Neuroimmunological Disorders
Central nervous
system immunological network
The central nervous
system (CNS) has relative immunological privilege compared with the
peripheral nervous system (PNS) and most other parts of the body. The reasons
for this are as follows:
• It
has a very poorly developed lymphatic drainage system.
•
There
is only low level expression of major histocompatibility complex (MHC)
antigens.
However, breakdown of
the BBB can greatly alter this situation. In the resting state some
activated T lymphocytes are able to cross the BBB and circulate within the CNS.
In addition, MHC expression is confined to only a few cells although the
situation is different in the inflamed state. Thus, once triggered, an immune response
can be amplified and propagated by the secretion of cytokines and induced MHC
expression, with the opening up of the BBB. In these circumstances the microglia
are thought to be important as the antigen-presenting cells and
their interaction with T-helper lymphocytes is then pivotal in generating a
full-blown immunological reaction.
Recently there has been
great interest in the possible role of inflammation in neurodegenerative
disorders of the CNS and the extent to which this is seen simply as a reaction
to the cell degeneration or as a primary contributory factor in causing the
loss of these cells (see Chapter 60).
Clinical disorders of
the central nervous system with an immunological basis Multiple sclerosis
Multiple sclerosis
is a common
neurological disorder in which the patient characteristically presents with
episodes of neurological dysfunction secondary to inflammatory lesions within
the CNS. Pathologically, these lesions represent small areas of demyelination
secondary to an underlying inflammatory (mainly T cell) infiltrate the trigger
and target for which is not clear. The lesions often resolve with remyelination
and clinical recovery, although with time a permanent loss of myelin ensues
with secondary axonal loss and the development of fixed disabilities.
To date the most
successful symptomatic therapy is high-dose steroids which hastens recovery
from acute relapses but does not alter the long-term disease process. Of late,
though, a number of more aggressive immunotherapies with drugs that target the
T cells seem to be more effective, especially if given early on in the course
of the disease before there has been significant axonal loss.
Acute disseminated
encephalomyelitis
This is a rare
inflammatory demyelinating disease of the CNS that occurs as a complication of
a number of infections and vaccinations (e.g. measles and rabies vaccination).
It is a monophasic illness (unlike multiple sclerosis) characterized by
widespread disseminated lesions throughout the CNS that pathologically consists
of an intense perivascular infiltrate of lymphocytes and macrophages with
demyelination. In some cases it is fatal. This condition resembles experimental
allergic encephalomyelitis, which is a well-characterized T cell-mediated
disorder against a component of myelin (probably myelin basic protein) induced
by inoculating animals with a combination of sterile brain tissue and
adjuvants. This disorder is often used experimentally to model multiple
sclerosis.
Other immunological
diseases
A number of other
diseases with an immunological basis can affect the CNS and these include those
diseases that primarily affect blood vessels (the vasculitides).
In addition, there is a
rare group of disorders in which there is CNS dysfunction as a remote effect of
a cancer, paraneoplastic syndromes. In these conditions
antibodies to components of the CNS are generated, presumably triggered by the
tumour, which then lead to neuronal cell death and the development of a neurological
syndrome, e.g. anti-Purkinje cell antibodies cause a profound cerebellar
syndrome by the immunological removal of this cell type in the cerebellum. The
exact mechanism by which these antibodies exert their effect is not known as
antibodies normally do not cross the BBB, but pathologically there is often
evidence of a lymphocytic infiltrate in the affected structure which implies
that the antibody is capable of inducing an immune-mediated process of neuronal
loss.
Finally it has been
shown that a number of CNS disorders are caused by antibodies to specific ion
channels or receptors e.g. anti-K+ channel antibodies causing a limbic
encephalitis or anti- N-methyl-D-aspartate (NMDA) receptor antibodies
causing psychoses, a movement disorder and encephalopathy – many of which are not
associated with any underlying malignancy but are primary immunological
disorders. Indeed there is a growing interest in the possibility that some
patients with psychiatric disorders may have an autoimmune disease targeting a
receptor/ion channel.
Clinical disorders of
the peripheral nervous system with an immunological basis
The PNS has fewer of the
protective features of the CNS so it is more susceptible to conventional
immune-mediated diseases.
· The peripheral nerve is
affected by a number of immunological processes, including Guillain–Barré
syndrome. In this condition there is often a preceding illness (e.g. Campylobacter
jejuni or cytomegalovirus infection) that induces an immune response which
then cross-reacts with components in the peripheral nerve (e.g. certain
gangliosides). This then induces focal demyelination in the peripheral nerve,
which prevents it from conducting action potentials normally (see Chapter 17).
In time the patient usually recovers, although they may require immunotherapy
with either plasma exchange or intravenous immunoglobulin. A similar condition
is seen in some diseases where abnormal amounts of a component of antibodies
are produced (the paraproteinaemias).
· The neuromuscular junction can
be affected by immunological processes as occurs in myasthenia gravis and
the Lambert–Eaton myasthenic syndrome (see Chapter 16).
· Muscles can be involved in inflammatory processes. The
most common form of this is polymyositis, which is a T
cell-mediated condition associated with proximal weakness and pain. In contrast,
dermatomyositis is a B cell-mediated disease centred on blood
vessels, which causes a painful proximal muscle weakness in association with a
florid skin rash. This latter condition can represent a paraneoplastic syndrome
in more elderly patients with tumours in the lung, breast, colon or ovary.
