MOLECULAR MIMICRY BETWEEN THE BASIC PROTEIN OF THE MYELINE, HTLV-1,
-2Gag p15, THE HUMAN HERPES VIRUS-6 AND RETROVIRUS MSRV (GAG, CAPSID):
EPITOPE RESTRICTED BY AND
INDUCING AN EXPERIMENTAL ENCEPHALOMYELITIS IN THE MOUSE
M.K.G. 1*, Caprani
11A1 Internat Médecine
du Travail-Santé Publique (Public Health), CHU Gabriel Montpied, 63 000
Clermont-Ferrand, France. Corresp. : 31 Avenue du Bois, Chatenay
Malabry, France. E-mail : firstname.lastname@example.org
2 University Paris
VII, France. E-mail : email@example.com
Association Positifs, Paris, France.
The multiple sclerosis (MS) is a clinically heterogeneous auto-immune
disease: Many clinicians think that there is not one, but several MSs,
gathered under the same term. It is a rigid clinical framework to
dismember, with the modern means we currently have. Right now, it seems
that one can distinguish approximately 5 different varieties, as
suggested by the histological studies (STORCH M and LASSMANN H, 1997).
Antigen HLA-DR2 is overrepresented in this disease; in particular, in
the multiplexing families where this antigen is expressed, the risk to
contract a SEP is up to 40 to 50 times higher than for a normal
population. Paradoxically, the studies among twins monozygotes show only
one agreement of 25-30%, i.e.
of the same order as for the poliomyelitis, a viral disease; what
suggests a prevalent environmental cause, in 70-75% of the cases, in the
SEP. Two viruses were implied in the SEP: The Virus Human Herpes 6
(VHH-6) (CHALLONER PB, 1995) and the retrovirus of SEP (MSRV= Multiple
Sclerosis Retrovirus) described by Herve PERRON. MULTIPLE SCLEROSIS AND
VIRUS HERPES HUMAIN-6 (VHH-6). With regard to the VHH-6 (re-examined in:
CAMPADELLI-FIUME G, 1999), virus ubiquitaire responsible for the
infantile roseola (exanthème sudden or 6th disease) and for 26% of the
feverish convulsions of the child, it was described an acute fulminant
demyelinisation due to the VHH-6 at a subject not immunodéprimé.
Rejections of Clerc's Offices and deaths by encéphalite are observed
among persons receiving a transplant (DROBYSKI WR, 1994; BOSI A, 1998).
Of IgM against the HHV-6 were found in the event of chronic syndrome of
tiredness, which is to be brought closer the tiredness frequently
observed in the SEP (tiredness, although nonspecific symptom, is a true
handicap specific to the SEP). In the same way, the HHV-6 was blamed in
a retinite at a sidéen (QAVI HB, 1989), recalling in this direction the
optical neuritis so evocative of the SEP. The HHV-6 can be responsible
for hepatitis (TAJIRI H, 1990), even of fulminant hepatitis mortal
(ASANO Y, 1990). Generally, the VHH-6 is regarded as a virus
ubiquitaire, contracted during the first 2 years of the life, which is
in agreement with the epidemiologic data on the SEP of the migrants,
though the serologic studies show that the VHH-6 is less frequent in
France (approximately 30% of seropositivity) and in Great Britain (~
40%) that in the United States (~90%). The tables of encéphalite
serious are seen especially in the event of immunodépression (AIDS and
persons receiving a transplant). Among persons receiving a transplant,
the HHV-6 is associated the rejection of Clerc's Offices (AGUT H, 1991).
How to explain that a virus as ubiquitaire as the HHV-6 can be in
question in the SEP? One can suppose that occurred of a SEP is due to
the meeting of a factor of risk like the antigen of susceptibility
HLA-DR2 and one or more virus. [An example is that of the virus of
measles which is extremely banal, but can in rare cases entrainer an
acute encephalitis or a Subacute Sclerosing Panencephalitis (PESS)
extremely serious]. Of another factors, like the female sex, where
antigens HLA are expressed than at the man, can intervene: It is known
for example that the autoimmune diseases, generally, have a greater
predilection for the women. The genetic study of the SEP showed several
candidates, of rather moderate effect (what corresponds well to the
concept of factor of risk, associated an environmental factor), rather
than a single major gene for important purpose: The SEP is not a
monogenic disease. Certain genes are found by several independent teams.
One can quote of course antigen HLA-DR15 and/or HLA-DR4 (chromosome 6q),
certain patients reached of SEP which can have the 2 HLA-DR (HLA-DR15
and HLA-DR4), but also another area close to HLA in the 6q (on this
subject, it is interesting to note that the MOG is located at the level
of the 6q). For the moment, certain genes seem to have a moderated
effect, but they ask to be confirmed in a final way by other teams: The
PBM of the myelin itself, but only in one Finnish population well
defined geographically, the receiver of ), the chains door of
immunoglobulin, the IL-2, the Protein Kinase C-delta (PKC- T-Cell
Receptor (TC R).
Nota Bene foot-note: The nomenclature of antigens HLA is enough changing,
with the result that the same antigen is called differently according to
whether the article is recent or old: HLA-DR2 is the old denomination of
HLA-DR15, which itself is dethroned by most modern but more complicated
nomenclature HLA-DRB1*1501. Antigens HLA were the subject of a recent
development (KLEIN J and SATO A, 2000). The genes of class II are
indicated with 3 letters: 1st (D) indicates the class, the 2nd (M, O, P,
Q, or R, respectively). HLA-DRB, for b
3rd (A or B) the chains. The b
gene of class II of the family R coding for the chains individual genes of system HLA are differentiated by Arab numbers,
and the notation for many the variable alleliques ones of these genes
is a number preceded by an asterisk (*). For example, HLA-DRB*1501 wants
to say varying allelic 1501 of the gene 1, which codes molecule of class II
to family R.
A recent Australian study seems to show that all is played on
level of a simple residue, a Valin (Valley or V) located at the level of
antigen HLA-DR: In this direction, it is more important to have this
Valin than to have antigen HLA-DR15. I.e. even without having antigen
HLA-DR15, one can make a SEP, since one has this crucial Valin. The
smoothness of the epitopic recognition is thus extreme, and it would be
from now on necessary to resort to a detailed and targeted sequencing,
in the search of this valin, to identify antigen HLA-DR (Valley) of
susceptibility to the SEP. It is interesting to note that the VHH-6 can
transactiver a retrovirus, if one remembers that the MSRV is a
retrovirus (RV=RetroVirus). The decisive study implying the VHH-6 in the
SEP is that of CHALLONER PB into 1995 which in found in the plates of
demyelinisation of the SEP, on the level of the oligodendrocytes, the
cells which synthesize the myelin central nervous system, but also on
the level of the neurons; it used a method of immunocytochemistry with
an anti-101K antibody (gp110) of the VHH-6. [We underline this detail,
because we found that the 101K has a sequence (QYLKSK) which is almost
identical to that of the bovine 1 human A an anti-VHH-6 activity in
vitro on b2
(EYLKSK); interferon-b interferon-blood
cord cells (FOLGER K, 1995) and is a drug authorized in the SEP, able in
the very early forms, as of the first sign, to decrease by 44% the risk
of occurred of a clinically definite SEP (JACOBS LD, 2000)]. SOLDAN SS
and BERTI R (1997) detect by PCR (Polymerase Chain Reaction) brood,
method more significant than the simple PCR, of the HHV-6 in ~ 40% of
SEP. It of IgM, and not of IgG, is directed against early protein p38/41
of the HHV-6, which is present in the SEP, testifying that it is about a
reactivation of the virus. Very many authors launched out recently in
the research of the VHH-6 in the SEP: In short, one can say that they
confirm, for the majority, the role of the VHH-6 (failures being able to
be explained by a technique different, less significant, and/or the
heterogeneity of the SEP): One can quote ABLASHI FD (1998) which finds
in 56¨% of SEP of IgM against the early antigen p41/38, ONGRADI J
(1999) in 44% of SEP of IgM against variable the 6B of the VHH-6, KIM JS
(2000) in 20,6% (7/34) of SEP by PCR brood. MULTIPLE SCLEROSIS AND
RETROVIRUS MSRV Of HERVE PERRON. With regard to retrovirus MSRV, one
notices first of all that other retroviruses were implied in the models
of SEP: Visna-CAEV (Caprine Arthritis Encephalitis Virus), a lentivirus
of the goat and sheep which has a sequence resembling myelin; Human T
Leukemia Virus HTLV-I (but also HTLV-II), person in charge for tropical
spastic paraplegia and the myelopathy associated with the HTLV in a very
small percentage with case, after a very long latency period, and whose
protein gag presents the very interesting sequence with a triplet of
prolines (Pro or P) “PPP”. On this subject, KOPROSKI H had found
antibodies anti-gag of HTLV-I (due to a cross reactivity) in the SEP,
and this work had initiated research on the specific retrovirus of the
SEP, whose result is the discovery by Herve PERRON of the MSRV in ~ 30%
of the SEP. We were also binterested in the
retrovirus, and found (TRAN MKG, 1999) a dream of interferon- of mouse
in the gp41 of the VIH1. There still, in the context of the SEP, one,
as in the case of the protein-b falls down very curiously on the
interferon-2 (TRAN MKG, 2000).
b101K of VHH-6, which is very homologous
with the interferon-b.
OTHER VIRUS AND
MULTIPLE SCLEROSIS. The other viruses are, in terms of frequency, less
important, and work with regard to them is less advanced. The candidates
are extremely many, most interesting are perhaps: The virus of the
disease of Square, or Canine Distemper Virus (COOK), of the same family
as the virus of measles, the virus herpes simplex (GAUTAM), [only one
publication gives a report on SEP associated with the virus herpes],
Coronavirus, of the family of the virus of hepatitis at the mouse (Murine
Hepatitis Virus or MHV) and the virus of EPSTEIN-BARR. The virus herpes
of the monkey squirrel SAIMIRI (GAUTAM) contains a homologous sequence
with final part NH2 of the PBM; when it is injected with complete
additive of Freund, it causes an experimental allergic encephalomyelitis
in the mouse (whereas if it is mixed with the incomplete additive, it is
protective). We studied this viral sequence more thoroughly, by
extending the bank of data and by indexing all the sequences published
of the species of myelin, and we are seen that it was homologous with
the ox myelin, species not analyzed by GAUTAM. Consequently, there is
the typical example of a molecular mimicry between a virus of the herpes
family, like the HHV-6, and the PBM, on the level of the NH2 terminus of
the myelin. This short viral encephalitogene is restricted by the TCR Vb
in the SEP. This data join the
b peptide studies of
genetics on the possible role of the TCR Vb, and also the only
and single publication on the implication of a virus herpes simplex in
the SEP. Although anecdotic, this study has the merit to highlight the
molecular mimicry between the herpes virus family and the myelin.
We seek to show the viral origin of the
SEP, because an antiviral treatment, available, against the VHH-6 [to
ganciclovir, and its bioavailable version to valganciclovir it (Laboratories
ROCK), whose advantage is to be usable by oral way, foscarnet for
example (AGUT H, 1989)], or an antiretroviral like those used in AIDS,
could be used to treat this disease.
In the same way a
vaccine against the SEP could be considered.
The comparison of the sequences in amino
acids of proteins and that of the corresponding nucleotidic sequences.
The Basic Protein encephalitogene of Myeline (PBM) and viruses are
analyzed HHV-6 (variable a: U 1102, variable b: Z29 & HST) and MSRV.
The choice was made on the PBM because it induces in the animal an
experimental allergic encephalomyelitis (EAE). In particular, in mouse
B10.RIII (H-2r), the épitope 89-101 of the PBM 89VHFFKNIVTPRTP101
causes a serious EAE, at early beginning, of evolution chronic and
repeating (JANSSON L, 1991). We also centered research on the peptide of
the PBM restricted by antigen HLA-DR15, a sub-type of HLA-DR2 (MARTIN R,
1991), which is overexpressed by the patients reached of SEP. It is that
this peptide 91-102 of the PBM has as a sequence
“91FKNIVTPRTPPP102”, i.e. it covers the same area as the peptide of
JANSSON. The statistical analysis is made according to OLDSTONE MBA,
which assumes that there are 20 Amino Acids (AA), that each one among is
balanced same unit coefficient 1.
Therefore, for example, if the molecular
mimicry relates to 6 successive identical residues, there is 1 chance
out of 20 power 6 (206 = 20x20x20x20x20x20 = 64.000.000) so that it is
due to the simple chance, according to the law of the great numbers. A
molecular mimicry is statistically significant starting from the size of
the hexapeptide (6 AA, 6 acids amino). The abbréviations employed in
peptidology are: With = Ala, Alanine; B = Asn or Asp, Asparagine or Acid
Aspartic; C = Cys or Cysteine; D = Asp or Acid Aspartic; E = Lime or
Acid Glutamic; F = Phe or Phenylalanine; G = Gly or Glycine; H = His or
Histidine; I = Iso or Isoleucine; K = Lily or Lysin; L = Leu or Leucine;
M = Met or Methionine; NR = Asn or Asparagine; P = Pro or Proline; Q =
Gln or Glutamine; R = Arg or Arginine; S = Ser or Serine; T = Thr or Thréonine;
V = Valley or Valin; W = Trp or Tryptophan; X = unknown; Y = Tyr or
Tyrosin; Z = Gln or Lime, Glutamine or Acid Glutamic.
(For the biologist, sequence PRTPPPS can be also written:
Pro-Arg-Thr-Pro-Pro-pro-Ser, and means:
There exists a perfect
molecular mimicry between the PBM, precisely on the level of this
peptide PRTPPPS, and the protein U24 (U = Unique) of VHH-6. This mimicry
extends over a length from 7 consecutive residues, which is very highly
significant: There is 1 chance out of 20 power 7 (207 = 1.280.000 000)
so that it is a simple coincidence. Downstream, there is a common RPWN
sequence. Upstream, there is IFVV (~the VVHFF opposite).
Virus the 3 VHH-6 (U24) VV IFK. PRTPPPS…
…RPAWN (U1102 stock)
Myelin PBM (exon 3-4) VVHFFK. PRTPPPS… …RP -
WN (PBM intron 4-5)
On the nucleotidic
level, one finds a homology of 19/22 identical bases (86,4%), of which a
perfect imitation on 11 consecutive bases.
HHV-6 (U24) DC cct cgg acg ccg ccg ccg human Tc
ccg cgt acc ccg ccg ccg Tc (KALMHOLZ J, 1986; NYE HS, 1995)
The MSRV (gag, capsid) is also
very homologous on the level with the triplet of prolines PPP:
MSRV (gag, capsid)
||PYVQTFF SPQSPPP Y
|| VV IFK PRTPPPSY
PBM (exon 3-4) (man)
PBM (exon 3-4) (bird)
PBM causing an EAE
PBM restricted by HLA-DR15
control, one can note that the VHH-7, which was never found in SEP, by
any author, despite all studies which were made (ONGRADI J, 1999), has
on this level (U24) sequence 1 MTHETPPPS 9 (MEGAW AG, 1998; NICHOLAS J,
1995), which one notes that it does not have a basic arginin (Arg or R),
but has an acidic Glutamic Acid residue (Lime or E).
However in the PBM
of the myelin, the arginin is essential, because it belongs to a motif
for RTP phosphorylation (Arg-Thr-Pro), which is preserved in VHH-6, but
not in U24 of VHH-7 which has ETP (Lime-Thr-Pro).
The sequence of U24
of VHH-7 is thus very different functionally, i.e. it cannot be
phosphorylated, although there is a little similitude, of purely
phylogenetic nature with VHH-6 (associated with species evolution,
without any medical consequence).
VHH-7 seems to be
implied in a skin trouble, the pink pytiriasis. In the same way the
VHH-8, isolated in patient with Kaposi sarcoma, but never among patients
with SEP, does not have this sequence either. One sees here the power of
the molecular mimicry like methodological approach, because one cannot
force negative controls to be mimetic to myelin.
is carried out by a serine/threonin kinase activated by the meiosis of
44kDa (p44mpk) on the threonin (Thr) residue T 97 of reason RTP (Arg-Thr-Pro)
of the sequence 91 NIVTPRTPPPSQGK 104 of the bovine myelin (SANGHERA JS,
There exists a molecular
mimicry between basic protein encephalitogene of the myelin and the
virus human-6 herpes (U24) and a strong homology with retrovirus MSRV
(gag, capsid). HHV-6 and MSRV are the 2 viruses implied in the multiple
sclerosis. The common area is also that restricted by antigen HLA-DR15
(a sub-type of HLA-DR2) overexpressed in the SEP; its injection in the
animal having the antigen suitable H2 causes an experimental allergic
encephalitis. We confirm work of CHALLONER PB and of many authors on the
role of HHV-6, like those of Herve PERRON on the MSRV, by unifying them
on same the epitope of MBP. Vaccine and antiviral drugs are possible in
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