Rapid progress in our understanding of immune function promises
more effective treatments for autoimmune disorders.
Autoimmune disorders occur when the body's immune system turns against
the body itself, attacking as if it were a foreign pathogen. They comprise
more than 50 distinct diseases and syndromes, and affect about 5% of the population
in Europe and North America, with two thirds of the patients being female1. Examples of autoimmune disorders include rheumatoid arthritis,
multiple sclerosis, juvenile diabetes, cardiomyopathy, antiphospholipid syndrome,
Guillain-Barré syndrome, Crohn's disease, Graves' disease,
Sjogren's syndrome, alopecia, myasthenia gravis, lupus erythematosus,
and psoriasis. In addition, such disorders complicate other diseases that
are not autoimmune in origin, such as Duchenne's muscular dystrophy and
artherosclerosis.
The total societal disease burden for autoimmune disorders is difficult
to estimate because while some of these are chronic and debilitating diseases,
others are less serious. Arthritis alone is estimated to cause a $65 billion
disease burden (see Arthritis, pp. 12−14),
so autoimmune disorders as a group are among the most expensive diseases faced
by society today. As a result, they are the subject of significant research
in both academic and industrial laboratories.
Historical perspective Although the clinical manifestations of autoimmune diseases have long been
known, the concept that the body's own immune system was responsible
did not become established until reproducible experimental evidence began
to be obtained from the mid-1960s onward. For example, auto-antibodies against
diseased organs in Sjogren's sydrome were first described in 19652. Animal models at the time also showed how antibodies could be formed
against red blood cells, suggesting correlations with some anemias3.
The mid-1960s also saw initial connections being made between viral infections
and autoimmune diseases, specifically hemolytic anemia, based on clinical
observations4.
In the early 1970s, autoimmune heart disease was first linked to -hemolytic
streptococcus5, and the first theories were developed linking
aging and autoimmunity6. Some autoimmune diseases also began
to be described in increasing molecular detail. For example, diagnostic correlations
were made between molecular markers, such as 2 microglobulin concentration
in saliva, and local inflammation in Sjogren's syndrome, suggesting how
it was possible to identify specific molecules that were involved in the development
of an autoimmune disease, and could therefore serve as diagnostics7.
By the early 1980s, there were significant concerns about the links between
bone marrow transplantation—a leading-edge procedure at the time—and
autoimmune disease side effects8. Ten years later, there was
an interesting application of autoimmune disease principles in a novel direction,
namely that of birth control by immunization against sperm9.
The past decade has also benefited from the advances of molecular biology
and other techniques that enabled the identification of specific autoantigens
involved in a variety of autoimmune disorders. This was critical for strategies
to combat these disorders effectively, by focusing on the triggers and actual
molecules that were involved. Significant progress has been made in these
molecular approaches by using appropriate animal models. One example is autoimmune
encephalomyelitis, a debilitating brain disease. Here, treatment of animal
models of the disease with a neuroantigen and an antibody against CD11a (leukocyte
function-associated antigen 1; LFA-1) protected the animals against the disease,
showing that with appropriate molecular intervention, it was possible to divert
the immune response from a destructive to a nondestructive response10.
These efforts and others have resulted in a variety of therapeutic approaches
against autoimmune disorders that continues to be refined.
Current state As autoimmune disorders cover such a wide variety of molecular and clinical
phenomena, it should come as no surprise that research efforts span the gamut
of approaches and therapeutic targets. The increasing understanding of the
molecular basis of these diseases is helping to focus research directions
in specific areas. Table 1 shows a selection of companies
active in the development of autoimmune disorder therapeutics. The approaches
range from gene therapy to antisense to administration of antibodies, vaccines,
and a variety of cytokines.
Table 1. Selected companies with autoimmune drug discovery programs
At present, the advent of large amounts of genomic information is enabling
a systematic attempt at correlating homologies between pathogens, such as
viruses and bacteria, and specific self proteins. The hypothesis is that these
pathogens might trigger an autoimmune response by virtue of these homologies.
For example, the novel thyroid autoantigen that is the sodium/iodide symporter
(NIS) has local amino acid sequence homologies with three other known thyroid
autoantigens, namely thyroglobulin, thyroid peroxidase, and thyrotropin receptor.
A recent report describes the application of a computer-aided search that
shows NIS to have significant local homologies with no fewer than 11 other
proteins from bacteria or viruses, such as Streptococcus or herpes.
NIS was also found to have extensive—but not local—homologies
with several unknown proteins from invertebrates such as Drosophila melanogaster
and Caenorhabditis elegans, and with bacteria such as Bacillus
subtilis and Xanthobacter11.
Animal models are being used extensively to discover and confirm antigens
involved in autoimmune disorders, and also to help develop effective therapies
based on that knowledge. A recent study describes how rats were induced to
have a particular version of myasthenia by injecting them with peptides derived
from the voltage-gated calcium channel found in neuromuscular junctions12. This protein is believed to be the target of autoantibodies found
in patients with this disease, and the rat model is helping to characterize
the specific epitopes of the protein that are recognized by these antibodies.
Such knowledge can then be used to tailor a vaccine or other therapeutic modality
to interfere with and perhaps abrogate this autoimmune response.
Industry challenges A key challenge to developing therapies for autoimmune disorders is the
cross-reactivity between normal body proteins and those of a variety of pathogenic
agents. For example, hepatitis B virus has an amino acid sequence in one of
its proteins that is highly homologous to that of myelin basic protein (MBP),
which is the target of autoimmune attack in multiple sclerosis. Brain inflammation
is caused in animal models injected with the MBP-homologous component of the
hepatitis B virus. Adenovirus type 2 is another virus with a protein that
has significant sequence homology to MBP. Another example is rheumatoid arthritis.
In animal models, inflammation of the joints can be caused by infection with
Mycobacterium tuberculosis, which has protein components similar to normal
cartilage. Finally, rheumatic fever is sometimes accompanied by damage to
heart valves. Animal models have shown the connection between such damage
and hemolytic streptococcus, which has a cell wall protein similar to heart
muscle myosin. Determining all of these sequence similarities that are not
by-products of evolutionary conservation but that actually have a causative
effect in autoimmunity is a major challenge to researchers. It is being addressed
by systematic analysis and sequence comparison derived from genomics coupled
with relevant clinical information.
Another challenge is identifying not only those autoantigens that are shared
with pathogens, but also those that are part of the native body itself, and
that trigger disease as a result of as yet poorly understood events. A good
example of new classes of such autoantigens is DNA itself. A recent report
highlights the identification and characterization of antibodies against DNA
itself, which might lead to numerous complications associated with cell division
and gene expression13.
Future directions As our understanding of the molecular and cellular aspects of autoimmunity
increases, we will continue to see more effective treatments for these diseases.
For example, multiple sclerosis (MS) is an autoimmune neurological disorder
thought to be mediated by antigen-specific CD4+ T helper (Th1)
T cells which cause demyelination of the central nervous system (CNS). Many
current therapeutic strategies attempt to downregulate the entire immune system
by causing generalized immunosuppression, in the hope that this will reduce
the specific action of the T cells involved. This approach, incidentally,
is widespread in autoimmune treatments in the absence of better options. Unfortunately,
generalized immunosuppression has not met with the success expected. Now,
new approaches tend to employ therapies based on immunomodulation, rather
than immunosuppression, by administration of cytokines such as interferon
(IFN)- and glatiramer acetate, and in the case of MS, these approaches
are proving to be more effective14. Refinements in our understanding
of the effects of immunomodulation versus more drastic measures will no doubt
help us devise even more effective therapies.
The future will also see the identification of putative autoantigens occur
at an increasing rate, based on the application of funtional genomics techniques.
For example, a new major histocompatibility complex (MHC)-restricted autoantigen
from the insulin B chain was recently identified in an animal model of type
I diabetes by screening a disease and pancreatic-specific cDNA library15. This epitope was found to be the same one recognized by pathogenic
CD4+ T-cells, and may thus be formulated into an insulin-derived
preventive therapy.
We are also likely to witness major efforts being undertaken to explain
the gender difference that is observed in susceptibility to autoimmune disease.
There are hypotheses that involve hormonal and other differences, but at this
point many questions have yet to be answered16.
The future will also see more work directed toward understanding the links
between autoimmune diseases, such as MS, and apoptosis or programmed cell
death17. The release of molecules following cell death may cause
immunse system sensitization and thus an autoimmune response, and exploring
this relationship for potential new therapeutic approaches is likely to increase.
A major physiological event that is being explored intensively is that
of oxidative stress damage to DNA. Recently, oxidative damage began to be
correlated with specific cell cycle checkpoint events, which itself opens
up direct links between cell cycle disturbance and several major diseases,
including autoimmunity, and this work is likely to be pursued intently because
of its potential for novel therapeutic targets inside cells18.
In addition, very intense efforts will focus on correlating specific genes
to autoimmune disorders, and also enhancing these correlations with population
studies that reveal polymorphisms and their links to predispositions toward
these diseases. For example, a recent study reports on the correlation between
the cytotoxic T-lymphocyte-associated serine esterase-4 (CTLA4) gene with
Graves disease, using the polymorphic marker Ala17Thr in a Moscow population
of Graves disease patients19.
Finally, further in the future, gene therapy approaches will become increasingly
important in the treatment of autoimmune disorders, based on the administration
of genes or mini-genes encoding for immunomodulatory cytokines or antigens
that would cause tolerization. Efforts are already underway with administration
of antiinflammatory cytokines such as transforming growth factor-1 and
interleukin 4, which had protective effects in animal models of experimental
allergic encephalomyelitis20.
Conclusions Autoimmune disorders are a family of diseases that represent a major societal
burden. While the pace of our understanding of the molecular and cellular
processes of these complex disorders have thus far been behind that of other
diseases, the advent of large-scale genomic and functional analysis tools
are now helping redress the balance. The enormous pressure to understand these
diseases and cure them is the best guarantee of progress in this area.
Reprinted from Nature Biotechnology 17, 1038−1039
(1999).
-hemolytic
streptococcus
2 microglobulin concentration
in saliva, and local inflammation in Sjogren's syndrome, suggesting how
it was possible to identify specific molecules that were involved in the development
of an autoimmune disease, and could therefore serve as diagnostics
