Page 102 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 5 The Major Histocompatibility Complex 87

KEY CoNCEPtS variants have been located within the noncoding regions of the
23
Human Leukocyte Antigen (HLA) in Infections, genome. It is therefore possible that disease association elements
may not only lie within the HLA genes but also be dispersed
Transplantation, Autoimmunity, and Cancer within the rest of the MHC. One possible genomic element that
• HLA and infections by pathogens is an interplay of balancing acts, can be located within the noncoding regions of the MHC and
whereby the pathogens try to avoid the immune response and HLA yet have a significant regulatory role is microRNA (miRNA). A
alleles adapt to secure a robust immune response. search for functional genomic elements within the noncoding
• Transplantation is an artificial system, and the transplant is perceived regions of the MHC genes revealed 12 miRNAs, including
by the immune response to be a foreign element. hsa-miR-6891 (miR-6891), which is encoded by intron 4 of
• Induction of tolerance is the objective. HLA-B. Thus some, and perhaps many, diseases associated with
24
• For the host to tolerate the graft, physicians attempt to engender
immune nonresponsiveness to the transplant by manipulating the specific MHC elements, whether HLA alleles or not, may involve
immune response pharmacologically. noncoding RNAs (miRNAs or long noncoding RNAs) with
• The presence of donor-specific antibodies is a major problem in important biological functions of a regulatory nature.
the field of transplantation because these antibodies are primarily Below is a compilation of selected diseases with strong
responsible for chronic rejection reactions we observe. HLA allele associations in different populations. A more extensive
• There are three features of the adaptive immune system that can set list of diseases and reference materials can be found in
the stage for pathogenic autoimmunity. other works. 25-27
• First, the individual’s adaptive immune system is determined by
the set of self peptides and self HLA molecules that select the Ankylosing Spondylitis
T-cell receptor (TCR) repertoire.
• Second, the drive to genetic polymorphism that generates many One of the more extraordinary observations in the MHC field
different alternative forms of peptide-binding HLA molecules influ- was made in 1973 when the frequency of HLA specificity HLA-B27
ences patterns of self and nonself reactivity. was found to be 95% in those with the disease ankylosing
• Third, certain HLA allotypes bind particular self peptides from critical spondylitis (AS) (Chapter 57). This impressive observation
target antigenic molecules that can predispose to autoimmune
responses and disease. implicated HLA-B*27 in the pathogenesis of AS and propelled
28
• Oncogenesis is associated with the modification of patterns of antigen the field of HLA and disease associations. Different B27 alleles
presentation by the cancerous cells to immune cells and by modification have different strengths of association with the disease, making
of immune cell responses to the cancerous cells. genetic testing useful over and above serological testing. Even
• This enables the cancer to avoid immune surveillance and detection though the association of AS to B27 is among the strongest
by the immune response. genetic associations with a common disease, the mechanism of
action remains uncertain. AS has been hypothesized to be triggered
by exposure to a common environmental pathogen. HLA-B*27:02
and B*27:05 demonstrate the highest degree of association. AS
HFE, which is in LD with HLA-A; and congenital adrenal is characterized by arthritis affecting the spine and the pelvis.
hyperplasia resulting from an allele of the gene CYP 21B, which Twin studies have confirmed that susceptibility to AS is genetically
causes 21-hydroxylase deficiency and is located within the class determined. Family studies suggest that <50% of the overall
III region of the MHC and thus in LD with HLA-B. genetic risk is caused by HLA-B27. HLA-B27 is found in 8–10%
A second category implicates antigen presentation by the of the population, with only a minority of carriers progressing
HLA allele. This category deals with diseases that have a strong to development of the disease. It is likely that other genes, both
immunological component. It has been hypothesized that inap- within and outside the MHC, are involved. A number of GWAS
propriate immune reactivity to some self antigens can reflect have demonstrated that non-HLA genes are also associated with
aberrant T-cell repertoire selection, immune cross-reactivity with AS. These include the interleukin-23 receptor (IL-23R) and the
foreign antigens, immune attack of “altered self” antigens, or protein-cleaving enzyme ER aminopeptidase 1 (ERAP1).
differences in the expression levels of certain HLA alleles that B27 testing can be an instructive component of the diagnostic
secondarily influence the course of infections or cancer. The work up of AS. Because of the chronic nature of the disease and
MHC cusp theory represents another hypothesis. In this case, its gradual debilitating nature, the value of B27 testing is that a
the MHC codes for allele-specific ligands in the cusp region of presumptive diagnosis allows institution of treatment early in
the molecule, which interact with non-MHC receptors and activate the disease when patients may have minimal symptoms.
various pathways. Aberrations in these pathways could cause
MHC-associated diseases. According to this hypothesis, the cusp Narcolepsy
region has a peculiar three-dimensional shape that has been Narcolepsy is a long-term neurological disorder characterized
preserved on both class I and class II molecules through evolution, by irresistible daytime sleep attacks. People with narcolepsy suffer
not dependent on antigen presentation, and is a hub for signal from episodes in which they fall asleep unexpectedly during the
transduction ligands that interact with a variety of receptors day. These “sleep attacks” can occur at any time and during any
and activate important biological functions. The MHC cusp activity. Narcolepsy affects approximately 1 in 2000 people. Often
theory posits that HLA molecules promote disease because of those affected have low levels of the neurotransmitter hypocretin
their auxiliary allele-specific, yet antigen presentation–independent, (also known as orexin). Hypocretin is a neuropeptide hormone
biological effect. 22 that is responsible for controlling appetite and sleep patterns.
Although many of these associations lie within the highly Even though the cause of narcolepsy is unknown, the disease is
1
polymorphic HLA genes, GWAS using SNP markers have believed to be of autoimmune nature.
established that not only HLA genes but also the MHC region Family studies have shown that genetic heritability plays a
as a whole harbors many SNPs associated with a large number role in narcolepsy. However, twin studies show that only 25–30%
of traits or diseases. Indeed, up to 90% of autoimmune disease of twins are concordant for the disease, again implicating