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R. Sorrentino - The role of HLA-B27 in autoimmunity: from the genetics to the function
Assessment of the functional effect of SNP
rs1264457 on the expression of HLA-E
Due to the difficulties to find a monoclonal antibody
specifically recognizing the HLA-E molecules, we
have spent several months to validate the MEM/02
antibody (a kind gift from Dr. Vaclav Horejsi) which
shows some cross-reactivity with the classical HLAclass
I molecules, usually expressed at much higher
amount than HLA-E. Having set up the right conditions,
we are now performing some functional experiments.
Meanwhile, we have validated the association
between Ankylosing Spondylitis and the SNP
rs1264457, the functional polymorphism of the
HLA-E molecules, analysing a larger cohort of
patients and HLA-B27 controls from Sardinia than
previously published (Cascino et al., Arthritis Rheum.
2007, 56:2640-51). We have confirmed the strong
association between AS and this functional polymorphism
(allelic difference between patients with AS
versus HLA-B27-matched controls p=0.0005). The
same cohorts have been also analysed for 5 SNP
mapping in the gene encoding for the VIPR1 gene
which is involved both in the down-regulation of the
inflammatory response and as donor of the pVIPR
peptide. Very interestingly we found that the presence
of HLA-B*2705 correlates with the presence of
T at the SNP896 in the 3’UTR of the gene. In addition,
this polymorphism correlates with a more
prompt down-regulation of the mRNA for VIPR1,
suggesting that subjects positive for HLA-B*2705,
the allele associate with AS, might have a different
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regulation of the inflammatory response associated
with the VIP/VIPR1 signaling. These data have
been published (Paladini et al., 2008).
Characterization of an alternative route for
antigen presentation
The question we wanted to answer was whether an
alternative pathway for antigen presentation previously
described by us as active in the case of HLA-
B27 molecules (Bettosini et al., J Virol. 2005,
79:15537-46), was specific for these molecules or was
of more general usage. We have therefore singled
out epitopes specific for HLA-B27 and HLA-A2 and
inserted them in the same chimeric proteins. The
results clearly show that this pathway is not accessible
to the HLA-A2 molecules. B27 mutants which
are unable to recycle from the cell membrane also
show that this pathway is not dependent from this
mechanism but rather from nascent molecules.
Experiments have been undertaken to verify the
influence of a Cys at position 67 which is absent in
all HLA class I molecules but HLA-B27.
Selected publications
Paladini F, Cauli A, Cascino I, Vacca A, Belfiore F,
Fiorillo MT, Mathieu A, Sorrentino R. A functional
polymorphism of the vasoactive intestinal peptide
receptor 1 gene correlates with the presence of
HLA-B*2705 in Sardinia. Genes Immun. 2008,
9:659-67.