The Human Leukocyte Antigen (HLA) Complex

The Major Histocompatibility Complex (MHC) is a genome region that has an important role
in regulating the immune response to foreign molecules. In humans the MHC is known as
the Human Leukocyte Antigen (HLA). This is a 3.6Mb segment found at 6p21.3. HLA is highly
polymorphic as it encodes for more than 220 genes (1). Three important HLA gene classes
are I, II and III. I contains the HLA-A, HLA-B and HLA-C genes. II is made up of the DR, DQ and
DP families. III consists of genes for complement components, Tumour Necrosis Factors
(TNFs), 21-hydroxylase and others (2). HLA class I molecules are recognized by CD8+ T cells
and orchestrate the binding of peptides to immune cells. The diversity in the HLA region
arises from the need to bind to the numerous foreign and local peptides produced by
antigens. This is evident by the presence of more than 1500 alleles for the HLA-B gene (1).
Resultantly, it is imperative that the donor and recipient in a transplant surgery are HLA
compatible, to prevent immune rejection (3).
The aforementioned Immune reactions have often been linked to gene alleles of HLA Class I.
Specifically, the HLA-B*15:02 allele has been strongly linked to CBZ induced SJS in the Han
Chinese population (4). This allele has also been linked to SJS/TEN in other Asian ethnicities
such as the Indian, Korean, Malay and Thai. No association was found in the Japanese
population (5) .However, there are several unresolved issues with this genetic association .
A case control study of Asian SJS/TEN patients revealed that only 4 out of 12 carried the
HLA-B*15:02 allelle (6). This indicates that the aforementioned allele is not necessary to
induce the SJS/TEN reaction. Furthermore, another study discovered that the allele was only
present in 59/60 of CBZ-SJS/TEN patients while 6/144 of the tolerant controls possessed the
allele. The CBZ-SJS patient who did not possess the allele had another allele, HLA-B*1558
(7). This data reaffirms that HLA-B15*02 is not necessary for the SJS reaction to occur, while
also demonstrating that it is not sufficient by the presence of healthy controls with the
allele. These findings expose the need to further analyse the linkage disequilibrium of HLA
alleles, as the high variety of the MHC region could be cloudinf the true effector Allele.
In European and Japanese populations, the HLA-A*31:01 allele has been associated with the
CBZ-SJS/TEN reaction (8) (9). Conversely, a meta analysis identified this allele to only be
associated with CBZ induced DRESS and not with CBZ-SJS/TEN in a European and Chinese
patient group (10). Similar to HLA-B*15:02, HLA-A*31:01 appears to be neither necessary
nor sufficient to induce SJS/TEN.
Additionally, HLA allelles that protect against CBZ-SJS/TEN, such as HLA-B*40:01 and HLA-
A*24:02 have been identfified in patients of Asian ethnicity . However, it is still not clear
whether these alleles exert a true protective effort of if they are identified more frequently
in healthy control groups (5) (11).
A proposed mechanism for CBZ-SJS/TEN is “the pharmacological interactions with immune
receptors” (p-i) model and. The p-I model proposes that the a drug may bind non-covalently
to the HLA molecule and/or T-cell receptors (TCR), bypassing the antigen peptide
processing pathway. Researchers found that bound-peptides were not modified by CBZ and
that the binding was non-covalent, strengthening this hypothesis (12). This was further
supported by a study, which demonstrated that endogenous peptide bound HLA-B*15:02
molecules, present carbamazepine to TCR of Cytotoxic T-lymphocytes to induce SJS/TEN
(13).

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