1.19.2 …or space and convergence: Olfactory images and spatial codes in olfaction?
1.20 Architectural differences with the immune system
1.20.2 Different mechanisms to generate diversity of specificities
A second, and related, difference between both systems lies in the mechanisms of diversity genera- tion. The complexity of theodorant receptor repertoire is estimated in mouse and rat at 2000genes, or about 3 percent of the genome, surpassing that of the immunoglobulinand T cell receptor genes combined (Mombaerts, 1999b). While the immune system has developed a sophisticated combina- torial mechanism to generate diversity, this does not appear to be the case with chemosensation, which uses a fixed (and large) repertoire of genes instead. Why? In particular, once one system appeared in evolutionary history, why was it not co-opted for a second function, since biology has shown to co-opt genes with much greater ease than that with which it evolves new ones? I believe the answers can be found by two converging lines of analysis.
The tradeoff between specificity and a small receptor set
First, could either of the mechanisms of diversity generation work in the other system? Because antibodies and T-cells cannot afford broad specificities (see above), a much larger diversity of mole- cules is needed to recognize as large a set of antigens. Furthermore, while a low-affinity receptor might provide enough signal for accurate odor detection and recognition, the immune system’s task requires much more than simple detection and recognition. It is not enough to detect the presence of a foreign antigen; each and every antigen-bearing molecule or cell that binds the receptor of an activated B-cell needs to be attacked. The immune system’s effectiveness in doing this depends directly on antibodies’ affinity for an antigen, and an ellaborate set of processes involving amplifica- tion of activated cells, somatic hypermutation and the germinal center have evolved to maximize antibodies’ affinity for the antigens that activate a B-cell. Thus, every second cell generated during
Architectural differences with the immune system
the process of hypermutation has a different receptor (Janeway and Travers, 1994). Clearly, it would be immensely costly in genome size, if not impossible, to achieve such a large repertoire of high affinity receptors with a fixed set of genes. Specificity of response calls for a more ellaborate system of diversity generation.
Could immunoglobulins work as odor detectors? Clearly, they could be expressed on the surface of olfactory receptor neurons; several members of the immunoglobulin superfamily are membrane- associated. Whether antibodies can evolve to bind small volatile molecules is an open question, but they are known to bind small molecules. Would the large repertoire of specificities of the immune system work in the olfactory system? Possibly not: each odorant receptor gene acts as a labeled line to the brain, not only to glomeruli in the mammalian olfactory bulb and insect antennal lobes, but also beyond into the insect protocerebrum (Wong et al., 2002; Marin et al., 2002), and it is unclear that the benefits of increased dimensionality of the olfactory representation offset the costs at increasingly large number of such labeled lines. Indeed, a large fraction of the members of the human odor receptor family are pseudogenes, suggesting that, at least in a species with little reli- ance on olfactory-mediated behavior as humans, there is not much selective pressure for an increased set of odor receptors. A gene family evolved from immunoglobulins could have developed broader specificities, though; MHC molecules are one such family. The critical question, then, is which came first: olfactory receptor genes or immunoglobulins. ORs came first, the reason for the evolution of immunoglobulins is apparent. If, on the other hand, immunoglobulins preceded ORs, then perhaps that indicates a fundamental inability of immunoglobulins to evolve affinity for small organic molecules or to develop broad-tuned response profiles.
Architectural differences with the immune system
The evolutionary history of the immune and olfactory systems
Let us take a brief look at the history of both systems. How old is the immune system? Although even primitive creatures such as sponges have means of distinguishing self components from non- self components, cellular immunity does not appear until worms or starfish, none of the complement system appears until arthropods, and immunoglobulins and lymphocytes do not appear but in verte- brates (Steiner, 1996; Encyclopaedia Brittannica Online, 2001) —although immunoglobulin-like domains have been found with functions different from antigen recognition in C. elegans and Droso- phila (Steiner, 1996). Analysis of genetic diversity suggests the divergence from the ancestral immu- noglobulin took place some 200,000,000 years ago. Based on paleontological evidence, this is about the same as the time at which amphibians are thought to have diverged from the main verte- brate line. It is not until one reaches the level of the terrestrial vertebrates—amphibians, reptiles, birds, and mammals—that a complete immune system with thymus, spleen, bone marrow, and lymph nodes becomes evident and that both IgM and IgG antibodies are made. Antibodies of the IgA class are only found in birds and mammals, and IgE antibodies are confined to mammals.
Olfactory receptors, instead, appear to be much older, and a complete olfactory system is present in insects as well as vertebrates, with simpler membrane-bound chemodetection systems present in worms, yeast and even bacteria (see §1.4). The evidence is thus consistent with the fact that immu- noglobulins evolved much later than odorant receptors to fulfill a function that odorant receptors could not have performed themselves.
Hereditary response profiles?
Note that the differences in the diversity-generation mechanisms dictates a secondary difference:
while odor-response profiles are largely hereditary, immune response profiles have both a genetic
Architectural differences with the immune system
and random components. Whether this difference was a driving force for the evolutionary differ- ences or a consequence is debatable: it is advantageous to both systems to preserve specificities selected for in the past, as it is advantageous to both systems to have a diverse set of specificities in a population.