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Objective. To investigate haplotype tagging single nucleotide polymorphisms (SNPs) in the tumour necrosis factor alpha (TNF-alpha) gene, in UK Caucasian idiopathic inflammatory myopathy (IIM) patients. Methods. A cross-sectional, case-control study of four TNF-alpha SNPs was undertaken, comparing cases of polymyositis (PM) (n = 121), dermatomyositis (DM) (n = 109) and myositis overlapping with other connective tissue diseases (CTD-overlap) (n = 73) with normal subjects (n = 177). Subgroup analyses were undertaken after stratifying for myositis specific/associated antibodies. Results. The TNF-308A allele demonstrated a strong association with each myositis disease subgroup vs controls [PM, odds ratio (OR) 2.8, 95% confidence interval 1.9-4.3; DM, OR 2.5, 1.6-3.8; CTD-overlap, OR 3.3, 2.1-5.1]. The TNF-308GA/AA genotype frequency was significantly increased vs controls (PM, OR 3.7, 2.1-6.3; DM, OR 3.2, 1.8-5.5; CTD-overlap, OR 5.0, 2.6-9.6) suggesting a dominant model. The association was strongest in patients possessing anti-aminoacyl transfer RNA synthetase (anti-synthetase) (OR 5.1, 3.3-8.0) or -PM-Scl (OR 5.0, 2.7-8.9) antibodies. The -1031T allele was also a significant risk factor in DM (OR 2.2, 1.4-3.6), anti-synthetase (OR 2.9, 1.6-5.3) and -PM-Scl (OR 5.6, 1.9-6.4) antibody positive patients. The TNF-308A association was lost after adjusting for HLA-B*08, but remained independent of HLA-DQB1*02 (both are alleles forming part of the common ancestral haplotype). The HLA-B*08/TNF-308A/DRB1*03/DQA1*05/DQB1*02 haplotype was a risk factor in all myositis subgroups vs controls (OR 3.0, 1.8-5.3). Conclusions. TNF-308A and -1031T alleles are significant risk factors in the IIMs. In the IIMs, the TNF-308A allele is part of the common ancestral haplotype, but is not independent of HLA-B*08 DA - 20070822IS - 1462-0324 (Print)LA - engPT - Journal ArticleSB - AIMSB - IM

Objectives. Polymyositis (PM) and dermatomyositis (DM) form part of the idiopathic inflammatory myopathies (IIMs). The chemokine monocyte chemotactic protein-1 (MCP-1) is expressed at sites of the T cell inflammatory response in the IIMs. We thus investigate whether genetic markers in the MCP-1 gene confer disease susceptibility for the development of PM and DM. Methods. DNA samples were analysed from a group of 195 UK Caucasian IIM patients, comprising 103 PM and 92 DM. Their results were compared with those of 162 ethnically matched controls. The polymorphic positions of three single nucleotide polymorphisms (SNPs) and one insertion-deletion sequence within regions coding for MCP-1 were tested. The SNPs examined were located in intron 1 (rs2857657, C/G), exon 2 (rs4586, A/G) and the 3′ untranslated region (rs13900, C/T). The insertion-deletion sequence was located in intron 1 (rs3917887, AGCTCCTCCTTCTC/-). Each SNP was tested for Hardy-Weinberg equilibrium and allelic/genotypic associations. Haplotype frequencies were estimated using the Expectation/Maximization algorithm. Results. There was strong linkage disequilibrium present between three out of these four markers. The majority of controls were in Hardy Weinberg equilibrium. No allelic, genotypic or haplotypic associations were detected when comparing PM or DM cases to controls, or when PM and DM were compared with each other. Conclusions. Genetic markers in the MCP-1 gene do not demonstrate significant genetic associations with the IIMs, and do not discriminate PM from DM in a UK Caucasian population. © 2007 Oxford University Press.

Cellular reactivity to Der p 2, a major allergen of the house dust mite (HDM) Dermatophagoides pteronyssinus, was studied in a group of 41 symptomatic HDM sensitive patients, using fresh peripheral blood mononuclear cells (PBMC) and assays of proliferation. Sixty per cent of the patients responded to Der p2, with reactivities being greater in patients with asthma as one of their clinical manifestations and also in those who had skin-test reactivity to a number of allergens. HLA-DR and -DQ serotyping was undertaken in 39 of the patients and the magnitude of T-cell proliferative responses to Der p 2 were found to be positively associated with DQ7 and negatively associated with DQ2. T-cell determinants within the Der p 2 molecule were identified by assays using a series of overlapping peptides (15- to 19-mers) spanning the entire protein. Fifty-nine per cent of the 41 HDM-sensitive patients responded to one or more of the peptides. All of the peptides were antigenic for at least one of the individuals, indicating the heterogeneity of the human repertoire reactive with Der p 2. There was a substantial variability in the number and location of epitopes recognized by T cells from the different allergic patients, the mean number per patient being 2.3 +/- 1.3 (SD). The most frequently recognized peptide was that spanning residues 111-129, being stimulatory in 66.7%, the other peptides were each recognized by between 8 to 25% of individuals. There was no correlation between the epitope recognized and the presence of particular HLA-DQ antigens.

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1 - 0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes J200632

An assay of cell-mediated immunity, the leucocyte migration technique (LMT), has been compared with the commonly used assay of humoral immunity to transplantation antigens, the microlymphocytotoxicity test. Five recently multiply transfused patients and nineteen haemodialysis patients who had been potentially immunized against transplantation antigens were studied by both tests. All five transfused patients gave positive LMT results while only two gave a positive serological test. Sixteen out of nineteen dialysis patients gave positive LMT results compared with nine with known anti-HL-A antibodies and four showing positive serological direct cross-matches. There was no correlation between cell-mediated and humoral immunity as detected by these methods, although there was a tendency, which was not absolute, for positive direct cross-matches between patients' sera and the panel's lymphocytes, to be associated with positive LMT results. There was a significant correlation (P less than 0-05) between the number of blood transfusions received by the dialysis patients and the detection of cytotoxic antibodies but not with the LMT results. It is felt that some of these positive LMT results are due to reactivity with non-HL-A antigens, and that false negative results also occur. For this reason the technique is not of great value in determining presensitization against HL-A before transplantation.

Studies of T lymphocyte subsets were carried out in a group of 50 scleroderma patients, of whom 46 were also HLA phenotyped. The total lymphocyte count was depressed in 22 patients, and CD4 (helper cells) numbers were normal. CD8 (suppressor-cytotoxic) cells were reduced in 27 patients, and the CD4/CD8 number ratio increased above normal in three additional patients, resulting in 30 patients being classified as CD8-deficient. In the 46 patients HLA phenotyped, DRw8 was significantly increased in the entire patient group, but when the patients were subdivided into CD8-deficient (n = 29) and CD8-normal (n = 17), the increase in DRw8 was confined to the CD8-deficient patients. B18 was also increased in patients with limited sclerosis, while DR4 and DRw53 were significantly decreased and DR5 significantly increased in patients with more extensive skin sclerosis. These findings suggest that scleroderma is a heterogeneous condition and that this heterogeneity is reflected in different HLA profiles in patients subtyped according to their clinical profile and subpopulations of T cells.

An immunogenetic study of autoimmune chronic active hepatitis (CAH) showed the relative risk (RR) for this disease was 11.6 for patients who were HLA-B8, 11.7 for patients who were DR3 and 2.3 for patients who were Gma+x+. Moreover, the Gm haplotype Gma+x+ was present in 18 of 40 (45%) patients with HLA-B8, but in none of 10 patients negative for HLA-B8, whereas in 180 healthy controls Gma+x+ was evenly distributed among those positive (24%) and negative (18%) for HLA-B8. The RR was lowest in patients lacking HLA-B8 but positive for Gma+x+. Relative to this low-risk group, the risk was increased 39 times in subjects with both HLA-B8 and Gma+x+, 15 times in subjects with HLA-B8 who were not Gma+x+ and twice in subjects who were neither HLA-B8 nor Gma+x+. Statistical analysis indicated that the three-factor effect (disease risk affected by non-additive effects of HLA-B8 and Gma+x+) was significant (P less than 0.01), as were the main effects of HLA-B8 (P less than 0.001) and Gma+x+ (P less than 0.02). Thus in the presence of HLA-B8, genes linked to Gma+x+, an immunoglobulin CH allotype, may contribute to the development of autoimmune chronic active hepatitis; in the absence of HLA-B8 these same genes appear to be inactive. This may indicate interactions between MHC gene products and VH gene products in the presentation and recognition of autoantigen(s) in autoimmune hepatitis.