Toll-like receptor 4 polymorphisms and ankylosing spondylitis

Ankylosing spondylitis (AS) is a chronic systemic rheumatic disorder, which is characterised by sacroiliitis, enthesopathy, and a variety of extra-articular manifestations. Despite having the strongest association ever described with a tissue antigen, HLA B27, the pathogenesis of AS remains poorly understood. Immunoregulatory genes and Gram-negative gut bacteria are thought to be important in disease expression. It is now known that mammalian immune response to Gram-negative bacteria is mediated by Toll-like receptor 4 (TLR4), a pattern recognition receptor. Two cosegregating missense mutations have recently been described in TLR4 that lead to a diminished host response to Gram-negative bacteria. We hypothesise that TLR4 mutations occur with an increased frequency in HLA B27-positive individuals who develop AS than in healthy HLA B27-positive controls, and allow increased survival and the systemic distribution of Gram-negative gut bacteria to the joints. This study aims to compare the frequency of two common TLR4 mutations (Asp299Gly, and Thr399Ile) between AS patients and HLA B27 healthy controls.

The TLR4 genotypes of over 100 patients and 100 HLA B27 healthy controls were determined using allele-specific PCR and restriction fragment length polymorphism analysis. The allele frequencies were compared using a chi-squared test of association.

There was no significant difference between the frequency of the Asp299Gly allele or the Thr399Ile allele in AS and healthy HLA B27 controls.

Two common TLR4 polymorphisms, which cause a functional deficiency in host immune response to Gram-negative bacteria, are not significant in AS.

Affiliations

1. Centre for Rheumatic Diseases, Division of Immunology, Inflammation and Infection, Glasgow Royal Infirmary University Trust, Glasgow, UK
   • R Adam
   • , JA Gracie
   •  & RD Sturrock

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