Molecular mimicry of measles virus phosphoprotein with platelet gpIIb.

Aim

MMR vaccination is complicated by rare cases of auto-immune purpura or thrombocytopenia in a chronological delay of about 10-24 days, which corresponds to the rise of antibodies (Autret E, 1996; Vlacha V, 1996). We have demonstrated that in the cases of HIV-1, Parvovirus B19, Chikungunya virus, Leptospira, the culprit is an epitope localized on the platelet integrin gpIIIaIIb, centred by a phenylalanine-proline FP (Tran MKG, Kirkiacharian S, ISHEID Toulon 2002); these auto-antibodies are very powerful with a very high affinity (Kd=10^{-9 M) for platelet surface} and induce in mice a thrombocytopenia (Nardi MA, 1997); allo-immunisation from mother to the newborn has the same epitope on gpIIIaIIb (Brouk H, 2009). We continue the same direction of research for MMR vaccine.

Methods

Comparison of amino acid sequences between gpIIIaIIb and MMR viruses (Measles, Mumps and Rubella) with BLASTP and/or visually by coloring. We included also for completion platelet gpIaIIa, gpV and gpIbα (349-357) epitope of chronic idiopathic thrombocytopenic purpura (He R, 1995) and various numerous viruses and infectious agents inducing thrombocytopenia and hemorrhagic fever (for example Dengue, avian influenza).

Results

1°) There is a molecular mimicry between gpIIb and measles virus (strain MVi/Victoria.Aus/12.99) phosphoprotein P; alignments include also hemorragic fever (Ebola, Chikungunya) viruses and snake anti-platelet disintegrin:

Of importance, the FP motif follows a RGNS similar to RGDS adhesion motif (underlined) (Ruoslahti E, 1987): This would explain why therapeutic anti-RGD antibodies are inducing a thrombopenia, by provoking auto-immune anti-gpIIb antibodies.

For measles virus, only rare strains possess this RGNSFP motif mimicking perfectly ITGA2b integrin, which explains why auto-immune thrombopenia is a rare complication of measles or MMR vaccination.

2°) Rubella virus was aligned with platelet gpV by centering on the motif LP (instead of FP):

For rubella, thrombopenia occurs during the neonate period.

Thus 2 viruses (Measles, Rubella) of the MMR combined vaccine are inducing auto-immune thrombopenia.

3°) Alignment of integrin ITG B3 gpIIIa with hemorragic fever or various agents inducing auto-immune thrombopenia is centered on the FP crucial motif; gpIIIa is by far the most frequent target:

4°) Epstein-Barr virus (EBV) and varicella zoster virus were matched with gpIbα (349-357), which is the epitope of chronic idiopathic thrombocytopenic purpura (He R, 1995):

Non-hemorragic viruses: Nipah virus, Ross River virus and Dengue virus 1, 3 and 4 (IVSLFPLCLS, SGIFPYS and VSGLYPLAIP) cannot be aligned and constitute the negative controls, confirming the importance of the FP motif in the context of gpIIIa.

Discussion

The occurrence of thrombocytopenia 2 or 3 weeks after MMR vaccination is an auto-immune phenomenon, on a peculiar genetic background prone to make auto-antibodies against phenylalanine-proline containing epitopes. MMR vaccine must be avoided in these patients with chronic idiopathic thrombocytopenia (Drachtman RA, 1994). The chronological argument is by itself convincing and confirmed here by the biological finding of the causal epitope on platelet. Thus we must be very cautious in presence of a MMR vaccine clinical auto-immune complication such as autism [Wakefield AJ (2005), Singh VK (2009)] and not discard it as a simple coincidence, but rather try to elucidate its mechanism and genetics (HLA-DR). In fact, we performed a complete meta-analysis of all the MMR vaccine trials hat revealed that autism was not researched correctly and its frequency hidden by methodological biais or non-independent studies. Furthermore we discovered that the measles hemagglutinin (HA) was a viral ortholog of MeCP2 Methyl CPG binding Protein 2 Methyl CPG binding Protein 2 Methyl CPG binding Protein 2 Methyl CPG binding Protein 2 (Methyl CPC Binding Protein 2), the gene of Rett’s syndrome: This is concordant with Wakefield’s work on measles HA.

MeCP2 humain (V332, P339 de Xenopus)    311-TVSIE--VKEVVKPLLVSTLGEKVGKGLKTP-K-340

HA du virus rougeoleux (SOA)    81-TNSIEHQVKDVLKPLFK-I IGDEV--GLRTPOR-110

morbilliforme du dauphin 81-TVSIEHHVKDVLTPLLK-I IGDEV--GLRMPQK-110

L'alignement de 29 Aas est très hautement significatif et est complété par celui avec la région MBP (Methyl DNA Binding Protein) de liaison à l'ADN du MeCP2 (Kumar A, 2008) s’étendant sur 43 Aas incluant les AAs cruciaux du site de liaison (W104, R111, D121, R133) en structure tridimensionnelle (Ho KL, 2008).

MBPs (dont MeCP2) 90-ARGPTLEDPTLGEGWKRKLKIRKSGRSFGKSDVYLINPQGLAFR-133

HA du virus rougeoleux    314-GKGVSFQLVKLGV-WKSPTDMR-SWVPLS-TDDPVIDRLYLSSHR-355

Ce sont précisément les anticorps anti-HA (du vaccin Merck) qui sont élevés dans 83% d’autisme (Singh VK, 2003).

The auto-immune pathogenesis of dengue hemorrhagic fever (DHF) caused by dengue virus (DV) infection was elucidated, as patients presented severe thrombocytopenia and (so-called “enhancing”) antibodies directed against DV nonstructural protein 1 (ns1) cross-reactive with human platelets leading to platelet destruction (Lin C-F, 2006).

The gpIIIaIIb FP epitope may serve as a chelating hapten for treatment. This is particularly crucial for 2 major Health Public problems like Avian Influenza H5N1 or Dengue Hemorragic fever 2 (where the concept of enhancing antibodies is renewed with their nature of anti-platelet auto-antibodies (Lin C-F, 2006)): Interestingly, AIDS anti-protease drugs mimick the Phenylalanine Proline FP motif and this raises the question of their activity as a hapten against auto-immune thrombopenia. Not all of them are efficient, for example some of them can bind to proteins and induce thrombocytopenia (tipranavir, lopinavir/ritonavir), but some others are never complicated by thrombopenia, probably because they protect against thrombopenia. These last (saquinavir, atazanavir for example), are candidates for testing them as a hapten blocking the anti-FP auto-antibodies.

Bibliography

SNAKE DISTINTEGRIN KISTRIN contains an RGD site at residues 49, 50, and 51 (in magenta). It binds to platelet GP IIb-IIIa reversibly.

One mature megakaryocyte showing glycoprotein IIb,IIIa stain positivity. The background platelets are also positive. The neutrophilic cells and NRBC are negative. GP IIb,IIIa stain. Normal marrow - 50X

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