a) Humoral response.
Numerous surveys of antibody titers specific to viruses have been carried out in MS patients compared to controls [Cook S.D. et al, 1980]. Measles has been studied extensively after Adams and Imagawa first demonstrated that patients with MS when compared to controls had higher titers of serum antibodies specific to the measles virus [Adams J.M. et al, 1962]. This observation has been repeated many times in the serum and in the CSF, with different methods. Moreover the humoral immune response is directed against more than one measles protein [Norrby E., 1978]. The measles antibody titer elevation is modest - about 2 fold higher than in the controls. It appears also that in most cases measles virus antibodies are being produced intrathecally as alterations in serum/CSF measles antibody ratios have been found in a number of studies [Haire M., 1977] [Norrby E. et al, 1974] [Vandvik B. et al, 1975] [Salmi A.A., 1972]. However, no relationship has been found between measles titer and
the measles serum antibody titer of MS patients’ siblings without evidence of MS also tends to be higher than that of controls [Henson T.E. et al, 1970] [Ammitzboll T. et al, 1972] [Panelius M. et al,
1973].
Other viral antibodies serum titers have been found elevated in MS populations compared to controls (although this is less consistent than for measles) for example with vaccinia, rubella, herpes simplex, mumps, canine distemper, Epstein-Barr virus, adenovirus [Cook S.D. et al, 1980] or HTLV- 1 (see below). Thus, it is thought that higher titers of serum antibodies to measles and to other viruses may reflect a non specific dysregulation of the immune system (either secondary or primary to the disease process).
In the CSF of MS patients intrathecal production of antibodies to viruses other than measles have been detected for example with vaccinia, herpes simplex, rubella, mumps and other viruses (for reviews see [Cook S.D., 1980] and [Walsh M.J. et al, 1983]).
Furthermore, multiple viral antibodies may be detected in the CSF from the same patient and fluctuations in titers may occur [Salmi A. et al, 1983] [Amadottir T. et al, 1979]. Salmi and colleagues
measured the intrathecal antibody synthesis to 16 different viruses in the CSF of 30 patients with MS and 29 neurological controls without demyelination. They found that, apart from 2 MS patients, all
showed intrathecal synthesis against more than one virus (usually about 10 different viruses), and, only 3 controls had antiviral
intrathecal synthesis but against only one virus. In the MS group the viruses that were over-represented were measles, rubella,
parainfluenza 1 and 3, herpes zoster and mumps [Salmi A. et al, 1983]. This multiple intrathecal anti viral response is interpreted as being the sign of a non specific stimulation of immunocompetent cells (B cells and plasma cells) trapped beyond the BBB in MS brains. In the same way, local synthesis of anti-measles and anti rubella antibodies has also been demonstrated in the synovium of a rheumatoid arthritis patient [Vandvik B. et al, 1977]
The antiviral response has never been convincingly related to the CSF oligoclonal IgGs which can be detected in over 90% of definite MS cases. For example a small proportion of the measles antibodies can be associated with oligoclonal banding but most of the anti-viral response is of polyclonal nature. Moreover measles
antibodies account for a minor proportion of the total CSF IgGs
to the paramyxovirus SV5 will be presented as part of the work in this thesis and background to this work is discussed subsequently in this chapter.
An IgM response (indicative of a primary response or of persistent infection) to measles as well as anti-mumps and anti varicella IgM can be detected in the CSF of patients suffering from MS [Chodi F. et al, 1987]. This was again interpreted as a sign of non specific intrathecal stimulation in MS brains.
In conclusion, the antibody specificity of the majority of the CSF IgGs produced intrathecally in patients suffering from MS has not been defined; a variable small fraction of these IgGs are found to be virus - specific. It is however possible that some CSF IgGs are directed against an unknown antigen involved in the cause of MS (viral or non-viral) even though most of the CSF IgGs are probably due to non specific intrathecal stimulation. On the other hand, it is possible that the cause of MS is different between patients and that one virus may induce MS in one individual, depending, for example, on the HLA status of this individual, whereas another virus may be the causative agent of MS in another person.
b) Cellular immune response.
The cellular immune response to viruses has been much more difficult to evaluate in MS patients and their controls than the
humoral immune response. This may be due to the difficulty of purification of viruses and viral proteins for T cell assays but also due to the incomparability of the techniques used to measure such a response. The antiviral T cell response has been measured by
multiple methods especially T cell proliferation assays (an indication of the T helper response), migration inhibition (more difficult to interpret) and cytotoxicity assays (an indication of the T cell cytotoxic response). Even skin tests (an indication of the delayed type hypersensitivity response) have been used. Numerous viruses have been tested - for example measles, mumps, parainfluenza virus, vaccinia, rubella, herpes simplex and cytomegalovirus (CMV) [Cook S.D. et al, 1980]. Overall, the results of the past decades are
inconclusive as the reported T cell responses of MS patients when compared to controls have been greater, less or the same with most of the viruses tested.
The techniques of cytotoxic lymphocyte (CTL) assays have recently improved with the recognition of HLA restriction. Target cells used in CTL assays are autologous (of the same HLA as the patient's CTL) whereas in the early days some of the cytotoxicity assays were done with heterologous target cells e.g HELA cells infected with measles. Jacobson and his colleagues have studied the CTL response to measles in patients with MS. First, they
demonstrated that in the measles system a high proportion of CTL were HLA Class II restricted and were CD 4 + [Jacobson S. et al,
1984 and 1989]. This was at odds with the concept that CTL must be Class I restricted. Other viral systems however also showed this predominance of class II restricted CTL response e.g herpex simplex virus [Schmid D.S., 1988]. Interestingly, it has also been
demonstrated that some CTL clones specific for measles viral proteins were HLA DR 2 restricted in some MS patients [Richert J.R. et al, 1986] (HLA DR 2 allele being associated with multiple sclerosis predisposition [Compston D.A.S., 1986] and thus it was suggested that this anti-measles response may be relevant in the MS process). In addition, the generation of specific CTLs against
multiple measles proteins was impaired in a number of selected MS patients [Dhib-Jalbut S., et al, 1989] and the authors suggested that this was due to a persistent infection of measles in MS patients. However, these observations were done on selected patients and thus need to be confirmed to be considered relevant to MS in general.
Natural killer (NK) cell activity in multiple sclerosis patients has been found to be decreased by a number of research groups
[Benczur M. et al, 1980]. The explanation for this phenomenon is unknown. Some have suggested that it is a sign of a persistent viral infection.