Out Of The Past: Evolution Of Immune Mechanisms
From the humble amoeba searching for food (top left) to the mammal with its sophisticated humoral and cellular immune mechanisms (bottom right), all cellular organisms can discriminate between self and non-self, and have developed defence systems to prevent their cells and tissues being colonized by parasites.
This figure shows some of the important landmarks in the evolution of immunity. As most advances, once achieved, persist in subsequent species, they have for clarity been shown only where they are first thought to have appeared. It must be remembered that our knowledge of primitive animals is based largely on study of their modern descendants, all of whom evidently have immune systems adequate to their circumstances.
All multicellular organisms, including plants, have evolved a variety of recognition systems that respond to common molecular patterns found on the surface of microbes (e.g. lipopolysaccharides) by stimulating a variety of antimicrobial responses. This broadly corresponds to vertebrate innate immunity. In contrast, only vertebrates appear to have evolved adaptive immunity (characterized by specificity and memory), mediated by lymphocytes and three separate recognition systems (see Fig. 3): molecules expressed on B cells only (antibody), on T cells only (the T-cell receptor) and on a range of cells (the MHC), all of which look as if their genes evolved from a single primitive precursor (for further details see Fig. 10). Why only vertebrates have evolved adaptive immunity has never been totally explained, but there is a growing appreciation that the adaptive immune system brings with it very significant evolutionary costs. These include energy demands in maintaining the system (the human immune system has at least as many cells as the human nervous system), and also the potential danger that excess immunity will lead to tissue damage (as out- lined in Figs 34–39). One of the consequences of the evolutionary quest to balance the pros and cons of the immune system is reflected in the extraordinary evolutionary diversity and genetic variability in many families of molecules involved in immune function (see Fig. 47).
Bacteria We think of bacteria as parasites, but they themselves can be infected by specialized viruses called bacteriophages and have developed sophisticated systems to prevent this. It is thought that the restriction endonucleases, so indispensable to the modern genetic engineer, have as their real function the recognition and destruction of viral DNA without damage to that of the host bacterium. Successful bacteriophages have evolved resistance to this, a beautiful example of innate immunity and its limitations.
Protozoa Lacking chlorophyll, these little animals must eat. Little is known about how they recognize ‘food’, but their surface proteins are under quite complex genetic control.
Research in this area is very active, partly because it has become clear that some invertebrates make very useful models for the study of vertebrate innate immunity, and partly because of the importance of some invertebrates in carrying human diseases (e.g. malaria transmission by mosquitoes).
Sponges and corals. Partly free-living, partly colonial, sponge and coral cells use species-specific glycoproteins to identify ‘self’ and prevent hybrid colony formation. If forced together, non-identical colonies undergo necrosis at the contact zone, with accelerated break- down of a second graft.
Worms Because of its relative simplicity and ease of propagation, the nematode Caenorhabditis elegans has become one of the most thoroughly studied animals on earth. Protection against infection is achieved by behavioural responses (mediated by a Toll receptor; see Fig. 5), a thick outer coat or cuticle and production of a range of soluble antimicrobial peptides and proteins.
Molluscs and arthropods are curious in apparently not showing graft rejection. However, both cellular and humoral immunity are present. An important humoral system involves the enzyme prophenyl oxidase, which is involved in production of toxic oxygen radicals and melanin, both thought to play a part in defence against potential pathogens. A common cellular response is encapsulation, in which invading microorganisms are rapidly surrounded by blood cells and sealed off, thus preventing spread of infection. A key feature of the insect immune response (studied especially in the fruit fly Drosophila melanogaster) is the production of an amazing number of different antimicrobial peptides. Two major cellular signalling path- ways are involved in switching on the production of these peptides, the Toll receptor pathway, which also plays an important part in mediating innate immunity in vertebrates, and the Imd pathway, which shares many features with the vertebrate tumour necrosis factor pathway.
Echinoderms The starfish is famous for Metchnikoff’s classic demonstration of specialized phagocytic cells in 1882. Allografts (grafts from one individual to another) are rejected, with cellular infiltration, and there is a strong specific memory response.
Tunicates (e.g. Amphioxus, sea-squirts) These pre-vertebrates show several advanced features: self-renewing haemopoietic cells, lymphoid-like cells, and a single gene complex controlling the rejection of foreign grafts. Most of the major components of the complement pathway are also first found in this group of animals. Although none of the major components of adaptive immunity have been found in any invertebrate, other molecules of the ‘immunoglobulin superfamily’, e.g. adhesion molecules, are already present in invertebrates.
Jawless fishes (cyclostomes, e.g. hagfish, lamprey) These descendents of the earliest vertebrates lack the immunoglobulin-based adaptive immune system. In a remarkable example of parallel evolution, they were recently shown to have two classes of lymphocytes, analogous to T and B cells, but to use a different type of variable lymphocyte receptor based on the leucine rich domain structure (see Fig. 5).
Cartilaginous fishes (e.g. sharks) The evolution of the jawed vertebrates marks the first appearance of classic antibody, T-cell antigen receptors and MHC, although details of isotype, isotype switching and somatic recombination differ from higher vertebrates. Many molecules of the classic complement pathway also make their appearance.
Bony fish Bony fish have most of the features of immunity familiar to us from a study of humans and mice. The zebra fish has become an attractive model species for the study of immunity and inflammation, because its transparent body structure allows high resolution imaging, and its small size facilitates the development of rapid screening assays for new immunomodulatory drugs. Interest in fish immunology has also been driven by economic considerations, as infectious diseases pose a major challenge for farmed fish such as salmon.
Amphibians During morphogenesis (e.g. tadpole → frog) specific tolerance develops towards the new antigens of the adult stage. Lymph nodes and gut-associated lymphoid tissue (GALT) and haemopoiesis in the bone marrow also appear for the first time.
Birds are unusual in producing their B lymphocytes exclusively in a special organ, the bursa of Fabricius, near the cloaca. The mechanisms for generating different antibody molecules also seem to be quite different, involving a process known as gene conversion. They have a large multilobular thymus but no conventional lymph nodes.
Reptiles have both T and B cells. As in birds, the major antibody class is IgY rather than IgG, although both IgM, IgD and possibly IgA may also exist.
Mammals are characterized more by diversity of Ig classes and sub-classes, and MHC antigens, than by any further development of effector functions. There are some curious variations; e.g. rats have unusually strong innate immunity and some animals (whales, Syrian hamsters) show surprisingly little MHC polymorphism. However, humans and mice, fortunately (for the humans), are immunologically remarkably similar. Members of the cammelid family (e.g. camels and llamas) have antibodies made up of a single heavy chain and no light chain (see Fig. 14).
Plants, like animals, possess sophisticated mechanisms to protect themselves against microbial pathogens. These responses are triggered by plant receptors that recognize molecular components of bacteria, fungi or viruses. The responses include secretion of a variety of anti- microbial substances, some of which (e.g. nitric oxide) are shared with vertebrate immunity. RNA silencing, in which short stretches of double-stranded RNA can trigger sequence-specific mRNA degradation, and hence gene silencing, forms part of another elaborate antiviral immune system in plants.