There are numerous proposed ways in which a virus could induce demyelination and some of these mechanisms have been elucidated by the study of viral induced demyelination in animals (see the corresponding sections).
Direct effect of the virus.
A virus can be cytopathic to oligodendrocytes and therefore induce demyelination by death of the myelin-producing and
maintaining cell or by interfering with the normal metabolism of the myelin-producing cell (as it appears to be the case in progressive multifocal leukoencephalopathy). In this case a secondary
inflammatory reaction may occur in response to this destruction as a scavenger effect.
Bystander effect due to viral infection .
On the other hand the inflammatory reaction may be
responsible for the demyelination when an immunological response is triggered against viral antigens expressed during a persistent infection (as possibly in the case of Theiler’s virus encephalitis). The destruction of the oligodendrocytes is, in this case, a bystander effect of the immune response to viral infected oligodendrocytes/myelin. This destruction could occur and be perpetuated non specifically for example by macrophages [Cuzner M.L. et al, 1988]. Antigenic modulation at the level of oligodendrocytes due to an antibody response against some viral antigens could induce a persistent infection without an overt inflammatory reaction and changes in antiviral titers influence the relapse in case of relapsing remitting demyelinating disease [Fujinami R.S. et al, 1984] [Randall R.E.R. et al,1990].
Bystander effects can be promoted by soluble factors released during a normal anti-viral immune reaction and these soluble factors e.g cytokines released by lymphocytes and macrophages or enzymes released by macrophages could have a deleterious effect on the myelin. Such soluble factors toxic to myelin have already been described e.g complement [Scolding N.J. et al, 1989] , proteinase from disrupted myelin sheaths [Chantry A. et al, 1988] or cytokines secreted by lymphocytes [Owen S.J. et al, 1988].
Autoimmunity as a bystander effect of viral infection.
The other possibility is that the demyelination is due to an autoimmune response triggered by a viral infection. In this case the virus need not be present in the brain. An autoimmune response is an immune reaction orchestrated by components of the immune system towards a component(s) of the body - e.g the myelin or the cell producing the myelin. The autoimmune response could be triggered by tissue damage due to viral infection (the viral damage is not the direct cause of demyelination but only a trigger).
a. Release of hidden antigens.
This autoimmune reaction could for example be triggered by a release of sequestrated autoantigen normally hidden from the
immune system e.g myelin basic protein (MBP) is normally not exposed in the mature myelin sheath in contrast to proteolipid
b. Presentation of autoantigen through increased expression of HLA molecules.
Along the same line of thought, it has been hypothesised that tissues threatened by viral infection increase their level of HLA molecule expression through the action of interferon or other
cytokines [Dalgleish A.G. et al, 1987]. This facilitates presentation of viral peptides but may inadvertently raise presentation of tissue specific peptides (MBP or other brain specific antigens) to levels that activate previously quiescent autoreactive T cells [Parham P, 1991]. This hypothesis follows on a more general hypothesis for tissue specific autoimmunity, according to which T cells directed against tissue-specific peptides presented by aberrantly expressed HLA molecules are the cause of autoimmune disease [Bottazo G.F. et al,
1983 and 1986] [Hanafusa T et al, 1983] [Londei M. et al, 1984]. Autoreactive T cells have been demonstrated in normal people e.g against MBP [Martin R. et al, 1990] or against acetylcholine receptor [Sommer N. et al, 1991] and it is thought that they escape the normal negative selection (deletion) because these antigens may not be
presented, in the thymus, during foetal life.
c. Insertion of a viral component into a host component. Retroviruses produce latent infection in infected cells.
Insertion of the viral genome into the genome of the cell is mostly random. The possibility that only part of the viral genome insert into the genome of the cell exists. This could induce transcription of a single viral protein during transcription of cellular proteins and expression of the viral protein alongside the cellular proteins. Some of the superantigens (see below) already characterised e.g the Mis system may have arise from this mechanisms. Such viral proteins could induce an autoimmune reaction if not tolerised.
d. The 'superantigen’ hypothesis.
Superantigens induce proliferation, deletion or anergy of certain T cell subsets through interaction of the superantigen with specific V|3 segments of the corresponding T cell receptors [Acha- Orbea H. et al, 1991]. It has been hypothesised that among the potential T lymphocytes stimulated, there may be lymphocytes specific for myelin component especially MBP [Rudge P., 1991].
e. Incorporation of a host component into a viral component. Another interesting possibility is the triggering of an
autoimmune reaction by the incorporation of host antigens into viral envelopes during viral release by ’budding' i.e any virus with a viral envelope e.g retroviruses or paramyxoviruses. This incorporation of cellular components e.g glycolipids into viruses has been proposed as a possible cause of natural tolerance breaking leading to autoimmune reaction. Viruses could then act as helper-carrier for the glycolipids which are considered as haptens [Webb H.E. et al, 1984] [Dalgleish A.G. et al,1987].
f. 'Molecular mimicry'.
The autoimmune reaction could also arise by 'molecular mimicry' - in other words as a result of molecular structures shared by host components and viral gene products [Fujinami R.C., 1988]
[Srinivasappa J. et al, 1986], In this case, the infectious agent does not need to be present in the brain or even in the body when
neurological symptoms occur. Indeed, an autoimmune reaction due to molecular mimicry by an initial viral infection could be kept under control by suppression mechanisms orchestrated by the immune system ('tolerated'). The breaking of tolerance could then happen by a non specific phenomenon for example another viral infection. Thus, Sibley and colleagues have shown that MS patients have more viral infections before their attacks than a control population [Sibley W.A. et al, 1985]. So far, molecular mimicry between viruses and host components has been demonstrated mainly with intermediate filaments (intermediate filaments are a large part of the host structure). For example, Fujinami and colleagues have demonstrated cross-reactivity with different antibodies between herpes and measles virus proteins and human intermediate filaments [Fujinami R.S. et al,1983] [Dales S.et al, 1983] [Nigg E.A. et al, 1982].
Fujinami and Oldstone immunised rabbits with a peptide of hepatitis B virus polymerase which shares some homology with an encephalitogenic site of myelin basic protein. Consequently, the rabbits developed neuropathological signs resembling experimental allergic encephalomyelitis; an antibody response and a T cell
proliferation were demonstrated against both the myelin and the hepatitis B virus polymerase [Fujinami R.S. et al, 1985].
Molecular mimicry can be determined by computer analysis of the primary sequence of the proteins of interest [Jahnke U. et al,
1985] [Shaw S-Yet al, 1986] [Weise M.J. et al, 1988] [Souberbielle et al, 1991]. However, it is likely that proteins with different primary structures could also induce molecular mimicry if their three
dimensional structure are similar as Rudensky and colleagues eluted proteins from a mice MHC molecule and found different peptide . sequence bound to this MHC molecule [Rudensky A.Y. et al, 1991]. In addition flanking regions of an antigenic site may influence its presentation [Eisenlhor L.C. et al, 1992] and thus flanking regions may be an additional important factor in molecular mimicry.
Some have also proposed that 'molecular mimicry' could arise between host antigens and idiotypes of antibodies specific for viral antigens. Idiotypes are antigens of the variable regions of antibodies and it is thought that some of these idiotypes are the internal image of the antigen specific for the antibody. It has been hypothesised that the immune system is thus possibly regulated through this network of idiotypes [Jeme N.K., 1974]. Thus a response against an idiotype (anti-idiotype) could react against the antigen [Plotz P.H., 1983]. For example it has been demonstrated that a monoclonal antibody raised against an antibody specific for the reovirus 3 haemaglutinin reacts also with normal lymphoid and other normal cells [Nepom J.T. et al, 1982]. Cooke and colleagues have proposed that T cell specific for idiotype on antibodies specific for an environmental antigen could recognise an autoantigen through molecular mimicry between the idiotype and the autoantigen (T- inducer bypass) [Roitt I.M., 1984] and it is one of the theories which deals with the disruption of the complex regulation of the immune system (see below).
It has also been hypothesised that autoimmunity could arise through non specific polyclonal activation of B cells after viral infections. Some of the antibodies produced could be directed to autoantigens. The classic example given is Epstein Barr virus infection which induce polyclonal activation of B cells [Roitt I.M.,
1984].
g. Disruption of the immune system regulation.
The immune system appears to be a closely regulated network of effector and suppressor cells and it has been proposed that
autoimmunity results from a disruption of this regulatory system
lymphocyte (e.g some specific suppressor cells) after viral infection could in turn trigger an autoimmune response towards a host
component. On the other hand, stimulation of autoaggressive cells could also follow viral infection through non specific activation of certain T cells or stimulation of T cell at a paracrine level. Brod and colleagues demonstrated that activated T cells expressing high
surface density of adhesion molecules were able to trigger neighbouring resting T cells to proliferate via these adhesion pathways. In the same way, this non specific T cells stimulation could arise thus after viral infection [Brod S.A. et al, 1990].
In the context of MS, all the possibilities developed above concerning infections of the myelin and/or the oligodendrocyte (or autoimmune reaction towards one of these biological structures) as a system could, in theory, also be applied to the brain vessels .