Download Autoimmune diseases: genes, bugs and failed regulation

© 2001 Nature Publishing Group http://immunol.nature.com
O VERVIEW
© 2001 Nature Publishing Group http://immunol.nature.com
In this Overview, common themes of the accompanying News & Views on RA, SLE, IDDM, thyroiditis and
MS are discussed. A unifying concept for the development of these and other autoimmune diseases
should incorporate genetic predisposition, environmental factors and immune dysregulation.
Autoimmune diseases:
genes, bugs and failed regulation
Joerg Ermann and C. Garrison Fathman
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA. ([email protected])
The five accompanying News & Views articles in this issue of Nature
Immunology review pathogenetic mechanisms in five clinical disorders
that are generally regarded as being autoimmune in nature: rheumatoid
arthritis (RA), systemic lupus erythematosus (SLE), insulin-dependent
diabetes mellitus (IDDM), autoimmune thyroid disease and multiple
sclerosis (MS)1–5. This article will explore three common themes that
underlie the induction and perpetuation of these, and other, autoimmune diseases: genetic predisposition, environmental factors and
immune regulation (Fig. 1).
What is an autoimmune disease?
The definition of an autoimmune disease is somewhat vague but
includes the demonstration of autoimmune phenomena such as autoantibodies and/or autoreactive lymphocytes (antibodies or cells that react
against self). Several autoimmune disorders—including Grave’s disease (hyperthyroidism due to stimulating antibodies against the thyroid
stimulating hormone receptor)4, myasthenia gravis, pemphigus vulgaris
and immune cytopenias—are mediated by pathogenic autoantibodies.
In most cases, however, it is not clear what mechanistic role the autoimmune processes have in the pathogenesis of the disease. Autoimmune
attack against “self” may be involved in the initiation and/or perpetuation of disease. The autoimmune processes seem to result, in certain
instances, from a normal (or aberrant) immune reaction against an
exogenous pathogen with subsequent “spreading” of the immune
response to recognize self tissue; this reaction can continue in the
apparent absence of the initiating pathogen. Most often, however,
autoimmune phenomena are simply phenomenological events (for
example, false-positive autoantibody tests) without pathogenetic relevance. As discussed in two News & Views1,5, the effector phase of some
autoimmune diseases, which cause organ damage and clinically
detectable disease, is mediated by nonimmune cells and events.
Genetic predisposition to autoimmune disease
A common feature of autoimmune diseases is their propensity to
appear in families, which suggests an underlying genetic susceptibility.
Not only humans with autoimmune diseases, but also their animal
model counterparts, share this apparent genetic predisposition. The
genetics of autoimmune diseases in humans and animal models are
complex and apparently involve many genes (for a Review on nonMHC genes see Wakeland in this issue6). Only a few of the genes
involved in the pathogenetic mechanisms that underlie autoimmune
diseases are actually known. More commonly, allelic variants of chromosomal regions have been linked to an increased disease risk. Some
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of these “susceptibility regions” are similar in humans and rodents.
More importantly, a number of the genetic loci relevant to at least four
of the five diseases discussed in the accompanying News & Views articles are shared in some manner6. It is not clear whether this “sharing”
is due to the clustering of different, perhaps related, genes specific for
individual diseases within these regions, or whether different diseases
share a common set of genes that predispose them to autoimmune disease in general, while other loci determine the target organ. Any analysis of the genetic predisposition to develop an autoimmune disease is
complicated by the existence of “protective genes” that may mask disease susceptibility and modify the risk imposed by “susceptibility
genes”; this is clearly demonstrated in a mouse model for SLE7. On the
positive side, however, the identification of such “protective genes”
may hold clues to new targets for therapeutic intervention.
One gene cluster stands out among all others in defining genetic
susceptibility to all five of the autoimmune diseases described in the
News & Views (as well as in their animal models): the region that
encodes the major histocompatibility gene complex (MHC). The association between MHC products and autoimmune diseases has been
known for more than 20 years and is one of the major arguments for a
central role of T cells in the pathogenesis of these diseases. As
Feldmann points out, RA (and other autoimmune diseases) can develop in the absence of the “disease-associated” MHC haplotype1. In a
disease as clinically heterogeneous as RA, indeed in most autoimmune
diseases, it may be that disease heterogeneity obscures any absolute
requirement for MHC identity among all diseased individuals.
However, the MHC association is sufficiently strong in human IDDM
to allow certain MHC alleles to be used as markers of genetic predisposition to the development of IDDM in models of disease prediction
and intervention (see the News & Views by Eisenbarth3).
The initial idea that the MHC class II gene product associated with
IDDM was “altered” in some way and, therefore, represented a diseasespecific gene product or a disease-associated mutation was dismissed
when it was shown, by sequence analysis, that the disease-associated
MHC gene seen in patients with IDDM was indistinguishable from the
same gene in nondiseased people8. However, it was found that in IDDM
(and RA), different allelic variants of disease-associated MHC molecules, which increase the risk of disease, share certain structural features,
as is described by Eisenbarth3 and Feldmann1 in this issue. In both human
IDDM and the nonobese diabetic (NOD) mouse model of spontaneous
IDDM, there is a substitution of a neutrally charged amino acid for the
negatively charged amino acid aspartic acid and mouse MHC class II
genes associated with diabetes susceptibility7. In RA, HLA-DR variants
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Similar mechanisms have been postulated for other diseases discussed
that confer an increased risk of disease, or severity of disease, contain a
short conserved amino acid sequence within a specific section of the β- here, some of which, like MS, show clear epidemiological features of an
chain of the disease-associated MHC class II molecule, the “shared epi- infectious disease5. However, MS has defied multiple and prolonged contope”. These data imply that it is the normal allelic variant of the MHC ventional analyses to define any particular etiologic pathogen. Studies in
molecule itself, and not some other gene within the MHC complex, that animal models, in particular experimental autoimmune encephalomyelitis
confers the increased risk of developing autoimmune disease. In addition, (EAE), have allowed a careful dissection of the kinetics of response and
because these structural features affect the peptide-binding characteris- the evolution of autoimmune disease. However, because patients who
tics of the MHC molecules, they point to a central role for antigen-pre- state that they are going to develop an autoimmune disease in the near
sentation events in the pathogenesis of these diseases. However, the man- future are not encountered in the doctor’s office, new and better methods
ner in which the MHC molecules affect predisposition to IDDM, RA or of epidemiological evaluation must be employed to provide a pathophysother autoimmune diseases is still not understood. MHC molecules serve iological link between the environment and the disease.
both as “thymic selecting elements” to create the repertoire of naïve T
One such example of an epidemiological analysis of the potential
cells, and then, in the periphery, present antigenic determinants of foreign relationship between the immune response to an infectious agent and
proteins to the same T cells to prime them
the subsequent induction of an autoimfor antigen-specific immune responses.
mune disease is the previous infection
Thus the role of these predisposing MHC
with Epstein-Barr Virus (EBV) of SLE
gene products could either be in selection
patients. This potential association highGenes
of the repertoire during thymic developlights the inherent problems in assigning
ment, in the presentation of (auto) antiassociations of previous infectious expogenic peptides to the T cells in the periphsure to an autoimmune disease. Only by
ery, or both. These alternatives have been
analyzing stored serum samples from
discussed9.
military personnel who developed SLE,
who had previously provided serum
samples for an epidemiological analysis
Environmental factors predisof another disease (AIDS), was one
posing to autoimmune disease
T
Autoimmune
group able to propose that exposure to
Another disconcerting fact about genetdisease
EBV may have triggered an immune
ic predisposition to autoimmune disease
B
response in SLE patients. They found
is the lack of concordance in identical
DC
Environment
that a single antigenic determinant on
twin pairs for any of the five diseases
EBV was shared with one of the known
discussed in the News & Views, as well
Immune
regulation
SLE autoantigens11. With such comas other autoimmune diseases that have
been studied. Autoimmune disease
pelling associations between exposure to
becomes manifest in less 50% of the
environmental antigens and resultant
twin siblings of an affected identical
long-term autoimmune sequellae, it is
twin; this poses a major problem for any
likely that more such associations await
Figure 1. Requirements for the development of an
simple explanation of the genetic condiscovery.
autoimmune disease. The immune response of a geneticaltrol of autoimmune disease developly predisposed individual to an environmental pathogen, in
association with defects in immunoregulatory mechanisms,
ment. To explain this low concordance
Immune (dys)regulation in autocan lead to the development of an autoimmune disease. The
rate among identical twin pairs, one has
immune disease
importance of the single components represented in this Venn
to either consider a certain stochastic
As pointed out by Lipsky in this issue2,
diagram may vary between individuals and diseases. However,
element in disease development (for
autoimmune
disease is not the same thing
the appearance of an autoimmune disease requires the convergence of all three components.T,T cell; B, B cell; DC, denexample, the creation and selection of
as autoimmunity. Autoimmune phenomena
dritic cell.
the expressed T cell repertoire) or
can be shown in healthy human individuals,
search for an initiating external event
most frequently in the siblings of affected
such as the response against an environindividuals: low-titer autoantibodies, for
mental pathogen.
example, are a relatively common finding (“false-positive autoantibody
Lyme arthritis represents an example for the potential evolution of an tests”). As a matter of fact, autoreactivity is a built-in feature of the immune
immune response against an infectious agent to an “autoimmune” system. The T cell receptor repertoire is positively selected on MHC–selfresponse directed at a cross-reactive antigenic determinant of the peptide complexes in the thymus, and naïve T cells require contact with
pathogen that is shared with a self-protein. This disease was originally self-MHC molecules in the periphery for their survival and effector functhought to represent a cluster of patients with juvenile RA but, through tion12. This means that all the T cells in the periphery are, by definition,
painstaking epidemiological analysis and diligent microbiology, was autoreactive. T cells bearing receptors that encounter self-antigens with a
shown to represent initial infection with a tick-borne pathogen with a high-avidity response during thymic development are negatively selected.
resultant autoimmune response to a self-protein, leukocyte function- However, this process is incomplete, as not all self-antigens can be suffiassociated antigen 1 (LFA-1, also known as CD11a and CD18). LFA-1 ciently presented during the thymic selection processes. In addition, the
shares an antigenic determinant with the outer surface protein antigen demonstrable ability to induce autoimmune diseases in rodents with suitof the inducing infectious agent, the spirochete Borellia burgdorferi10. able immunization protocols (as in EAE or collagen-induced arthritis) is
In about 10% of patients, antibiotic treatment does not resolve the dis- evidence that autoreactive lymphocytes with pathogenic potential exist in
ease, which suggests that the autoimmune process continues indepen- the periphery of normal animals and, by inference, in normal humans. A
number of tolerance mechanisms exist in the periphery that keep these
dently of pathogen persistence.
Bob Crimi
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O VERVIEW
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© 2001 Nature Publishing Group http://immunol.nature.com
O VERVIEW
potentially dangerous self-reactive cells in check: clonal ignorance, deletion, anergy, immune deviation and suppression13. However, it is still
unclear how important any of these mechanisms are in preventing autoimmune disease.
Nevertheless, a number of examples from mouse models (and a few
from patients) have shown that the disruption of distinct immunoregulatory pathways can lead to the development of disorders with autoimmune features. First, MRL lpr/lpr mice, which harbor a disruption of the
gene that encodes Fas, spontaneously develop a multi-organ autoimmune disease with symptoms that are similar to SLE. The same phenotype is found in gld/gld mice, in which the gene that encodes the ligand
of Fas (FasL) is disrupted. Fas-FasL interactions are thought to be
important for the termination of immune responses through activationinduced cell death (AICD) of lymphocytes. In a small number of human
subjects, a similar disease has been described as autoimmune lymphoproliferative syndrome; these patients have variable mutations in their
Fas genes14. Second, cytolytic T lymphocyte–associated antigen 4–deficient (CTLA-4–/–) mice succumb to a severe lymphoproliferative syndrome with organ infiltration within first 3–4 weeks of life. Third, mice
with targeted mutations of interleukin 2 (IL-2) or CD25 (the α chain of
the high-affinity IL-2 receptor) develop a fatal disease characterized by
lymphoproliferation, lymphocytic organ infiltration, colitis, autoantibody formation and anemia15. Despite the fact that lymphoproliferation
is not a prominent feature of all the diseases discussed in the News &
Views, it is noteworthy that CTLA-4 has been mapped as a susceptibility gene in both human autoimmune thyroid disease4 and IDDM3,
whereas IL-2 (as well as CTLA-4) are found in genetic regions linked to
disease susceptibility in the NOD mouse3.
The phenotype observed in CTLA-4–/–, IL-2–/– and CD25–/– mice has
been explained as being the consequence of a lack of negative regulatory signals in the CTLA-4–/– mice and insufficient priming for AICD
in the IL-2–/– and CD25–/– animals15. More recently, a defect in
CD4+CD25+ regulatory T cells has emerged as an interesting alternative
hypothesis. These CD4+CD25+ regulatory “suppressor” T cells were
originally described in mice. After neonatal thymectomy, adoptive
transfer of CD4+CD25+ cells from adult animals can prevent multiorgan autoimmune syndrome from occurring in susceptible mouse
strains. Removal of these cells has since been shown to lead to autoimmune diseases in a number of rodent models (reviewed by Powrie in
this issue16). Interestingly, when analyzed ex vivo, CD4+CD25+ T cells
have high intracellular concentrations of CTLA-4. Although controversial, it has been proposed that CTLA-4 signaling is in some way important for the function of these cells. In addition, CD4+CD25+ regulatory
T cells are missing in mice that lack IL-2 or components of the IL-2
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receptor signaling pathway and these mice have severe autoimmune
phenotypes. This suggests that CD25 is not “just a marker” for this population of regulatory T cells, but that signals provided by IL-2 are
essential for their generation and/or homeostasis. It is now clear that
regulatory CD4+CD25+ T cells exist in humans and that they show in
vitro characteristics that are similar to those seen in studies of their animal counterparts17. Future investigations will show whether
CD4+CD25+ T cells have any role in human autoimmune diseases, that
is, whether quantitative or qualitative defects in these cells contribute to
disease development.
Conclusion
A unifying concept for the development of an autoimmune disease
needs to incorporate genetic predisposition, environmental factors and
immune (dys)regulation (Fig. 1). Among the genetic markers of predisposition to autoimmune disease are specific sets of genes for MHC
molecules that both shape and regulate the specificity of the adaptive
immune response. In addition, variations in a number of other genes
that are important in the regulation of immune responses have been
associated with the development of autoimmune diseases. The genetic
makeup of humans and mice determines not only how the immune system deals with antigenic challenges from the environment, but also how
the immune system is regulated to remain tolerant towards self. Under
certain environmental conditions, such as an infection, failure of regulatory mechanisms and/or an inappropriate immune response to crossreactive self-antigens ensues, which leads to organ damage and/or dysfunction. Many of the steps involved in the pathogenesis of the autoimmune diseases discussed here await further studies. Future data will,
hopefully, lead to a better understanding of the mechanisms that control the autoimmune “phenotype” and the development of new and better treatment strategies.
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