancer-specific immunotherapies
recognition of the peptide–HLA complex of the donor tissue by involving tumor-specific antigens presented by HLA molecules
the T cells of the recipient. This is possibly through structural to T cells has been successfully tested in a number of tumors
similarities of the HLA molecules of the donor that allow the (Chapter 77), including testicular cancer and melanoma. These
TCR of the recipient to interact with the peptide–HLA complex. T-cell immunotherapies require adoptive transfer of T cells that
The second involves the “indirect” presentation of donor’s HLA have been expanded ex vivo and transferred back to the patient.
antigens processed by the recipient’s APCs, generating peptides Another approach is the use of retroviral vectors to transfer
presented by the recipient’s HLA molecules to the recipient’s T tumor-specific TCR genes into the patient’s T cells before reinfu-
21
cells. This indirect mechanism operates the same way as the sion. Even though HLA molecules are involved in these processes,
presentation of a foreign antigen, whereby the HLA molecule is histocompatibility testing is not necessary in these therapies
now the foreign antigen processed by the antigen-processing because the original T cells are derived from the patient. However,
mechanisms of the recipient. if the mechanism of immunotherapy involves neoantigens
By using appropriate immunosuppressive agents and therapies, (epitopes of mutated proteins) from tumors presented by specific
T-cell activation by the donor’s HLA molecules after clinical HLA alleles, such individualized therapy needs to take HLA alleles
transplant can be controlled (Chapter 81). However, the major into account.
long-term problem is the presence of donor-specific antibodies
that develop against mismatched HLA antigens. Controlling the HLA AND DISEASE ASSOCIATIONS
antibody responses to mismatched HLA molecules has been very
challenging, and there is a need for continuous monitoring of Over the last several decades, a large number of studies have
their development. An approach holding some promise for the established strong associations between certain diseases and
future is the utilization of regulatory T cells (Tregs), which have individuals carrying particular HLA alleles. In spite of extensive
important immunoregulatory role in all immune responses and study, the mechanisms underlying HLA–disease associations
can possibly induce transplant-specific tolerance (Chapter 18). remain unclear.
Hypotheses generated to explain these associations can be
HLA in Autoimmunity grouped into two general categories. The first category invokes
Selection on the self peptide presented by self HLA allotypes in linkage disequilibrium between a particular HLA allele that is
the thymus can predispose to autoimmunity because the T-cell associated with a given disease and another neighboring genomic
portion of the adaptive immune system is entirely selected on element on the haplotype that is actually causative of the disease
the self peptide. The inherent autoreactivity of the T-cell system and does not involve HLA molecules directly. This can occur
can thus set the stage for the development of autoimmune diseases because the genes within the MHC are in extensive LD among
associated with the recognition of particular self peptides, or themselves. Examples of this type of associations include heredi-
peptides from external antigens that mimic these self peptides tary hemochromatosis, where an apparent association with HLA-A
18
and are effectively presented by self HLA. Certain alleles encode alleles results from mutations in a nonclassic HLA class I gene,