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CHAPtER 5 The Major Histocompatibility Complex 89

The implicated HLA molecules are the class II antigens DQ2 KEY CoNCEPtS
and DQ8. The DQ2 molecule mostly associated with CD is
encoded by the HLA-DQA1*05:01–DQB1*02:01 alleles, with a Human Leukocyte Antigen (HLA) and
small proportion encoded by the DQA1*02:01–DQB1*02:02 Disease Associations
genotype. The DQ8 molecule associated with CD is DQA1*03– • HLA molecules are associated with many diseases.
DQB1*03:02. Approximately 90% of patients with CD express • HLA alleles frequently confer a higher risk for a number of immune
the HLA-DQ2 molecules, with the remaining 10% mostly related diseases than other genomic factors.
expressing the HLA-DQ8 molecule. Deaminated by transgluta- • Most associations reflect situations where the HLA molecules are
minase, negatively charged gluten peptides bind strongly to directly involved in the disease process.
HLA-DQ2 and -DQ8 to present an HLA–gluten peptide complex • Some associations reflect linkage disequilibrium with other non-HLA
that activates CD4 T cells. The immune response also includes genes that are directly involved and responsible for the disease
phenotype.
the development of antibodies against gluten and autoantibodies • In some cases, the HLA molecule, the associated peptide, and the
to endogenous tissue transglutaminase. T-cell receptor (TCR) are sufficient for the development of disease.
Genetic testing for HLA-DQ as a complement to histology • In others, the HLA molecule may be necessary, but not sufficient
can help confirm the diagnosis in patients not known to be for the development of the disease.
positive for tissue transglutaminase antibody. • Twin studies have demonstrated that genetics is not the only component
of many of HLA-associated diseases and that environmental of
metagenomic modifications are also likely involved in the disease
process.
DRUG HYPERSENSITIVITY AND
PHARMACOGENOMICS
Severe cutaneous adverse reactions to drugs include syndromes, METHODS OF DETECTING HLA POLYMORPHISMS:
such as Stevens-Johnson syndrome/toxic epidermal necrolysis HLA TYPING
and drug reaction with eosinophilia and systemic symptoms
36
or drug-induced hypersensitivity syndrome (Chapter 48). Since the discovery of the HLA genes over 50 years ago, there
Although their incidence is very low, they are severe, life- has been a concerted effort to properly categorize and characterize
threatening adverse drug reactions with mortality rates as high these very polymorphic genes. Our understanding of the complex-
as 5–12.5%. The associations reported between drug hypersensitiv- ity and polymorphic nature of the HLA genes has been substan-
ity and specific HLA alleles has been a recent finding and tially improved as the technologies for characterizing these genes
has led to the possibility that hypersensitivity reactions may have improved (Fig. 5.5).
be predictable and preventable. Drugs associated with immu- Initial serological and cellular testing in the 1960s (antibody
nologically mediated drug-induced hypersensitivity include the and mixed lymphocyte culture [MLC]), supplemented by two-
anticonvulsant carbamazepine and the antiretroviral agents dimensional electrophoresis and restriction fragment length
nevirapine and abacavir. Regulatory agencies, such as the US polymorphism (RFLP) analysis in the 1970s to the 1980s, made
Food and Drug Administration (FDA), have issued relevant and us aware of the high degree of polymorphism that was not
informative pharmacogenomics guidelines: (http://www.fda.gov/ properly revealed by the technologies used earlier. The develop-
Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ ment of the polymerase chain reaction (PCR) in the mid-1980s
ucm083378.htm). revolutionized our understanding of these genes at the molecular
level. From PCR, methods utilizing sequence-specific oligonucle-
Carbamazepine otide probes (SSOPs, or SSO) and sequence-specific primers
Carbamazepine is an aromatic amine anticonvulsant, used for (SSPs) provided the means for more directly evaluating the highly
the treatment of epilepsy and other seizure disorders, trigeminal variable sequence motifs within the HLA genes. Subsequently,
neuralgia, and bipolar disorder. Approximately 10% of patients Sanger sequence-based typing (SBT) in the 1990s significantly
develop mild cutaneous adverse reactions. Carbamazepine has advanced tissue typing and transplantation genetics by providing
been shown to be associated with the HLA class I allele an unprecedented molecular view of HLA polymorphism in the
HLA-B*15:02 or A*31:01. context of exonic variation. Most recently, NGS appears to have
revolutionized the field by addressing the HLA typing complexity
Nevirapine in a very definitive way. NGS provides entire HLA gene charac-
Nevirapine is a nonnucleoside reverse transcriptase inhibitor, terization and haploid sequence determination. 37
widely prescribed for human immunodeficiency virus 1 (HIV-1) To meet the growing demand, clinical HLA typing over the
infection. Hypersensitivity HLA class I and II associations have past decade has transitioned from a combination of serological
been described for DRB1*01:01, B*35:05, Cw8, and B*14:02. and DNA-based methods to more direct, faster, more affordable,
and more informative DNA-based techniques. Even though
Abacavir serological typing may continue to have some clinical or research-
Abacavir belongs to the family of nucleoside reverse transcriptase based testing in determining the expression of the HLA molecule
inhibitors and is used for the treatment of HIV-1 infection. Two at the cell surface (a function that DNA-based testing cannot
recent abacavir studies have shown that 100% of patients who always verify), direct DNA-based typing techniques have all but
develop abacavir drug hypersensitivity carry the HLA-B*57:01 replaced serological methods in routine HLA typing.
allele. This predictive value supports the use of HLA-B*57:01
typing of patients prior to initiating treatment with abacavir, DNA-Based Typing Techniques: SSO, SSP, and SBT
even though not all of HLA-B57:01-positive patients develop The techniques primarily in use today in clinical immunogenetics
hypersensitivity. laboratories are SSO, SSP, and SBT. The genomic regions analyzed