Statistics from Altmetric.com
In 1998, in this journal, we reported the cases of two B27 positive patients with undifferentiated spondyloarthropathy (uSpA) and showing dactylitis also affecting the synovial sheaths in the palm of the hand.1 Neither patient had axial disease but showed peripheral manifestations of spondyloarthropathy (SpA), such as peripheral arthritis, peripheral enthesitis, and dactylitis.
Recently, one of our two patients (No 2) was subtyped and found to be B*2709 positive. As far as we know this subtype has never been found in patients with SpA.
DNA typing of HLA class I alleles was performed using a DNA sample prepared from peripheral blood lymphocytes by the salting out procedure.2 The class 1 ABC SSP UNITRAY low resolution kit (Pel-Freez) was used. The primer sets amplify all alleles described by the International Nomenclature Committee of WHO in 19953and in 1997.4 Polymerase chain reaction amplification with sequence-specific primers (PCR-SSP) was used. A control primer pair was present to verify the integrity of the PCR reaction. Molecular typing of B27 variants was carried out by a PCR-SSP technique with a DYNAL HLA-B27 kit (DYNAL AS, Oslo, Norway), which identifies all the phenotypically different HLA-B27 alleles, B*2701-11, recognised by the HLA Nomenclature Committee in 1973.3 The typing results for our patients were: HLA-A*0101-02, *3201-02; HLA-B*0801, *2709; HLA-C*0102-03, *0701-07.
To confirm these results HLA-B locus sequence based typing was performed. A unique DNA amplification, encompassing exon 1 to intron 3, and four fluorescent sequencing reactions, covering exon 2 and 3, were used.5 Two intronic amplification primers generated a 1 kb length product useful for direct sequencing. For complete subtyping of the allelic variants PCR-SSP was used. Cycle sequencing reactions allowed the incorporation of fluorescently labelled dideoxy terminators for detection on a DNA automated sequencer (ABI PRISM 377, Perkin Elmer). Data processing and allele assignment were performed automatically with specific analysis software that compares the sequencing results against a sequence library and provides individual allele assignment for each sequence. The HLA-B class 1 high resolution typing of our sample was HLA-B*0801/2709 in agreement with the low resolution typing performed by PCR-SSP.
SpA has a strong association with the HLA-B27 molecule. Studies in humans and transgenic rodents suggest a direct involvement of HLA-B27 in the pathogenesis of the disease. Thirteen subtypes of HLA-B27 (B* 01–13) have been described, differing from each other by one or more amino acid changes, mainly in the peptide-binding site.6 7 Of these B*2701, 02, 03, 04, 05, 07, 08, and 10 are associated with ankylosing spondylitis (AS). B*2711–13 are rare, which has precluded assessing their putative association with AS. B*2706 is not associated with AS in South East Asia. However some B*2706 positive patients with AS have been reported in China.8 It has been suggested that the B*2706 might protect against SpA. Recently, a study on families in which both B*2704 and B*2706 occurred has suggested that B*2706, although not associated with SpA, does not protect against SpA.9
B*2709 has been found in Sardinia and in continental Italy, where the frequency of HLA-B27 in the general population is around 2%. B*2709 accounts for 25% of HLA-B27 subtypes in Sardinia and 3% in continental Italy.10 D'Amato and coworkers have tested 35 Sardinian patients with AS and 40 Sardinian B27 positive healthy subjects by genomic typing.10 None of the patients with AS were found to be B*2709 positive, in contrast with 25% among the healthy controls. The authors suggested that B*2709 is not associated with AS. B*2709 differs from B*2705 by a single substitution (Hisv Asp) at position 116, which is located in the F pocket of the peptide-binding site. In the opinion of D'Amato and his colleagues the substitution at position 116 might exclude the acceptance of arthrogenic peptide from the B*2709.
Our patient was born in the south of Italy, she is B27 positive, and has uSpA with an erosive and disabling peripheral arthritis. Our case, also, suggests that the B*2709 might be associated with SpA and that the negative association found in Sardinian patients with AS10 should be confirmed in other studies. These should include the full spectrum of SpA and not be limited to AS.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.