In recent years, numerous brain-reactive antibodies have been identified in human sera and have been proposed to associate with neurological or neuropsychiatric symptoms (). These antibodies can be divided into three categories: antibodies that have a causal relationship with the development of symptoms; antibodies that are generated as a secondary symptom during brain disease, perhaps as a result of brain injury; and antibodies that will turn out to not be associated with disease as more careful studies are carried out (false-positive cases).
Antibody-related disorders of the peripheral and central nervous systems
At present, few of these antibodies have clearly delineated mechanisms of neuro-toxicity, but three main mechanisms of antibody function are possible (). Some antibodies might act as receptor agonists (by either mimicking ligand binding or acting through allosteric modulation) or antagonists. Some antibodies might cause antigenic modulation, thereby altering the density of the target antigen on the cell surface (for example, altering the density of a receptor through internalization). Other antibodies might require interaction with diverse components of the immune system to mediate their effects. For example, some antibodies might activate complement, whereas others might engage Fc receptors on resident cells in the brain or on infiltrating inflammatory cells. It is also possible that some antibodies bind brain antigens but have no effect.
Antibodies can have a range of effector functions
Brain-reactive antibodies have been observed in patients with several neurological malignancies, autoimmune diseases, seizures, movement disorders and ischaemic brain syndromes. Individuals with altered behaviour, abnormal cognition and neurodegenerative diseases also have these antibodies (). For example, antibodies specific for several different glutamate receptors have been reported in seizure disorder, malignancy-associated encephalopathy and neurodegenerative disease7
. It is not yet clear which of these antibodies cause brain pathology or by what mechanism, although some of the antibodies have been shown to act as agonists for AMPA receptors and kainate receptors in vitro8
. Antibodies specific for aquaporin 4, a water channel that is expressed on astrocytes, are useful for the diagnosis of neuromyelitis optica. These antibodies initiate complement activation at the site of deposition. Expression of the astrocytic glutamate transporter depends on the presence of aquaporin 4; so, antibody-mediated modulation of the density of aquaporin 4 might affect the cell surface expression of the glutamate transporter and in turn expose surrounding cells to the excito-toxic effects of increased levels of glutamate9
. Limbic encephalitis, both paraneoplastic and idiopathic, is often associated with antibodies that are specific for voltage-gated potassium channels10
. It is not clearly established whether and how these antibodies contribute to symptoms of this disease, but they might cause autonomic hyperexcitability. Antibodies specific for ribosomal P protein are present almost exclusively in patients with SLE. These antibodies have recently been shown to crossreact with a 331 kDa membrane protein on neurons and to stimulate calcium influx that results in cell death11
. Clinical data indicate that these antibodies might be associated with psychosis12,13
Antibodies that are generated as part of a protective response to infection have also been shown to bind brain antigens through molecular mimicry. Elegant studies have shown that antibodies specific for an N
-acetyl-β-D-glucosamine epitope on polysaccharide from streptococcal bacteria crossreact with a lysoganglioside expressed on neurons14,15
. These antibodies have been shown to trigger the phosphorylation of calcium/calmodulin protein kinase II, which is found in neurons throughout the brain and is a component of many activation pathways. In patients with rheumatic fever14
, the lysoganglioside-specific antibodies target an antigen that is preferentially expressed or is particularly accessible on neurons in the basal ganglia, a group of brain structures that have a role in movement control. Because titres of these antimicrobial and brain-specific cross-reactive antibodies are high in the cerebrospinal fluid (CSF) of patients with rheumatic fever and chorea and decrease as the involuntary movements become less frequent, it is presumed that these antibodies are responsible for the effects of rheumatic fever on the CNS. Staining of brain sections from patients with rheumatic fever using a lysoganglioside-specific antibody shows that there is regional specificity of the antigen within the basal ganglia, the brain region from which the abnormal movements are initiated14
. This observation further supports the causal role of antibodies in the chorea of patients with rheumatic fever14,15
. It remains unclear whether antibodies specific for streptococci have a role in other movement disorders and in neuropsychiatric syndromes16
Another example of brain-reactive antibodies that crossreact with microbial antigen is provided by the ganglioside-specific antibodies that are present in patients with Guillain– Barré syndrome
that crossreact with a lipooligosaccharide on the surface of Campylobacter jejuni
. These antibodies impair schwann cell function through a complement-dependent process. This example differs from the other cases described in this Opinion article, as the blood–brain barrier (BBB; BOX 1
) does not isolate the target antigen, which is present on perisynaptic Schwann cells encasing the nerve root. These cells are located outside the BBB and are exposed to circulating antibodies and complement proteins17,18
Box 1. The blood–brain barrier
The blood–brain barrier (BBB) is composed of a network of endothelial cells, pericytes and astrocytes, and functions to limit the entry of soluble molecules and cells into the brain parenchyma58
. The BBB is tightest in capillaries, in which solute diffusion is controlled, and is weaker in postcapillary venules, where leukocyte recruitment takes place59
. Indeed, areas of leukocyte infiltration do not frequently correspond to capillary sites, where classical markers such as tagged dextran or tagged albumin permeate the BBB60
. The BBB is robust in capillaries owing to specialized endothelial cells that express proteins forming tight junctions between cells. In addition to the adhesion molecules that are expressed by endothelial cells in other tissues61
, endothelial cells in the brain also express a unique adhesion molecule, integrin cytoplasmic domain-associated protein (ICAP)62
, which recruits blood-borne mononuclear cells into the brain.
The BBB is fully formed by the end of gestation (the precise timing during gestation is not known), but its integrity can still be modulated. The regulatory mechanisms include alterations in paracellular permeability (by affecting the strength of tight junctions) and changes in transcellular permeability (by affecting the capacity of endothelial cells to internalize molecules through endocytosis)58
. It has been assumed that molecules present in plasma cross the BBB mainly through paracellular routes; however, recent reports show that certain cytokines and chemokines are transported through transcellular routes using receptor-mediated endocytosis63
It is not known how antibodies cross the BBB during moments of compromise to barrier integrity. Capillary and postcapillary sites in the BBB might be transfer sites depending on whether antibodies are transported by transcellular endocytosis or by paracellular routes (tight junction dysfunction), or are produced by lymphocytes undergoing transendothelial migration (). It is probable that cytokines are crucial for modulating antibody influx. Cytokines might have different effects on capillary and postcapillary compartments of the BBB. Structural differences in the BBB in different regions of the brain and structural differences in different compartments of the BBB might help to explain the diversity of antibody-mediated brain pathologies. Alternatively, in some cases antibodies might be synthesized within brain tissue by B cells penetrating the BBB, and the effects of antibodies will be proximal to the B cell infiltration.
Schematic representation of the possible mechanisms regulating the influx and efflux of antibodies through the blood–brain barrier
In general, the antibodies that are associated with CNS disease seem to be generated in secondary lymphoid organs and thereafter gain access to the CNS from the circulation. The molecular pathways that are triggered or blocked by presumed pathogenic brain-reactive antibodies are not well understood. The identification of antibodies that are specific for neurons or glial cells should allow the molecular identification of the target antigen and an understanding of the pathways that are activated after antibody binding. Indeed, antibodies arising in pathological conditions that bind to brain antigens could teach us a great deal about differences in the phenotype and function of neurons and glial cells in different regions of the brain.