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and IFN
in ankylosing
spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene
polymorphism
a Rheumatology,
Department of Medicine, University Hospital Benjamin Franklin, Berlin,
Germany, b Deutsches Rheumaforschungs- zentrum,
Berlin, Germany, c University Hospital Benjamin Franklin and
Deutsches Rheumaforschungs- zentrum, Berlin, Germany
Correspondence to: Dr J Braun, Rheumatologie, Med Klinik IV, Universitätsklinikum Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany jbraun{at}zedat.fu-berlin.de
Accepted for publication 26 April 2000
OBJECTIVE
To test the
hypothesis that ankylosing spondylitis (AS) is a T helper cell type 2 polarised disease by quantifying the T cell cytokines interferon 
(IFN), interleukin 4 (IL4), tumour necrosis factor 
(TNF), and
IL10 at the single cell level in patients with AS in comparison with
healthy HLA-B27 negative and HLA-B27 positive controls.
METHODSPeripheral
blood mononuclear cells from 65 subjects (25 HLA-B27 positive patients
with active AS, 18 healthy HLA-B27 positive controls, and 22 healthy
HLA-B27 negative controls) were stimulated with phorbol myristate
acetate/ionomycin for six hours, surface stained for CD3 and CD8,
intracellularly stained for the cytokines IFN, TNF, IL4, and
IL10, and analysed by flow cytometry. TNF production was related to
the genotype of the TNF promoter at the -308 and -238 polymorphisms.
RESULTSIn peripheral
blood the percentage of TNF+ T cells was significantly lower in
HLA-B27 positive patients with AS (median 5.1% for CD4+ T cells) than
in healthy HLA-B27 negative controls (median 9.5%; p=0.008).
Surprisingly, the percentage of TNF+ T cells was also
significantly lower in healthy HLA-B27 positive controls (median 7.48%) than in healthy HLA-B27 negative controls (p=0.034). Furthermore, the percentage of IFN+ T cells was lower in patients with AS and in healthy HLA-B27 positive controls than in healthy HLA-B27 negative controls (p=0.005 and p=0.003, respectively). The
percentage of IL10+/CD8+ T cells was higher in patients with AS than in
both control groups. In HLA-B27 positive subjects, TNF1/2
heterozygosity at -308 (n=6) was associated with a higher percentage of
TNF+ T cells than TNF1/1 homozygosity (n=25; median 9.97%
v 5.11% for CD4+
T cells; p=0.017). In contrast, in HLA-B27 negative controls (n=18)
there was no such genotype/phenotype correlation (median 9.4%
v 10.6%).
CONCLUSIONSThe lower
T cell production of TNF and IFN shown at the single cell level
in HLA-B27 positive patients with AS and healthy HLA-B27 positive
controls may contribute to the increased susceptibility of HLA-B27
positive subjects to develop AS. Preliminary genotype-phenotype correlations suggest that in HLA-B27 positive subjects TNF2 at -308 or
a linked gene results in higher TNF production and, therefore, might
be a marker for a protective haplotype.
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