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, dvs@jax.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 ߃2m 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.
For comments, corrections or to contribute teaching slides, please contact Dr. Eisenbarth at: george.eisenbarth@ucdenver.edu