Autoreactive T and B cells in nervous system diseases.

Background: Abnormal autoimmunity could play a role in the pathogenesis of multiple sclerosis (MS), in analogy with its model experimental allergic encephalomyelitis (EAE) which can be transferred by T cell lines directed to myelin basic protein (MBP) and myelin proteolipid protein (PLP), and worsened with antibody to myelin oligodendrocyte glycoprotein (MOG). Whether T and B cell reactivities to these autoantigens, and to myelin-associated glycoprotein (MAG) which is another possible target for autoimmune attack, occur in MS and then especially in the cerebrospinal fluid (CSF) with its close relation to the nervous tissue, is not clear. Myasthenia gravis, a prototype for autoimmune disease in humans, is characterized by IgG antibodies to acetylcholine receptor (AChR) in serum, but it is not known whether an augmented T cell response to AChR occurs in this disease. Nerve trauma has been speculated upon to be associated with exacerbations of MS; if nerve trauma recruits augmented autoimmune T and B cell responses is not known. High numbers of anti-myelin protein and anti-AChR antibody secreting cells have been described in cord blood, but whether corresponding T cell reactivities occur remains to be settled.

Methods: Antigen specific T cell responses in blood and CSF are studied regarding specificity, quantity and functional differentiation by counting numbers of cells which, upon antigen stimulation, respond by secretion of interferon-gamma (IFN-gamma). Similarly, the B cell responses to autoantigens are evaluated by counting cells which, in presence of antigen, secrete specific antibodies of IgG, IgA and IgM isotypes.

Results: MS is characterized by elevated numbers of T cells recognizing MBP, PLP, MAG and MOG as well as the synthetic MBP amino acid sequences 1-20, 63-88, 89-101, 96-118, 110-128 and 148-165, without immunodominance for any of these components. PLP, MOG and MAG reactive T cells are strongly enriched in the patients' CSF, as previously also shown for MBP reactive T cells. Similarly, elevated numbers of B cells with these specificities and enriched in CSF were found in MS. No preferential autoimmune T cell response was apparent after subdivision of the MS patients according to their HLA-DR genotype. A majority of patients with myasthenia gravis had AChR and alpha-subunit reactive T cells in peripheral blood, and also anti-AChR antibody secreting cells of the IgG, less frequently IgA and IgM isotypes. Peripheral nerve trauma in form of diagnostic sural nerve biopsy is accompanied by transient elevation in blood of T cells recognizing MBP and MAG which are common to the central and peripheral nervous system, and to the peripheral nerve myelin proteins P0 and P2. Myelin protein and AChR reactive T and B cells occur also in patients with other neurological diseases and tension headache, and in healthy subjects, but less frequently and at lower numbers than in MS and myasthenia gravis, respectively. Cord blood contains higher numbers of myelin protein and AChR reactive T cells in comparison with blood from healthy adults.

Conclusion: Antigen-specific T cells recognizing multiple myelin proteins and MBP peptides constitute a regular finding in MS. These autoimmune T cells are strongly enriched in CSF. In myasthenia gravis, increased levels of AChR and alpha-subunit reactive T cells as well as anti-AChR IgG, less frequently IgA and IgM antibody secreting cells can be demonstrated in most patients. T and B cells with the mentioned specificities can also be identified in patients with tension headache and healthy subjects but less frequently and at lower numbers, and they are assumed to reflect normally occurring autoimmune T and B cell repertoires. These are augmented after nerve trauma and in the newborn...