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 The
human immune system is undoubtedly one of the masterpieces of evolution.
The processes of gene rearrangement and somatic hypermutation allow for
the generation of an immense range of binding specificities in both antibodies
and T-cell receptors. Almost any foreign material which find its way into
the human body can be targeted and removed or destroyed with exquisite
specificity. However, the immune system has not arisen in isolation but
is the result of a biological arms race, conducted over millions of years,
between man and the microorganisms that can enter the body and cause disease.
As the immune system has developed, microorganisms have evolved strategies
to subvert or evade its surveillance.
For
the microbes, one logical tactic in this battle has been the development
of camouflage. If the immune system cannot distinguish an invading microbe
from its own tissues, then the battle is all but won. It is therefore
logical that microbial or viral pathogens should evolve surface antigens
that share sequence homology with normal cellular proteins, or at least
present a similar surface structure to the immune surveillance mechanisms.
An
inevitable consequence of this argument is that if an immune response
should be mounted against the pathogen’s antigens, then damage to
host tissues will occur. This tissue damage may continue even if the invading
organism that triggered the immune response has been cleared completely
from the system.
This
is the basis of the “molecular mimicry” hypothesis of autoimmune
disease. An infectious agent gains access to the body and instigates an
immune reaction that eventually clears the pathogen from the system. However,
the antimicrobial antibodies continue to recognize native proteins bearing
cross-reactive epitopes and continue to cause tissue damage. The binding
to host proteins leads to cellular damage and the release of more autoantigen.
This results in reamplification and spreading of the immune response.
In the most fulminate cases, autoimmune destruction of the tissue results.
Since
this hypothesis was first proposed in the early eighties, a huge body
of evidence has accumulated supporting the view that a number of diseases
are caused by molecular mimicry. Over the next several months, this column
will review autoimmune disorders. The coverage of this topic is due to
the recent resurgence of interest among researchers, clinicians, and families
in autoimmunity hypotheses and their possible involvement in the etiologies
of childhood neuropsychiatric disorders.
A
large amount of data has demonstrated both structural similarities and
antigenic cross-reaction of various bacterial, viral, and protozoan antigens
with proteins in human tissues or cellular components of those tissues.
Much circumstantial evidence links the onset or exacerbation of autoimmune
disease with recent infections. In animal models, immunization with either
viral peptides or their tissue antigen homologues can result in the development
of autoimmune tissue destruction that closely mimics certain autoimmune
diseases. Similarly, autoimmunity can be triggered very efficiently in
certain animal models by systemic viral infections. A direct cause-and-effect
relationship for infection and naturally occurring autoimmune disease
in humans still eludes us. Nonetheless, a presumptive role of infectious
organisms is now accepted in many autoimmune diseases, including insulin-dependent
diabetes mellitus (coxsackie viruses), HLA-B27–associated ankylosing
spondylitis (various Gram-negative bacteria), Guillain-Barré syndrome
(Campylobacter), myasthenia gravis (herpesvirus), lyme disease
arthropathies (Borrelia), and multiple sclerosis (various viruses).
Multiple
sclerosis (MS) is a prime example of an autoimmune disease in which the
circumstantial evidence for a viral trigger is becoming almost overwhelming.
As yet, however, there is still no “smoking gun.” MS is caused
by the immunological destruction of myelinated nerves. It has a strong
genetic element to its etiology, with almost two thirds of sufferers carrying
the HLA DR2 allele. Monozygotic twins have a 30% concordance rate (10-fold
higher than dizygotic twins have). The fact that the concordance rate
in monozygotic twins is not 100% strongly suggests that environmental
factors play an important role. There is also an intriguing finding that
individuals who migrate from an area of high incidence to one of low incidence
before their 15th birthday carry the lower risk factor, while those who
migrate after this age retain the high risk factor.
The
course of the disease follows a cyclical pattern of activity and remission,
with exacerbations often following viral infections. The main target of
the immunological effectors in MS is the myelin basic protein (MBP) and
proteolipid-protein components of the myelin sheath, although the oligodendrocyte
antigen transaldolase, and other minor components, are also targeted by
autoantibodies. It is likely that the minor antigens targeted in MS result
from epitope spreading during the course of the disease. (Fig.
1)
Immunization
with MBP, or its component peptides, is sufficient to induce experimental
allergic encephalomyelitis (EAE), which closely mirrors MS, in animal
models. The epitopes that are recognized by the majority of autoantibodies
and self-reactive T cells in MS have been mapped to amino acids 84–103
of MBP, and homologies to peptides within this region are found in protein
components of hepatitis B virus, influenza, adenovirus, Epstein-Barr virus,
papillomavirus, and, most recently, human herpesvirus 6. For example,
the encephalitogenic MBP peptide sequence Tyr-Gly-Ser-Leu-Pro-Gln occurs
in the polymerase protein of hepatitis B virus. A 10 amino-acid peptide
of HBV polymerase containing that sequence, when injected into New Zealand
rabbits, can cause EAE with very similar pathology to MS including both
humoral and cellular immune responses to MBP.
The
genetic linkage of MS to the HLA DR2 allele and the genetic linkage of
other autoimmune disorders to other HLA alleles can be explained to a
large extent by major histocompatibility complex (MHC) restriction. Foreign
antigens are not presented to the immune system as whole molecules. Instead,
they are first cleaved by antigen-presenting cells into short peptides.
These peptides in turn associate with MHC molecules inside the cell and
are only then brought to the cell surface as a complex where they are
recognized by the T cells as a peptide-MHC complex. To a large extent,
the immunogenicity of particular peptide fragments are determined by their
capacity to fit into the peptide-binding groove of the MHC molecules borne
by the cell. Thus, small differences in the MHC proteins will still allow
them to bind the peptide, but will now present slightly different epitopes
on the surface of the cell for recognition by antibodies. The putative
cross-reactive peptide sequence may be effectively presented to the immune
system by only one particular MHC allele. If you do not have that specific
MHC allele, then that specific peptide will not be present on the surface
of the cell. This is thought to be the basis of the genetic restriction,
which is associated with many autoimmune diseases.
As
has been mentioned, there is a strong linkage in the case of MS between
the class II molecule HLA DR2 and disease susceptibility. Similarly, HLA
DR4 is associated with an increased risk of rheumatoid arthritis and HLA
DQ8 with diabetes. The strongest HLA association with autoimmune disease
is that of ankylosing spondylitis with HLA B27, although in this case
the HLA molecule actually bears the cross-reactive epitope itself and
is not simply presenting it to the immune system. It should be noted that
the microbial peptides implicated in the development of an autoimmune
response do not necessarily have to share exactly the same sequence to
elicit cross-reactivity. Two quite disparate sequences that bind in the
groove of the MHC can potentially present a similar molecular surface
to the scanning T cells and, therefore, will elicit a cross-reactive response.
In the case of certain viral peptides known to mimic MBP epitopes, as
few as 4 out of 11 amino acids need match the cognate MBP peptide sequence
for cross-reactivity to be detectable.
Although
molecular mimicry provides a simple and credible model for the initiation
of autoimmunity, it cannot be sufficient in itself to cause disease. The
process of tolerance to self-antigen must also be overcome. The immune
system is strongly biased against self-reactivity. Autoreactive T cells
are generated continually by the hematopoietic system but are largely
removed by antigen-induced apoptosis before they can escape into the peripheral
tissues, a process referred to as clonal deletion. Autoreactive B cells
are not destroyed but are rendered anergic to normal stimuli. In addition,
there are immune effector cells that actively suppress autoreactive responses,
a phenomenon referred to as peripheral tolerance. All these systems must
be broken down for autoimmunity to become a pathogenic process. This fact
is highlighted by the finding that T cells bearing receptors that bind
the encephalitogenic peptides of MBP are found frequently in normal individuals,
but no evidence of autoimmune damage is found even during viral infections.
The autoreactive cells must therefore be effectively suppressed by a mechanism
that is presumably defective, or lacking, in individuals with MS.
It
should be stressed that there are also several other credible theories,
which might explain the linkage between infection and autoimmunity. “Bystander
activation” refers to the aberrant activation of rare autoreactive
cells due to an over-robust immune response occurring during an infection.
In effect, the autoreactive cells receive activation and proliferation
signals not meant for them. “Epitope spreading” is the process
of the sequential development of an immune reaction to epitopes neighboring
the initiating antigen, a well-documented process in both normal immune
responses and systemic autoimmune disease. For instance, many viruses
use intracellular structures as assembly frameworks for the construction
of new viral particles. These associations may well bring the cellular
components into highly immunogenic immune complexes. Indeed, transient
autoantibody production to cytoskeletal antigens is a common finding during
viral infections. “Mistaken self” refers to the misexpression
of antigens normally resident in immunologically privileged sites, or
the release of normally cryptic antigens, by the process of immunological
damage which inevitably follows a robust antimicrobial response. Other
potential contributory factors include the inappropriate overexpression
of class II HLA molecules or the excessive release of proinflammatory
cytokines.
We
can expect a great deal of argument about the physiological relevance
of each theory, but it is likely that all the mechanisms outlined above
will be found to contribute, to varying degrees and in varying combinations,
to the complex array of autoimmune diseases currently recognized.
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