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 The
immune system fights infection by recognizing and destroying invading
pathogens. To do this effectively, it must distinguish between proteins
that are foreign and those that are not. Once this skill is acquired,
the immune system is able to recognize foreign antigens and initiate an
immunological response against them while ignoring proteins that are not
foreign.
Occasionally
the immune system malfunctions and attempts to destroy self-proteins,
mistaking them as foreign. This phenomenon is known as autoimmunity. Autoimmune
diseases comprise a group of more than 75 chronic and disabling illnesses
that can target almost any of the body’s tissues. It has been suggested
that a subset of neuropsychiatric disorders result from autoimmune processes.
The next several columns will review how the immune system normally functions
and what happens when it malfunctions in autoimmune reactions. The importance
of this area lies in the recent hypothesis that vulnerable individuals
may develop several psychiatric disorders including Tourette’s syndrome
and obsessive-compulsive disorder through an autoimmune process. It is
important for us as clinicians to understand this phenomenon and how it
might arise as well as the controversies that exist in the current debate.
The
immune system can be divided into two distinct arms: the innate and the
adaptive systems. Innate immunity is the more primitive component and
is found in many organisms. It refers to systems that are already in place
and that do not require any further modifications to operate. Skin is
a good example of innate immunity. Another is the ability of phagocytic
lymphocytes to recognize certain proteins such as bacterial lipopolysaccharide
molecules and to engulf organisms that have these proteins on their surfaces.
Over the millennia pathogens have been evolving mechanisms to evade detection
while mammalian immune systems have been evolving more sophisticated means
of destroying them. Adaptive immunity is a more recently evolved immune
mechanism. It differs from the innate mechanisms by having the capacity
to recognize millions of different antigens associated with specific proteins,
thereby generating a more specific immune response. In addition, an adaptive
immune response takes several days to develop, in contrast to the innate
response, which is always present and therefore immediate (Fig.
1). Finally, once an adaptive response is mounted against a specific
antigen, a memory of that antigen is maintained throughout the life of
the organism, making possible a more rapid response to subsequent infections.
Three
cells are critical for the adaptive response: B cells, T cells, and antigen-presenting
cells (APCs). B cells are the lymphocytes that produce antibodies: the
proteins—also called immunoglobulins—that bind to foreign antigens.
Their production is one of the important early steps in signaling the
detection of a foreign protein.
T cells are divided into two types based on the expression of specific
receptors on their cell surfaces. T cells with CD8 receptors are called
killer T cells. These cells are responsible for the destruction of cells
that are infected with pathogens. T cells with CD4 receptors on their
surfaces are called helper T cells. These cells provide signals to antibody-producing
B cells and instruct them to make antibodies.
The
third cell type critical to the adaptive immune response, the APCs, present
antigens either to T cells or to B cells within the lymphoid tissues,
thus informing them of an ongoing infection. When viruses or other foreign
pathogens are engulfed by an APC, the proteins that make up the organisms
are digested into small peptides of only 10 to 15 amino acids in length.
These smaller peptides are bound to specific proteins, members of the
major histocompatability complex class of proteins (MHC I or MHC II).
Once the peptide associates with the MHC proteins, the resulting immune
complexes are transported to the surface of the APCs. The presentation
of these protein-peptide complexes on the cell surface activates a small
subset of T cells and B cells that are programmed to recognize the foreign
peptide.
In
general there are two types of infection, each of which requires a different
immune response: cell-mediated and humoral immunity. Killer or cytotoxic
T cells become activated in cell-mediated immunity. These lymphocytes
seek out infected cells and target them for destruction. In humoral immunity,
B cells become activated through T helper cell stimulation. The B cells
secrete specific antibodies directed against the antigens, and these antibodies
initiate their own sequence of immune events to combat the foreign proteins.
Cell-mediated
immunity is exemplified by the mammalian response to viral infections.
Viruses specialize in getting inside the host’s cells and using the
host cell’s genetic material to replicate. There is not much that
can be done to save a cell once it has been infected with a virus. The
immune strategy that has evolved is simply to destroy the infected cells.
APCs also become infected with the viruses that cause the more widespread
infection. The APCs digest portions of the infecting pathogen into peptides,
bind these peptides to MHC I proteins, and present these immune complexes
on their cell surfaces.
Killer
T cells that recognize the MHC I-peptide complexes then become activated.
They multiply in lymphoid tissue and move into the circulation in search
of other virally infected cells that carry similar MHC I-peptide complexes
on their cell surface. The close apposition of T cells with infected cells
stimulates the secretion of several signaling molecules that activate
the apoptotic (cell death) pathway in targeted cells. In this way, virally
infected host cells are destroyed as a means of combating the infection.
Certain viruses have learned to evade the APC system; they remove all
MHC I proteins from the cell surfaces. A parallel strategy has evolved
in mammalian cells in response to these specialized viruses. Natural killer
cells recognize cells that lack MHC I proteins and specifically target
them for destruction.
In
the second type of infection, which stimulates a humoral immune response,
the host’s cells are not infected. Instead, the pathogen replicates
in the extracellular space outside of the cell. As with cell-mediated
immunity, APCs engulf some of the pathogenic organisms and digest them.
Once again, small peptides are attached to MHC proteins for presentation
on the cell surface of the APCs. This time, however, the peptides are
attached to the MHC II class of proteins.
The
APCs migrate to lymphoid tissues and the peptide-MHC complexes are again
recognized, but this time by helper T cells. The activated T cells in
turn stimulate specific B cells to produce antibodies against the peptide
displayed on the surface of the APCs. Antibodies are secreted into the
circulation and bind to the pathogens when they encounter them. As the
antibodies bind to the extracellular pathogens, larger immune complexes
accumulate and attract phagocytic cells that ingest the pathogens. In
this way, a humoral response is mounted that helps to clear the bacterial
infection.
As
mentioned above, it is critical for the immune system to recognize the
difference between foreign antigens and antigens that are not pathogenic,
but part of the self. Tolerance is the term used to describe how
the body learns to differentiate self from foreign antigens. When B and
T cells are first generated (B cells in bone marrow, T cells in the thymus
gland), each cell expresses a specific receptor on its surface. Each is
unique, but as a group they are capable of recognizing virtually all possible
antigens, including those on the cells of the self. Cells that recognize
and target self-antigens for destruction must be eliminated if the body’s
own tissues are to be protected from an immune response.
Three
different mechanisms have been proposed to explain how tolerance arises:
ignorance, apoptosis, and anergy. The simplest of the tolerance mechanisms
is ignorance, which occurs when the immune system is never exposed to
certain proteins and thus does not react to them. This happens with immune
privileged sites such as the eye, brain, and testes. In addition, certain
proteins are sequestered, or hidden, inside the cells and thus never presented
to the immune system.
The
majority of B and T cells that recognize self-proteins are eliminated
when they are still immature through a second tolerance mechanism. The
developing immune cells that recognize self-proteins on cell surfaces
are deleted from the immune repertoire through genetically programmed
cell death—apoptosis. A slightly different situation is thought to
happen to immature B and T cells that are exposed to soluble self-proteins.
These cells become unresponsive or anergic to the antigen. Anergy is a
third form of tolerance.
The
net result of these processes is that the immune cells that might respond
to self-proteins are either shielded so they do not know the self-proteins
exist, or are killed or prevented from maturing. When tolerance mechanisms
operate normally, only a fraction of the B and T cells that are born actually
develop into mature lymphocytes. That is, only the immature cells that
have not encountered self-antigens during earlier stages of development
mature normally. They migrate from the bone marrow, where they are born
to the peripheral lymphoid tissues, where they develop into mature immune
cells.
We
now turn to some of the ways that tolerance fails. Sequestered or hidden
antigens such as those on intracellular proteins are likely not to have
been recognized as self-proteins because the immature T or B cells were
never exposed to them. If these proteins are later released into the circulation,
they may elicit an autoimmune response. For example, the eye disease,
sympathetic ophthalmia, occurs after serious trauma to an eye. The release
of proteins from this normally privileged site leads to an immune response
directed against the released proteins that are also present within the
good eye. The resulting autoimmune response often leads to damage and
blindness in the undamaged eye. Immunosuppressant medication and the immediate
removal of the damaged eye can help to prevent an autoimmune reaction.
Superantigens
have also been put forward as an etiological explanation for certain autoimmune
disorders. Some bacteria or viruses produce toxic peptides. These toxins
are potent stimulators of T cells. They inappropriately bind to, and activate,
a significant subset of the population of T cells. As described above,
the typical presentation of antigen to T cells occurs through APCs. Superantigens
circumvent these normal mechanisms by forming an inappropriate bridge
between MHC II proteins on the APC and the T cell receptor on T cells.
The bridge that is formed activates the T cells even though the T cell
receptors would never have recognized the MHC proteins. Superantigens
are thus capable of eliciting an enormous immune response by activating
approximately 1 in 10 T cells. The activation and expansion of these T
cells results in the release of large amounts of inflammatory cytokines
as well as the stimulation of antibody-producing B cells.
The
final mechanism to be discussed is molecular mimicry. The idea of molecular
mimicry is based on the observation that certain epitopes are shared by
both a foreign antigen and a protein in the host. The individual responds
normally to the foreign protein by producing antibodies directed against
it. However, the antibodies then cross-react with host tissues and target
them for destruction.
Paraneoplastic
cancers are an important example of this process. Paraneoplastic neurological
disorders are autoimmune disorders that occur in patients with specific
types of malignancies. The tumor cells in these malignancies inappropriately
produce certain proteins that are normally found only within neurons in
the CNS. When these proteins are expressed by the tumor cells, they act
as immunogens and initiate an autoimmune process. High titers of antibodies
are secreted as the body attempts to eradicate the tumor cells. Unfortunately,
the antibodies also recognize the protein normally expressed in the CNS.
They bind to it and compromise its usual neuronal function. These patients
often present with neurological symptoms rather than symptoms more directly
related to the underlying tumor. When the underlying malignancy is removed
or effectively treated, the neurological symptoms frequently disappear.
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