S17(T)
ARE HUMAN ENDOGENOUS RETROVIRUSES A TRIGGER FOR LUPUS
NEPHRITIS BY MOLECULAR MIMICRY OF TYPE IV COLLAGEN AND OTHER
AUTOANTIGENS?
Rylance, P1, Lovatt, T2, Nelson, P3, Barham-Morris, J3, Roden, D3
1
Nephrology and 2Immunology, Royal Wolverhampton Hospitals and 3Immunology
Research Group, Research Institute in Healthcare Science, University of
Wolverhampton
BACKGROUND: Systemic Lupus Erythematosus (SLE) is associated with more than 30
autoantibodies, including to type IV collagen. We and others have previously postulated that
SLE might be triggered by a viral agent that could provoke an undesired antibody response.
Antibodies may recognise only a few amino acids as a target epitope. Mechanisms such as
molecular mimicry and epitope spreading can lead to antibodies targeting proteins and
mediating immune complex deposition. The Human Endogenous Retrovirus ERV-3 has been
implicated in SLE as a potential trigger and we have investigated any similarity in linear
structure and shape of ERV-3 proteins to potential autoantigens associated with SLE.
METHODS: Advanced bioinformatic computer programmes were used to detect similarities
of amino acid sequence between ERV3 envelope (env) protein and candidate autoantigens.
Individual sequences of autoantigens and ERV-3 were extracted from the National Center for
Biotechnology Information database. Comparison of viral and autoantigenic proteins was
assessed using Sim-Prot, and a molecular display and design programme (utilising the
Brookhaven protein data bank) was used to generate 3-dimentional molecular models.
Peptide sequences, where homology has been identified between ERV-3 env proteins and
SLE autoantigens using bioinformatics, have been synthesised. We have developed a multianalyte ELISA test using these peptides, which might be potential antigenic targets in SLE
patients. This work is based on our previously published immunoassay for investigating the
serological response in rheumatoid arthritis patients to the endogenous retrovirus HERV-K10.
RESULTS:
Bioinformatics
identified
identical amino acid sequences in both ERV-3
and type IV collagen (GITIG) (Fig. 1) and
ERV-3 env / type IV collagen homology
Collagen IVα6 (GSEGV), which might be key
antigenic regions. The probability by chance
of a 5 amino acid sequence identity is 1:3
million. SmD1 demonstrated a repeating motif
(GRGRGRGRGRG) whilst ERV-3 contained
GRG. Other similarities have also been
identified between ERV-3 (SRSRDEK) and
Ribosomal P (SRSRDKE) and Ro (GMWG).
Fig 1. Molecular mimicry between ERV-3/Collagen IV
Preliminary ELISA data showed that the synthesised peptides that have homology between
ERV-3 env protein and type IV collagen, SmD1 and Ro autoantigens bound to serum from
lupus patients, which contains autoantibodies, but not to a control polyclonal antibody.
CONCLUSIONS: This bioinformatic analysis and the preliminary laboratory data suggest
molecular mimicry between the HERV ERV-3 env and type IV collagen and other
autoantigens in SLE might be a mechanism of development of lupus nephritis. Further
analysis of patients is being undertaken to substantiate these observations together with an
analysis of common amino acids between SLE autoantigens. Synthesised retrovirus peptides
might be used in diagnosis, but might offer the possibility of therapeutic blocking peptides.