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The Major Histocompatibility Complex

Dimitrios S. Monos, Robert J. Winchester

A primary objective of the immune system is to protect our GENOMIC ORGANIZATION OF THE MHC
bodies against pathogens. The major histocompatibility complex
(MHC) comprises a genomic region that has evolved to include The human MHC region includes approximately 3.8 million
many genes responsible for coordinating the immune response. base pairs (Mbps) of DNA on the short arm of chromosome
It is named the histocompatibility complex because it was first 6 (6p21.3) and is defined as the region spanning from the
identified as the site of numerous genes that determined whether gamma-aminobutyric acid receptor (GABBR1) gene on the
transplanted tissue would be accepted or rejected. We now know telomeric side of the region to the kinesin family member C1
that this region coordinates immunological functions far beyond (KIFC1) gene toward the centromere (ENSEMBL 86 GRCh38.
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those related to histocompatibility. The MHC region includes p7 coordinates chr6: 29555629-33409924). More recent work
genes that determine both innate and adaptive immunities and has suggested that the functional MHC region may include
thus influences responses to pathogens (viruses, bacteria, fungi, additional downstream and upstream sequences totaling seven
and parasites), transplantation, autoimmunity, cancer biology, or more Mbps.
vaccinations, responses to drugs, and possibly other functionalities The classic 3.8Mbp MHC region is among the most gene-dense
presently unknown. This chapter describes some aspects of the segments of the human genome. It includes 158 protein-coding
genomic organization of the MHC region and its immunological genes and 86 pseudogenes of unknown functionality (ENSEMBL
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importance, focusing primarily on the human leukocyte antigen 86 GRCh38.p7). At least 65 (41%) of the coding genes are
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(HLA) genes and their encoded molecules. These HLA molecules involved in innate and adaptive immunities. The MHC is one
play a central role in adaptive immunity. They serve as the of the most studied regions of the genome because it includes
structures that present self and foreign peptides to T cells (Chapter the genes that encode the highly polymorphic HLA proteins,
6). They also participate in aspects of innate immunity by which play a pivotal role in immune recognition. The MHC is
interacting with receptors on the surface of natural killer (NK) divided into three regions: class I, class II, and class III (Fig. 5.1).
cells (Chapter 17). The terms HLA and MHC are often used The class I region is at the telomeric end and includes the classic
interchangeably. However, in this chapter, “MHC” is reserved HLA class I genes (HLA-A, HLA-B, and HLA-C), the class I–related
for the broader genomic region, and “HLA” is used to indicate (like) genes (MICA, MICB), the nonclassic HLA class I genes
the genes and their respective encoded protein products in (HLA-E, HLA-F, and HLA-G), and four pseudogenes (HLA-H,
humans. HLA-K, HLA-J, and HLA-L). The class II region occupies the
centromeric end and contains the DRA and DRB1 genes
and, depending on the DR haplotype, one or none of the
DRB3, DRB4, DRB5 genes that code for the DR, DR52, DR53,
or DR51 molecules, respectively; the DQA1 and DQB1 genes
CLINICAL RELEVANCE that encode the DQ molecule; and the DPA1 and DPB1 genes
that encode the DP molecule. It also includes the DM and DO
• HLA molecules regulate antigen-specific immune responses by binding genes encoding the antigen-processing molecules DM and DO
pathogen-derived peptides and then presenting them to either CD4
or CD8 T cells. involved in the class II antigen presentation pathway (Chapter
• CD4 T cells activated by MHC class II peptide complexes can 6), as well as the TAP and LMP genes encoding proteins involved
stimulate B cells to produce antigen-specific antibodies. in the classic class I antigen presentation pathway (Chapter 6).
• CD8 T cells activated by MHC class I peptide complexes become The class III region, interposed between class I and II regions,
cytotoxic and can kill the cells that present the pathogen-derived is a very gene-dense region and contains many immune and
peptides. non-immune related genes, including those encoding some
• Certain HLA alleles are the major genetic determinants of susceptibility
to many autoimmune diseases or drug hypersensitivity reactions. complement components, lymphotoxin α and β, tumor necrosis
• The process involves a combination of self peptides or small factor (TNF), heat shock proteins (HSPs), NFKB, NOTCH4, and
molecules (drugs) bound to specific HLA alleles and then recognized 21-hydroxylase (CYP21). The genes within the HLA class I and
by T-cell receptors. class II regions demonstrate the sequence and structural homology
• HLA molecules play a key role in governing transplant rejection and that marks evolution through mechanisms of gene conversion,
appear to regulate placental development in pregnancy. gene duplications, insertions, deletions, and subsequent mutations,
• Cancerous cells modify expression of their HLA genes to avoid recogni-
tion by the immune response. resulting in divergence of function. Although the genomic
organization of class I and class II genes is quite distinct, the

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