Quantitative analysis of the T cell repertoire selected by a single peptide-major histocompatibility complex.

The positive selection of CD4+ T cells requires the expression of major histocompatibility complex (MHC) class II molecules in the thymus, but the role of self-peptides complexed to class II molecules is still a matter of debate. Recently, it was observed that transgenic mice expressing a single peptide-MHC class II complex positively select significant numbers of diverse CD4+ T cells in the thymus. However, the number of selected T cell specificities has not been evaluated so far. Here, we have sequenced 700 junctional complementarity determining regions 3 (CDR3) from T cell receptors (TCRs) carrying Vbeta11-Jbeta1.1 or Vbeta12-Jbeta1.1 rearrangements. We found that a single peptide-MHC class II complex positively selects at least 10(5) different Vbeta rearrangements. Our data yield a first evaluation of the size of the T cell repertoire. In addition, they provide evidence that the single Ealpha52-68-I-Ab complex skews the amino acid frequency in the TCR CDR3 loop of positively selected T cells. A detailed analysis of CDR3 sequences indicates that a fraction of the beta chain repertoire bears the imprint of the selecting self-peptide.

Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005.

OBJECTIVE: To investigate and compare the prevalence, comorbidities and management of gout in practice in the UK and Germany. METHODS: A retrospective analysis of patients with gout, identified through the records of 2.5 million patients in UK general practices and 2.4 million patients attending GPs or internists in Germany, using the IMS Disease Analyzer. RESULTS: The prevalence of gout was 1.4% in the UK and Germany. Obesity was the most common comorbidity in the UK (27.7%), but in Germany the most common comorbidity was diabetes (25.9%). The prevalence of comorbidities tended to increase with serum uric acid (sUA) levels. There was a positive correlation between sUA level and the frequency of gout flares. Compared with those in whom sUA was <360 micromol/l (<6 mg/dl), odds ratios for a gout flare were 1.33 and 1.37 at sUA 360-420 micromol/l (6-7 mg/dl), and 2.15 and 2.48 at sUA >530 micromol/l ( >9 mg/dl) in the UK and Germany, respectively (p<0.01). CONCLUSIONS: The prevalence of gout in practice in the UK and Germany in the years 2000-5 was 1.4%, consistent with previous UK data for 1990-9. Chronic comorbidities were common among patients with gout and included conditions associated with an increased risk for cardiovascular disease, such as obesity, diabetes and hypertension. The importance of regular monitoring of sUA in order to tailor gout treatment was highlighted by data from this study showing that patients with sUA levels >or=360 micromol/l (>or=6 mg/dl) had an increased risk of gout flares.