The immune system responds to invading foreign antigens. Once the target foreign antigen has been eliminated, the reduction in the immune response is rapid, and the affected host tissue is able to recover from the damage inflicted by the inflammatory response. In autoimmune diseases, the immune system responds to self-antigens; as a result, the target antigen is usually never eliminated, thus the response is often sustained and the tissue damage may not completely subside. Periods of reduced damage are, however, common - thus the relapsing-remitting course of all of the chronic autoimmune diseases discussed in this review. Autoimmunity is now believed to be a naturally occurring phenomenon gone awry in autoimmune disease.

Many of the diseases discussed in this review are presumed to be autoimmune (Table 1). In theory, certain criteria should be met if a disease is to be considered to have an autoimmune etiology: autoantibodies or tissue-directed T cells should be detectable in serum or the affected tissue; they should be present before the onset of symptoms; and there should be evidence of an immune-mediated pathology in the affected tissue. Examples of experimental evidence are if isolated autoantibodies, activated T cells, or the presumptive autoantigen recreate disease when injected into healthy animals. This type of direct evidence is perhaps strongest for Myasthenia Gravis (MG) and Gullain-Barre syndrome (GBS), where neonates sometimes mimic the autoimmune disease of their mother. Further, symptoms should show improvement with the use of immunosuppressive or immunomodulatory drugs. Lastly, in some autoimmune diseases, there may be evidence of pre-existing infections, associated with disease onset or relapse; this is often the case for GBS, and perhaps for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multiple sclerosis (MS) as well.

Each autoimmune disease or syndrome described in this review represents a heterogeneous set of disorders with common features (see Table 1). This heterogeneity can result from a common disease manifesting itself in distinct genetic and epigenetic circumstances - seen, for example, in animal models of MS, where the disease course varies with the genetic background. Alternatively, heterogeneity can arise from distinct pathogenic mechanisms manifesting as observed common clinical features. The establishment of useful classification schemes is a dynamic, ongoing process influenced by one or more factors - including clinical features, prognosis, therapeutic response, underlying pathogenic mechanisms, and biomarker data. These classification systems are valuable for diagnostic purposes - and so inclusion in laboratory and clinical research studies, for prognostic purposes and for determining individualized treatment strategies (i.e., predicting treatment response or risk of adverse effects).

Autoimmune diseases of the nervous system can be grouped according to whether they affect tissue of the central nervous system (CNS), peripheral nervous system (PNS), or both (see Table 1). As with all classification systems, this one has its limitations. CNS lesions are sometimes present in patients with PNS autoimmune disease, such as CIDP; however, these CNS features are usually clinically silent. Conversely, clinically silent PNS lesions are sometimes present in patients with MS. The general rule is that patients with demyelination in both the CNS and PNS are usually symptomatic at one site or the other, but not both. Systemic lupus erythematosus (SLE) is one of the exceptions to this rule. In addition, there are poorly understood CNS-PNS overlap syndromes. Further, some diseases have their etiology outside the nervous system altogether, but end up affecting the nervous system as the disease progresses; the development of CIDP in patients with diabetes provides one example.

Autoimmune diseases tend to be predominantly (auto)antibody mediated or Th1 cell mediated. Examples of the former are MG, GBS, and SLE; MS is a typical T cell-mediated disease. The situation with CIDP is less clear. There is diagnostic and therapeutic advantage to identifying the autoantigens and, among them, the primary target. In the case of antibody-mediated autoimmune disease, characterization of patient autoantibodies can reveal the identity of the autoantigen(s), although not always the primary one. In Tcell-mediated autoimmune diseases, on the other hand, the autoantigen recognized by the T cells is often unknown.

One might expect autoimmune diseases to be characterized by autoantigens that are exposed to immune attack - that is, either secreted or intramembrane molecules. However, in some diseases, patients exhibit autoantibodies to intracellular antigens. In MG, this results from a process known as intermolecular epitope spreading, whereby cytoplasmic epitopes are exposed upon destruction of the cell membrane. In SLE, many of the autoantigens are located in the nucleus.

Autoimmune diseases can present asymmetrically, symmetrically, or unilaterally. It is perhaps curious that a disease with a systemic component should present asymmetrically or even unilaterally, but this is the case in MS (particularly ON), MG, in some forms of CIDP (MMN and MMSN, see Table 1), and is often the case in amyotrophic lateral sclerosis (ALS) or in brachial neuritis. Perhaps use or disuse, as well as trauma, can predispose one not necessarily to disease itself but to a particular asymmetric manifestation of disease.

Sexual dimorphisms are apparent in the prevalence of some autoimmune diseases. For example, MS, early onset MG, and SLE disproportionately affect females; for SLE, predominance can be as high as 5:1 in childbearing years. Further, the clinical onset of SLE often coincides with menarche, pregnancy, postpartum, or menopause. MS patients

Table 1 Autoimmune diseases of the nervous system

Disease US Incidence Subtypes

(annual, per 100000)

Central nervous system

Multiple sclerosis (MS) 3 Clinically isolated syndrome (CIS)

Relapsing-remitting MS (RRMS) Secondary progressive MS (SPMS) Primary progressive MS (PPMS) Relapsing progressive MS (RPMS) Benign MS Optic neuritis (ON)

Neuromyelitis optica (NMO) or Devic's syndrome

Central nervous system/peripheral nervous system

Systemic lupus erythematosus (SLE) 7.3 Juvenile SLE

Lupus nephritis (LN) Neuropsychiatric SLE (NPSLE) Non-neuropsychiatric SLE (non-NPSLE) Anti-phospholipid antibody syndrome (APS)

Peripheral nervous system

Guillain-Barre syndrome (GBS) 1.5-3 Acute inflammatory demyelinating polyradiculoneuropathy (AIDP)

Miller-Fisher syndrome

Acute motor axonal neuropathy (AMAN)

Acute motor sensory axonal neuropathy (AMSAN)

Pure sensory neuropathy

Pure autonomic neuropathy (acute pandysautonomia) Atypical presentations of AIDP Regional presentations of AIDP Myasthenia gravis (MG) 0.2-2 Generalized MG:

Acetylcholine receptor (AChR) Ab-positive

(85% of generalized MG patients) Early onset MG (<50): higher AChR Ab titer; thymic hyperplasia; no other Abs Late onset MG: lower AChR Ab titer; thymic atrophy;

titin, RyR Abs in 50% Thymoma MG; lower AChR Ab titer; thymoma

(usually cortical); titin, RyR Abs in 95% AChR Ab-negative (15% of generalized MG patients) Early onset MG: MuSK-positive and -negative subtypes Late onset MG: MuSK-positive and -negative forms Ocular MG:

AChR Ab-positive (60% of ocular MG patients) Chronic inflammatory demyelinating ND Sensory ataxic neuropathy (SAN)

polyradiculoneuropathy (CIDP) Subacute motor sensory demyelinating neuropathy


Chronic motor sensory demyelinating neuropathy (CMSDN)

Multifocal motor sensory neuropathy (MMSN,

Lewis-Summer neuropathy) Pure motor demyelinating neuropathy (PMDN) Multifocal motor neuropathy (MMN) Diabetes-associated CIDP

CIDP-associated with monoclonal gammopathies have lower relapse rates during pregnancy, worsening of MS during menstruation, and correlation of high estradiol and low progesterone with magnetic resonance imaging (MRI) monitoring of disease activity. These findings and the gender asymmetries in prevalence, as well as clinical trial data, suggest a possible role for estrogens and androgens in the pathogenesis of some autoimmune diseases.1 In fact, current clinical trials are testing the therapeutic safety and efficacy of sex hormones in the treatment of MS.

In addition to possible hormonal factors, the development of these autoimmune diseases appears, in general, to be influenced by both genetic and environmental factors.2 In addition, the disproportionate prevalence of some autoimmune disease in older patients (e.g., late onset MG and GBS) suggests that the effects of aging on the immune system may also play a role.

In this chapter, the general features of several autoimmune diseases and syndromes affecting the nervous system are examined with consideration of the therapies currently in use and in development to treat them.

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