An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles.

The tumor necrosis factor (TNF) alpha gene lies within the class III region of the major histocompatibility complex (MHC), telomeric to the class II and centromeric to the class I region. We have recently described the first polymorphism within the human TNF-alpha locus. This is biallelic and lies within the promoter region. Frequency analysis of the TNF-alpha polymorphism, using the polymerase chain reaction and single-stranded conformational polymorphism, in HLA-typed individuals, reveals a very strong association between the uncommon TNF allele and HLA A1, B8, and DR3 alleles. This is the first association between TNF-alpha and other MHC alleles and raises the possibility that the uncommon TNF-alpha allele may contribute to the many autoimmune associations of the A1,B8,DR3 haplotype

An interleukin-1 genotype is associated with fatal outcome of meningococcal disease

To determine whether known variants of the interleukin-1 (IL-1) and tumor necrosis factor (TNF) gene families are associated with severe manifestations of meningococcal disease, 276 white patients 4-70 years of age (median, 17 years) were genotyped. All patients had microbiologically proven Neisseria meningitidis infection; 39 died and 237 survived. A significant association (P&lt;.001) was found between fatal outcome and genotype at IL1B (nucleotide position -511). Homozygous individuals, both for the common (1/1) and the rare (2/2) alleles, had increased odds ratios (ORs) for death, compared with heterozygous individuals (1/2): ORs (95% confidence intervals [CIs]) were 3.39 (1.39-8.29) and 7.35 (2.51-21.45), respectively. The mortality rates according to genotype at IL1B (-511) were 18.0% (1/1), 6.1% (1/2), and 32.3% (2/2), compared with 14.2% overall. The composite genotype, consisting of heterozygosity of IL1B (-511) together with homozygosity of the common allele of the IL-1 receptor antagonist gene (IL1RN) at +2018, was significantly associated with survival (P=.018; OR, 7.78 [95% CI, 1. 05-59.05]). There was no association between TNF genotype and fatal outcome. These data suggest that IL-1 genotype influences the severity of meningococcal disease.</p

A functional polymorphism of toll-like receptor 4 is not associated with likelihood or severity of meningococcal disease

Human Toll-like receptor 4 (TLR4) transduces proinflammatory cytokine release by human cells in response to lipopolysaccharide (LPS). This study tested the hypothesis that, if TLR4 is rate limiting for a successful response to bacterial LPS in humans, a human gene polymorphism that results in the amino acid substitution Asp299Gly and causes reduced expression and function of TLR4 should influence susceptibility to or severity of natural gram-negative infection. The allele frequency of the Asp299Gly polymorphism was 5.9% among 879 blood donors, 6.5% among 1047 patients with microbiologically proven meningococcal disease, and 4.1% among 86 patients who died of meningococcal disease. No significant differences were observed, including those analyzed after stratification of the infected population by age and by meningococcal serogroup. Therefore, this functional TLR4 polymorphism does not influence susceptibility to or severity of meningococcal disease.</p

Cytokines in rheumatoid arthritis.

An ever-growing number of cytokines that play a critical role as soluble mediators of immune and inflammatory responses are being described. Not surprisingly, most of them have been detected in SF or serum of patients with RA. However, given the numerous interactions within the cytokine network--e.g., agonistic and antagonistic properties and natural inhibitors--one should beware of over-simplistic views, the most so as extrapolation from in vitro and animal models is always a challenge. From a clinical viewpoint, more work is required before measurements of cytokines in RA be used as activity indices and--more importantly--as prognostic marker

IL-1RN gene polymorphism is associated with peri-implantitis

Objectives: Interleukin (IL)-1 alpha, IL-1 beta and their natural specific inhibitor IL-1 receptor antagonist (IL-1ra) play a key role in the regulation of the inflammatory response in periodontal tissues. Polymorphisms in the IL-1 gene cluster have been associated with severe adult periodontitis. We aimed to investigate the IL-1 gene cluster polymorphisms in patients with peri-implantitis. Material and methods: The study included 120 North Caucasian individuals. A total of 71 patients (mean age 68 years, 76% smokers) demonstrating peri-implantitis at one or more implants as evidenced by bleeding and/or pus on probing and bone loss amounting to > 3 threads on Branemark implants and 49 controls (mean age 66 years, 45% smokers) with clinical healthy mucosa and no bone loss around the implants were recruited for the study. The titanium implants, ad modum Branemark, had been in function for at least 2 years. Mouthwash samples were collected and used for genotyping of the bi-allelic polymorphisms IL-1A(-889), IL-1B(+3953), IL-1B(-511) and a variable number of tandem repeat IL-1RN gene polymorphisms using PCR technique. Results: Significant differences were found in the carriage rate of allele 2 in the IL-1RN gene between peri-implantitis patients and controls (56.5% vs. 33.3%, respectively; odds ratios (OR) 2.6; 95% confidence interval (CI) 1.2-5.6; P=0.015). Logistic regression analysis taking smoking, gender and age into account confirmed the association between the IL-1RN allele 2 carriers and peri-implantitis (OR 3; 95% CI 1.2-7.6; P=0.02). Conclusions: Our results provide evidence that IL-1RN gene polymorphism is associated with peri-implantitis and may represent a risk factor for this disease