Type 1 Diabetes: Cellular, Molecular & Clinical Immunology
Theoretical Essay G - Was There Type 1 Diabetes in the Olduvai Gorge?
David V. Serreze* and Derry C. Roopenian*
*The Jackson Laboratory, 600 Main St., Bar Harbor, Maine 04609, Phone-207-288-6403, Fax-207-288-6079, firstname.lastname@example.org
The T cell mediated autoimmune destruction of insulin producing
pancreatic beta cells that leads to type 1 diabetes (T1D) in both humans and
NOD mice is under complex polygenic control [reviewed in
(1-2)]. Insulin treatment, without which T1D is a lethal disease, was
not developed until the 1920s. Furthermore, T1D often strikes individuals
at a young pre-reproductive age. Hence, if genes predisposing to T1D were
inherently deleterious, it might be expected that they would long ago have
been eliminated by natural selection from the human gene pool. This has clearly
not occurred since in many parts of the developed world the frequency of T1D
is increasing (3). The question then becomes
why are genes contributing to T1D still maintained in the human gene pool?
Perhaps the answer is that at some time these genes actually conferred a selective
advantage to humans under environmental stresses differing from those of the
present, and the induction of such alternative gene functions suppressed T1D
development. One such beneficial function of "T1D genes" may be
an ability to generate highly effective immunological responses against pathogens
that are no longer commonly encountered by humans living in aseptically privileged
societies. If this were true, then it is possible genes currently thought
to only exert sinister diabetogenic effects were present in the earliest hominids
residing in the Olduvai Gorge, but instead of eliciting T1D, they exerted
other functions that allowed such individuals to ward off a wide range of
infectious agents, and thus survive to become our ancestors.
Studies in the NOD mouse have provided insight to how particular genes might reciprocally contribute to T1D susceptibility or an ability to mount potent immunological responses to infectious agents. It appears that susceptibility genes both within and outside the major histocompatibility complex (MHC) interactively regulate the extent to which antigen presenting cells (APC) which are comprised of B-lymphocytes, macrophages, and dendritic cells can activate T cell responses [reviewed in (2)]. T cells display different functional outcomes when achieving various activation thresholds. These functional outcomes include positive selection, induction of effector activity, or apoptotic deletion either in the thymus (negative selection) or in the periphery [reviewed in (4-6)]. Intrathymic or peripheral deletion of T cells expressing a T cell receptor (TCR) that recognizes a peptide derived from a normal endogenous protein bound to a "self" MHC molecule on APC represents an important mechanism for preventing autoimmunity. The level of APC mediated T cell activation required to trigger such a deletional response is higher than that needed to induce positive selection, or effector function. Since they are relatively abundant compared to those from "foreign" pathogens, peptides derived from endogenous proteins are normally presented at sufficiently high levels to induce the deletion of any T cells that recognize them. However, if the combined effects of particular genetic variants decreases the stimulatory capacity of APC, this could preferentially diminish their ability to trigger the deletion, but not the positive selection or functional activation of autoreactive T cells. Indeed, the combined effects of genes both within and outside the MHC contribute to APC from NOD mice having a lower immunostimulatory capacity than those from control strains. This is likely to be an important factor in the development of autoreactive diabetogenic T cells in NOD mice [reviewed in (2)]. MHC gene products likely contribute to decreased APC stimulatory capacity through their peptide binding and presentation functions. Non-MHC genes contribute to fewer APC reaching a full maturational state in NOD mice than in control strains, which could also lead to diabetogenic T cells not being activated to a deletional threshold. Defects in APC maturation have also been reported in human T1D patients (7-9). While the presence of APC with a relatively low immunostimulatory capacity may have a dangerous component of impairing the deletion of autoreactive T cells, this situation could simultaneously confer a selective advantage of broadening the overall T cell repertoire allowing for resistance to a wider array of pathogens.
The advantage gained of broadening a pathogen responsive T cell repertoire by reducing the ability of APC to mediate deletional, but not effector mechanisms, would be negated if the autoreactive T cells generated as a byproduct of this process became functionally activated. Such a concern would be obviated if activation of pathogen reactive T cells eliminates or functionally suppresses the autoreactive effectors. Evidence that this may occur is provided by the fact that T1D development is strongly suppressed in NOD mice exposed to a wide range of microbial agents or other immunological stimuli [reviewed in (10)]. Indeed, NOD mice survive infection with murine hepatitis virus, which is lethal to most strains, and at the same time are rendered T1D resistant (11). The question is how this occurs? One possibility is that the array of cytokines induced in response to a pathogen infection, as well as Toll receptor stimulation, feeds back to APC in a way that now increases their stimulatory capacity to a level sufficient to trigger the deletion of autoreactive T cells, or perhaps also activate some other immunoregulatory mechanisms. As described above, since endogenous antigens would be relatively more abundant than those derived from pathogens, autoreactive rather than microbial reactive T cells would be the most likely to undergo deletion following an increase in APC stimulatory capacity. It should be noted that some infectious agents, in particular Coxsackie viruses, have been proposed to serve as a positive environmental trigger of T1D development in genetically susceptible individuals [reviewed in (12-13)]. However, studies in NOD mice have indicated that a Coxsackie infection can only accelerate T1D onset if it occurs after a critical threshold level of autoimmune responses against beta cells have already developed (14-15). Furthermore, a Coxsackie virus infection of NOD mice that have not yet developed significant levels of beta cell autoimmunity actually inhibits T1D development, perhaps through the mechanisms described above (15).
The scenario described above for NOD mice could also partially explain why in humans there is a higher rate of T1D in sub-tropical rather than tropical populations, and that more advanced economic development is also associated with increased risk (3, 16-17). Of course, one contributing factor is that the frequency of certain MHC susceptibility variants, such as the DQ8 class II gene product, are enriched in high risk populations [reviewed in (18)]. However, there is epidemiological evidence that when exposure to dangerous pathogens is high, what are now thought to be "T1D permissive" MHC variants also exert beneficial effects. This is illustrated by the fact that the Dutch colonists who survived the multiple tropical diseases of Surinam were preferentially those who inherited MHC alleles also associated with T1D susceptibility (19). Such protection was not due to a founder effect. It was not determined whether these pathogen resistant Dutch settlers and their descendents developed T1D at a lower frequency than the relatively high rate characterizing MHC-matched individuals in their home country. However, given their subsequently high survival and reproductive rate, it is tempting to speculate that T1D was rare among the pathogen-exposed Dutch residents of Surinam that carried what are normally considered to be high risk MHC variants for this disease. If so, one contributing factor to the lower levels of T1D in tropical than sub-tropical environments might be that the former is more conducive to the outgrowth of pathogenic microbes, and this forces what would otherwise be T1D permissive MHC variants to exert an alternative beneficial function of warding off infection. Conversely, the more economically developed countries will usually possess advanced sanitation systems which might reduce exposures to microbial pathogens, and hence allow MHC variants that would normally protect against infections, to instead mediate deleterious autoimmune functions leading to T1D.
A further indication that T1D susceptibility genes do not represent inherently deleterious variants is increasing evidence they are actually common physiologically normal alleles which exert pathogenic functions only in certain combinatorial contexts. Jorn Nerup was the first to hypothesize this would be the case (20). Supporting evidence has come from a study that was the first to determine the actual identity of a T1D susceptibility gene outside the MHC in NOD mice. This study found that two allelic variants of ß2-microglobulin (ß2m) differing by a single amino acid conferred susceptibility or resistance to T1D (21). However, neither variant represents an aberrantly functional mutant, as both dimerize with and induce normal expression of MHC class I molecules on the cell surface, but in a subtly different structural conformation which determines the extent to which they select diabetogenic T cells. Furthermore, while the pairing of particular ß2m and MHC class I allelic variants appears to be an important component of T1D development in NOD mice, this pairing is not inherently pathogenic since it also occurs in many other strains lacking autoimmune proclivity. Similarly, there is epidemiological evidence that when expressed in conjunction with particular class II alleles, the presence of common HLA-A2 MHC class I molecules (present in ~40% of Caucasians) can lead to a very rapid onset of beta cell autoimmunity and T1D (22). This was supported by the finding that human HLA-A2.1 MHC class I molecules transgenically expressed in NOD mice can mediate autoreactive T cell responses that further accelerate T1D development (23).
In conclusion, what we now think to be deleterious T1D susceptibility genes, may very well have been present among our earliest ancestors residing in the Olduvai Gorge. The fact that these genes were not subsequently removed by natural selection processes that would be expected to occur if their only function was to induce what was an early lethal disease throughout most of human evolution, indicates they actually have other primary functions. These alternative gene functions are hypothesized to entail a loosened selectional process that allows for development of a broadened repertoire of pathogen reactive T cells enabling the individuals carrying them to survive what would otherwise be lethal infections. The development of autoreactive T cells would be a byproduct of such a loosened selectional process. This would not be a problem if the autoreactive effectors were kept in check by mechanisms induced through recurrent activation of pathogen reactive T cells. However, the autoreactive T cells could elicit dangerous outcomes, including T1D development, if pathogen exposure was reduced through migration, improved sanitation, or other means. This scenario of conferring beneficial functions under environmental stresses that have greatly lessened in modern times, could explain why allelic variants currently defined as conferring susceptibility to T1D remain in the human gene pool, and now exert pathogenic rather than life saving activities.
Reference List - links to PubMed available in Reference List.
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