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Immune
system self tolerance
The immune system is a complex defence network unique to every
individual with the primary task of defence against foreign and
dangerous external organisms. Its ultimate 'objective' is to defend
and prolong survival of the individual in the face of competition.
The stimulus for immune system response is based on the ability
to identify self from non-self tissues or possibly due to the
alternative explanation of identifying danger from non-danger
(Matzinger 1994).
The distinction of self from non-self has been the focus of
considerable debate. Self has been described as anything under
the skin save for "privileged sites" which are at least
partially protected from immune system surveillance such as the
brain, cornea, placenta and testis (eg Barker 1977). However,
Matzinger Fuchs et al have suggested this view fails to
take into account that an individual's antigen make up is continually
shifting through puberty, with production of new proteins, mutations
in the genome and exposure through disease to initially intracellular
sequestered antigens (Matzinger 1994). In other words, our immune
system can come into contact with self antigens which they have
never seen before at various points in our lives. Even non-self
is difficult to define with an individual's body daily accepting
foreign food proteins (Matzinger 1994).
Consequently an alternative hypothesis has been put forward
where the immune system responds via antigen presenting cells
(APCs) to danger, distress, destruction and death of body cells
after challenge by exterior influences (Fuchs 1993, Matzinger
1994). Regardless of the distinctions, our immune system must
have the ability to tolerate antigenic challenge from our own
tissue but to defend against infection for ourselves to remain
healthy.
Mechanisms
of tolerance
Within an immune system where defence is reliant on the ability
of a cell population to respond to any challenge and where cells
have single antigen specificity, there will inevitably be cells
capable of responding to an individual's own tissue. Potentially
a naive immune system of any one individual is capable of responding
to any antigen. It needs to be educated as to what is an appropriate,
and more importantly what is an inappropriate antigen to respond
to.
When the ability of the immune system to discern between self
and non-self, danger or non-danger, breaks down, autoreactivity
can arise, where self attacks self. Inappropriate responses can
be held in check by a number of methods. At the same time the immune
system must tolerate self, without compromising reactivity to foreign,
dangerous antigens. In the normal functioning of a human immune
system there are believed to be four main methods of holding autoreactive
immune cells in check. These are clonal deletion, clonal anergy,
active suppression of self reactive clones and sequestering (hiding)
of potentially stimulatory antigens.
"Clonal deletion" was an idea first put forward by Burnett
(1957, 1959). He suggested that if an antigen attached to the receptors
of a young, immature T cell that particular cell would die rather
than become an activated cell. T cells are believed to be rendered
tolerant to self antigens in the thymus (Ramsdell 1990). As immature
CD4- CD8- lymphocytes are produced in the bone marrow they immediately
migrate to the thymus. Here the thymocytes, as immature T cells
are called, must undergo positive or negative selection to determine
each cell's fate. (Kappler 1987, Sprent 1987). If an individual
cell interacts with self MHC plus self antigen peptide on dendritic
APCs or macrophages, cell death (apoptosis) swiftly follows (Berg
1989). It is clear that the thymus is very important in ensuring
clonal deletion by presenting self antigens in this controlled environ.
The thymus does not express all self antigens and so "clonal
anergy" helps circumvent problems with surviving self reactive
mature T cells released from the thymus, particularly those responsive
to MHC class I proteins plus antigens. MHC class I only attach to
bits of antigens (peptides) derived intracellularly (from inside
cells) (Germain 1986). Not all intracellular peptides are present
in the thymus particularly those produced by specialist, differentiated
cells (Mueller 1989) as might be present in hair follicles.It is
possible the thymic epithelium may be involved in some clonal anergy
although evidence is so far only provided by actively preventing
clonal deletion in a disease model and subsequently revealing clonal
anergy (Ramsdell 1990). Clonal anergy in the peripheral blood system
however, can be supported by a convincing level of evidence. Clonal
anergy is a mechanism where mature T lymphocyte cells are made unresponsive
to antigens (but not killed). Clonal anergy is believed to be brought
about by presentation of self antigens in the absence of co-stimulation
(Schwartz 1990). In other words peripheral autoreactive T cells
can be tolerised by coming into contact with appropriate antigen
and MHC on a cell so long as they do not receive co-stimulation
to promote them to a reactive state.
Mature T cells are believed to require two simultaneous signals
before being activated and capable of destruction. The first comes
from binding of the T cell receptor to the MHC plus antigen peptide.
The second is believed to come from binding of two cell surface
receptors one called CD28 on T cells and the other B7 on the surface
of professional macrophages, Langerhan's cells, dendritic cells
and/or activated B cells. However, if a T cell binds to MHC plus
antigen peptide but not B7 due to its functional absence, the T
cell is inactivated (Schwartz 1990) (The co-stimulation signal need
not be the CD28/B7 binding but another similar mechanism). Although
it survives, the T cell is incapable of producing cytokine IL-2
and is subsequently unresponsive to further restimulation (Quill
1987, Schwartz 1990). Most peripheral tissues express MHC class
I and various antigen peptides but not the co-stimulatory signal,
consequently T cell anergy readily occurs after being released from
the thymus.
The third method of avoiding self reactivity is based on active
suppression of autoreactive T cells (Fowell 1991). It is known that
normal, healthy humans can possess T cells that could potentially
cause autoimmune disease (Mason 1992). This can be shown by partially
depleting T cells in an individual and consequently releasing autoreactive
cells from the constraints of "suppressor cells". Further,
it has been postulated that CD8+ T suppressor cells can be induced
by exposure to antigen. These cells when stimulated also act as
a brake on immune system responses (Roitt 1989). This brake on the
immune system makes sense as once a foreign antigen challenge has
been repelled the stimulated immune cells must be quickly returned
to a resting state to limit any non-specific self tissue damage.
Some regions of tissue in our bodies are regarded as "immune
privileged". The immune system either cannot physically enter
these areas on their surveillance patrols or the immune cells cannot
"see" the antigens which they would normally regard as
foreign because the antigens are not presented in complex with self
MHC antigens on somatic cells (this is described as antigen sequestering).
The classic privileged site is the cornea of the eye (Barker 1977).
The cornea has no blood vessels running through it and so the immune
cells are physically unable to enter it. Alternatively, certain
antigens are hidden away inside individual cells. The problem in
hiding away our own antigens is that the tissue antigens cannot
be used as part of our body's controlling mechanism of anergy induction
to stop self reactive cells from being activated.
Self antigen recognition and consequent autoantibody production
by B cells is normally avoided by methods similar to those employed
in T cell tolerance. The B cell population is "tolerised"
through clonal deletion, anergy and/or sequestering of antigens
within an organ (Goodnow 1990, Basten 1991). Where T cell help is
required to activate B cells exposed to thymus dependant antigens,
suppression of the T helper CD4+ cell population will prevent possible
autoantibody production (Janeway 1993). Lack of stimulus by cytokines
and/or appropriate receptor linking will also result in non-recognition
(Balkwill 1989). Any breakdown in these normal processes will result
in loss of tolerance.
Loss
of immune system tolerance
There are several, general hypotheses to explain the initiation
of autoimmunity. The main ones are:
- A) the forbidden clone hypothesis
- B) the sequestered antigen/privileged site hypothesis
- C) the antibody/immune complex hypothesis
- D) the cross reactivity hypothesis
The distinction between these different hypotheses is not clear
cut. Autoimmune disease can be based on a combination of these factors.
A) As already described, immune cells that can react with our
own body antigens should normally be prohibited from doing so by
a variety of mechanisms (eg Blackman 1990). But in this case the
cells somehow escape the attention of the body's normal controlling
mechanisms and become free to do their damage (Mason 1992). Clearly
for any true autoimmune disease to develop by this hypothesis or
others below there must be a supply of autoreactive cells but the
method by which they are stimulated with self antigen can vary considerably.
B) Hair follicles may hide their antigens away from immune cell
recognition. They can do this by keeping the antigens inside individual
cells, or due to a lack of MHC expression (Sprent 1990, Matzinger
1994), or the basement membrane (BM) and the abscence of blood vessels
in parts of many hair follicles/epidermis may physically prevent
immune cells from coming into contact with the hair shaft and sheaths
of follicles (Barker 1977). Barker et al provide evidence
for hair follicles being partially sequestered sites by briefly
commenting on the fate of cells from allografts of skin epidermis
applied to genetically non-associated recipients. The grafts were
rapidly rejected but subsequent hairs produced at the site of the
graft contained donor graft cells for up to 250 days and it was
suggested that immunogenetically alien cells that are contained
in the hair bulbs are much less vulnerable to immune cell attack
compared to graft cells in the normal epidermis (in Barker 1977).
C) The antibody/immune complex idea is based on the immune system
defending itself from infection in a normal manner. As antibody
proteins are produced against, for example, a bacterial infection
by our immune cells they bind to the bacteria and destroy it in
the usual way. But bits of degraded material plus attached antibodies
(called immune complexes) in our blood system can become lodged
in tissues - particularly areas of high pressure such as the kidney.
When this happens the immune system continues to attack the immune
complexes to get rid of them but the cells' actions also non-specifically
affect and disrupt surrounding tissue (Wilson 1978, Wilson 1983).
This destruction of our own tissue can stimulate the immune system
into direct targetting of our tissues as well as the immune complexes.
D) The cross reactivity hypothesis relies on the possibility that
an invading organism could have an antigen very similar to one of
our own antigens. The immune system mounts an attack on the foreign
invader but because the antigen(s) it recognises are so similar
to our own, the immune cells are fooled into attacking our own tissues
as well (Roitt 1989, Klinman 1994).
There are also more complex hypotheses put forward to explain
a certain specialised minority of autoimmune disease types such
as - Polyclonal activation of B cells by superantigen stimulation.
In this case all B cells are non-specifically stimulated to produce
antibody, some of which will inevitably target self tissues (Roitt
1989, Johnson 1992). So far this phenomenon has only been shown
by artificial induction. Further, destruction of suppressor cells
that control autoreactive T and B cells may result in autoimmunity
(Fowell 1991). This could occur after viral attack by HIV on CD4+
cells in patients and may be one of several contributing factors
to the deterioration of AIDS patients. Altered exposure of host
antigens can occur as a result of adverse chemical activity. This
can occur for example in heavy drinkers where excessive alcohol
causes structural alteration to the liver and kidney inducing IgA
nephropathy autoimmune disease (Sweny 1989).
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