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Into The Future: Immunology In The Age Of Genomics


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’).

Into The Future: Immunology In The Age Of Genomics

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.
 Immunoglobulins The antigen-specific  receptor  on B  cells  is dis- cussed in detail in Fig 14. Like T-cell receptors, immunoglobulin chains are put together by rearranging genomic fragments during lymphocyte development (for details see Fig. 14). A remarkable achievement of genetic engineering has been to introduce the whole genomic sequence coding for human light and heavy chains into a mouse. This allows production of completely ‘human’ antibodies, which can be used for therapeutic purposes without the danger of being recognized as foreign, using all the techniques of classic mouse immunology.
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.