Injury and Autoimmunity

There are no direct indications that injury of the brain is followed by a T-cell autoimmune response, not even against strongly immunogenic antigens from myelin such as basic protein. MBP is released into the CSF and serum following traumatic injury and cerebrovascular damage,61,62 but there is no evidence that EAE nor its prototype MS follows brain injury. Facial nerve section in Lewis and BN rats has been reported to increase the numbers of MBP-reactive T cells in the superior cervical lymph nodes, and some perivascular T cells were found in the facial nucleus.42 These effects were more pronounced in the Lewis rat, a strain with a greater susceptibility to EAE, underlining the significance of the genetic background in determining the level of the immune response.

Autoantibodies, including antibodies reactive with neural antigens, can be found in normal healthy subjects and although of low titre these can be of high affinity.63 Such antibodies appear to be more frequently seen in patients with a variety of neurological diseases, particularly those of a chronic neurodegenerative type,64 65 and chronic viral encephalopathy.66 Antineurofilament antibodies occur with higher frequency in patients with CJD, familial Alzheimer's, and Parkinson's dementia, but also in viral encephalopathies such as subacute sclerotic panencephalomyelitis (SSPE) and acute herpes simplex encephalitis.67

In experiments in the rat, lesioning of the hippocampus or anterior olfactory nucleus does not generate antineurofilament antibodies, whereas they are produced after lesioning of the olfactory bulb and the grafting of PC12 cells in all sites,68 indicating again that the site within the brain strongly determines the immunological outcome. Antineurofilament antibodies are not considered to be pathogenic since the target antigen is intracellular. However, intracellular injection of antibody against the intermediate neurofilament protein into cells of the early Xenopus embryo leads to later axonal abnormalities,69 and an anti-large neurofilament antibody isolated from a case of ALS also reacted with neuronal surface proteins.70 Previous head injury is a factor in the development of Alzheimer's7172 and epilepsy.73 74 Activation of microglia is found in both of these conditions and autoantibodies are elevated in about 50% of Alzheimer's patients,64 but at present specific autoimmunity is not considered to be significant in their pathogenesis.

Rasmussen's encephalitis is a possible exception. This is a rare form of focal epilepsy associated with pronounced focal cortical inflammation. The condition may be associated with antibodies to the glutamate receptor type R375-77 and it has been suggested that it is triggered by brain damage or infection, these events opening the BBB to the circulating antibodies, although how these arise is not known (it is possible that they represent cross-reactive antibodies generated against bacterial periplasmic amino acid-binding proteins78). Interestingly, the lesion is typically unilateral and does not spread to the contralateral hemisphere even after hemi-spherectomy.79 Why the lesion does not spread is unclear if all it requires is a break in the BBB subsequent to an activation of microglia and perivascular macrophages. Activation of these cells following unilateral lesioning appears not to spread generally across the midline (personal observations), as is also the case with astrocyte activation.80 Similarly, following a local antigenic induction of inflammation the response spreads throughout the ipsilateral cortex but not the contralateral.2839 It is unlikely that this asymmetric spread of activation is due to either a humoral factor alone or intrinsic neural paths, but may reflect a spread along the ipsilateral vascular tree, possibly through a paracrine mechanism via the perivascular macrophages and microglia.

Since autoantibodies are detectable in healthy subjects it is not possible to say whether or not their increased detection in CNS degenerative and inflammatory disease is a result of a new primary response or the stimulation of preexisting B-cell clones by the macrophage transfer of antigen from the brain. In a chronic inflammatory disease with a suspected autoimmune aetiology such as multiple sclerosis there has been a failure to identify a primary pathogenic autoantigen, but many studies have identified immunity against a number of myelin and myelin-related and unrelated antigens with variable incidence.6581-85 These again may reflect "epitope spreading" or secondary immune responses arising from damaged tissue in the context of ongoing inflammation or may represent a stimulation of preexisting autoimmunity.6583 Overall it must be assumed that the generation of antibrain antibodies following trauma will be limited by the normal mechanisms operating to restrict the production of autoantibodies and a poor T-cell immunisation to brain antigen may further reduce the chances of a humoral response.

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