Personalized Medicine for HLA-associated Drug-hypersensitivity Reactions

Mandvi Bharadwaj; Patricia Illing; Lyudmila Kostenko


Personalized Medicine. 2010;7(5):495-516. 

In This Article

Understanding the Immunology & its Application

Although genetic-association studies may highlight HLA alleles as risk factors in ADR and be useful in genetic screening, without a more direct observation of their role in the clinical manifestation of the disease it is hard to tell if they are true risk factors or merely in LD with a causative polymorphism. For this reason, understanding the immune phenomena behind these hypersensitivities and isolating the role of the associated allele is a desirable step forward, not only to confirm the true nature of the alleles as risk factors but also to look for alternative treatment regimens that may negate the need for testing, or could be used in affected individuals.

As mentioned previously, T-cell-mediated drug hypersensitivities occur via the drug-induced presentation of an immunogenic ligand, typically the drug or one of its metabolites, in an MHC dependent manner.[2] MHC-I are expressed by most nucleated cells and consist of a heavy chain in the form of one of the highly polymorphic HLA class I, often referred to as the α-chain, which contains three extracellular domains (α1, α2 and α3) and is membrane bound, and an invariant, single domain, light chain known as β-2-microglobulin (β2m) (Figure 1). MHC-I are responsible for displaying peptides representative of the protein expression occurring within the cell. Such peptides are generated in the cell cytosol via proteasome-mediated protein degradation and transported into the endoplasmic reticulum by the transporter associated with antigen processing. Here, they are loaded onto empty MHC-I with the aid of the chaperone tapasin, and the complete MHC-I–peptide complex is trafficked to the cell surface.[104] The MHC-I–peptide complex is able to interact with the TCR of CD8+ T cells. Under immunogenic conditions, if the TCR recognizes a peptide and identifies it as a nonself peptide, a cytotoxic CD8+ T-cell response will be initiated, targeting cells displaying the culprit peptide for CD8+ T-cell-mediated cytotoxicity. The purpose of this response is to eliminate cells expressing inappropriate proteins such as those harboring intracellular pathogens.

Figure 1.

Structure of the MHC.
Ribbon structures of the extracellular domains of MHC alleles HLA-B*5703 and HLA-DR4, representative of MHCI and MHCII respectively. Individual polypeptide chains are depicted in purple and red, disulfide bonds are in yellow. The extracellular domain of MHCI (left) consists of the polymorphic heavy or α-chain (purple), and the invariant light chain, β2m (red). The heavy chain contains three domains; α1, α2 and α3. Together α1 and α2 form the peptide-binding groove; each providing four antiparallel β strands to the β sheet at the base of the groove and one α helix to the side of the groove. α3 bears an immunoglobulin-like fold and connects to the transmembrane region of the protein responsible for anchoring MHCI to the plasma membrane. β2m is an immunoglobulin-like domain similar to α3 and interacts with the heavy chain in a noncovalent manner. By contrast, the extracellular domain of MHCII (right) consists of two polymorphic chains, the α- and β-chains. Each comprises of two domains, with α1 and β1 forming the peptide-binding groove in a similar manner to α1 and α2 in MHCI. Parallel to α3 and β2m in MHCI, α2 and β2 are immunoglobulin-like domains, but both domains are linked to transmembrane domains securing MHCII to the cell membrane. PyMOL software was used to construct these images from the HLA-B*5703/KAF11 structure published by Stewart-Jones et al.[146] and the HLA-DR4/SEB published by Bolin et al.[147]

MHC-II show a more restricted distribution, generally expressed by specialized antigen presenting cells (APC) such as macrophages and dendritic cells. By contrast to MHC-I, they are formed by dimerisation of two polymorphic membrane bound chains, known as the α- and β-chains, each of which contains two extracellular domains (α1 and α2, and β1 and β2, respectively) (Figure 1). The purpose of MHC-II is to present an array of peptides representative of the proteins present in the cell's external environment. This is accomplished by ingestion of the external milieu, proteolytic degradation of ingested proteins in acidified endosomes, loading of the peptides onto MHC-II and subsequent display of the MHC-II–peptide complex at the cell surface. MHC-II–peptide complexes interact with CD4+ T cells, foreign peptides instigating a CD4+ T-cell response. These responses are of a more regulatory nature and will be guided by other signals received from the APC that provide information on the nature of the danger.

Although, both MHC-I and -II can present drugs to T cells, the associations of drug-hypersensitivity reactions with MHC-I are stronger and better defined, and will therefore, be utilized to discuss the mechanistic models of the ensuing immune response in these reactions.