Into The Future: Immunology In The Age Of Genomics
The completion of the first complete DNA
sequence of the human genome in
2003 was a landmark in the history of science. Remarkably, despite containing
over 3 billion base pairs, the genome is believed to code for only around 20
000 genes, far fewer than most scientists had estimated. The function of much
of the rest of the DNA remains unclear, although much of it is likely to be involved
in regulating gene expression. An increasing number of genomes of other
organisms (including of course the indispensable laboratory mouse) are already,
or will be shortly be, available. Genome-wide comparisons between species are
already providing fascinating new insights into the process of evolution. The
next major phase of the genome project, to define the diversity of the DNA
sequence within a species, is now under way. Current data suggest that the DNA
sequences of any two humans differ from each other by an amazing 10 000 000
base pairs. The most common type of difference are called single nucleotide
substitutions, or SNPs, (pronounced ‘snips’).
All this information has had a
major impact on immunology, allowing rapid discovery of many new molecules
involved in the interaction between the host and the pathogen. The figure shows
the 22 human autosomes, plus the X and Y chromosome, stained with a DNA dye
that gives a characteristic banding pattern known as the ideogram. Each band is given a number (e.g. 14q32 means band
32 on the long arm of chromosome
14, p refers to the short arm) which unambiguously identifies that region of
the chromosome. The figure illustrates in green the ideogram positions of the
genes that code for some of the most important molecules making up the human
immune system, all of which are discussed elsewhere in this book. One striking
discovery, illustrated in this figure, is the extent to which the immune system
is made up of multigene families, which have presumably arisen by multiple
duplication events. Many immune genes are also polymorphic. The extent of
immune gene duplication and polymorphism (far greater than in most non-immune
genes) is testament to the enormous selective pressure exerted by the microbial
world during our past evolutionary history. Mutations in several genes have
been associated with (often very rare) diseases affecting the immune system.
The list is not exclusive, as new examples are rapidly being discovered. You
can find information about any other gene you may be interested in by searching
at the American National Centre for Biotechnology Information.
Knowledge of one’s own genome and
of its likely gene associations will offer exciting and extraordinary
possibilities, but also disturbing ethical challenges, to both the medical
profession and the individual.
T-cell receptors T lymphocytes recognize antigen using a two-chain receptor made up either of γ/δ or, much
more commonly, α/β chains. These genes, like those of immunoglobulin,
are unusual in that the complete gene is put together only during T-cell
development by recombining different gene fragments (see Figs 10 and 12). Thus,
T and B cells break the dogma that all cells carry identical genomic DNA
sequences.
Chemokine ligands (CCLs) and
their receptors (CCR) A large
related family of genes coding for soluble messengers, and their receptors (see
Fig. 23), which have a key role in directing the localization and migration of
all immune cells. There are two main clusters of chemokine genes, coding for
two different, although related, families, and one major cluster of chemokine
receptor genes. A genomic deletion (absence of sequence) is present in about 1%
of white Caucasians, which results in a complete absence of the CCR5 receptor. Remarkably,
this deletion confers almost complete protection against HIV infection. The
absence of CCR5, however, predisposes to another human pathogen, African West
Nile virus, perhaps accounting for the absence of this deletion in African
populations.
Cytokines act as messengers between one immune cell and
another, binding to specific target receptors, and hence orchestrating the
complex series of events that constitute an immune response (see Figs 23 and
24). There are several families of structurally related cytokines (only one
example is shown, for simplicity). Defects in the IL-17 receptor predispose
to serious mucocutaneous fungal infection, while mutant forms of the IL-12 and IFNγ
receptor increase the risk of developing tuberculosis. Defects in the genes
coding for components of the cytokine signalling pathways (e.g. the DNA-binding
protein STAT3) can lead to complex and often life-threatening failures
in the proper regulation of immune responses.
CD28 family of cell surface receptors are found especially on T cells, where
they interact principally with members of the B7 family of ligands. These
molecules have a critical role in regulating the magnitude and termination of
immune response. A small group of volunteers were injected with a monoclonal
antibody specific for CD28, as part of a trial for a potential therapeutic for
autoimmune disease. Instead, the injection resulted in massive uncontrolled
inflammatory response, almost killing some of the volunteers – a warning of the
complexity of the immune system, and the potential dangers of tampering with
it! Mutations in the autoimmune regulator gene (AIRE), which
regulates protein expression in the thymus, and in the FAS and FAS ligand receptors
which regulate apoptosis can lead to a breakdown of self- tolerance (see Fig.
22), and consequent autoimmune disease (see Fig. 38).
Type I interferons A family of antiviral proteins that also have
powerful immunomodulatory activities (see Fig. 2). Several genetic defects in
the signalling machinery that transmits the interferon signal have been linked
to increased susceptibility to several viruses (one such gene, UNC93B,
is linked to herpes simplex encephalitis), and this is turn may lead to serious
asthma. Remarkably, the human genome contains genes for 13 type I interferons,
all of which bind to the same receptor. The biological significance of this
remains totally mysterious, but may be related to the need to switch on
interferon production in so many
different cell types, and under so many different situations.
Mutations that reduce the activity
of the enzyme NAPDH oxidase result in a reduced ability of phagocytes to kill
bacteria, and were one of the first mutations shown to lead to a specific
deficiency of innate immunity, chronic granulomatous disease (see Fig. 33). Mutations
in an iron transporting protein, NRAMP, also impair innate immunity and
increase the risk of tuberculosis and leprosy. An interesting recent discovery
is that immunodeficient individuals who carry a mutation in the DNA binding
protein IRF8 have a complete absence of monocytes and dendritic cells.
Toll-like receptors The prototype pathogen recogntion receptors of
innate immunity (see Fig. 5). The human genome contains 10 functional TLRs
recognizing a wide range of viral and bacterial components. A genetic defect in
TLR5, which recognizes a major component of bacterial flagellae, predisposes to
Legionnaires’ disease.
Major histocompatibility complex
An enormous complex of genes
(many of unknown function) stretching over 3.6 megabases on chromosome 6, which
includes the classic class I and II major histocompat- ibility molecules that
direct peptide presentation to the T cell (see Fig. 11). These genes are the
most polymorphic known, with hundreds of different alleles of some chains
already described. These differences have received enormous attention, partly
because they determine the strength with which grafts between different
individuals are rejected, but also because particular variants are associated
with many infectious, autoimmune and allergic diseases.
X-linked immunodeficiencies (see
Fig. 33). The
X chromosome is the only one that
is found ‘unpaired’ in males, as males have a Y chromosome in place of a second
X chromosome. For this reason, recessive mutations on X chromosomes
can behave as
dominant in males, giving rise to the so-called sex-linked diseases.
Several X-linked immunological diseases have been described. Two examples are
shown in the figure. A defect in the IL-2 receptor gamma chain, a
receptor required for lymphocyte development, gives rise to severe combined
immunodeficiency syndrome, in which all lymphocyte development is blocked at
an early stage. This disease is one of the first to have been treated
successfully by the new gene therapy technologies (see Fig. 33). In contrast, a
defect in CD40 ligand, a receptor on the surface of B cells, gives rise
to a more subtle immuno- deficiency, hyper IgM syndrome, in which B cells
cannot receive the correct signals from T cells and are therefore arrested at
the IgM production stage, rather than switching to IgG as the immune response
progresses.
