Low TNF-a and IFN-? in ankylosing spondylitis

Context

This study compares the prominence of Th1 and Th2 responses in ankylosing spondylitis (AS) patients with HLA -B27⁺ and -B27^- controls. The influence of TNF-a promoter polymorphisms on T cell TNF-a production are also investigated.

Significant findings

The median percentage of CD4⁺ and CD8⁺ T cells producing TNF-a and IFN-? was lower in 25 AS patients (all B27⁺) than in 22 healthy B27^- controls (P <0.01). This difference was also evident in 18 healthy B27⁺ controls compared with B27^- controls (P <0.04). The percentages of IL-4-positive cells were similar in all groups. In the 18 B27^- subjects, the TNF-a promoter genotype, defined by polymorphism at TNF-a-308, was not associated with different proportions of TNF-a- producing T cells. However, in 31 subjects (16 patients and 15 controls) from the B27⁺ group, individuals with the rare TNF-a-308 genotype 1/2 (n = 6) had higher percentages of TNF-a-producing T cells than individuals with the common genotype 1/1 (P <0.02) (n = 25). Indeed, the B27⁺ TNF-a-308 genotype 1/2 individuals had percentages of TNF-a-secreting T cells which were comparable with those in the B27^-group.

The authors conclude that this suggests Th1 insufficiency in AS, rather than Th2 overactivity. A rare TNF-a promoter-308 allele (or another gene on that haplotype) modifies this phenotype in B27⁺ individuals and may be protective.

Comments

This is a well presented study which attempts to bridge the gap between association of B27 with AS and pathophysiology. The authors have explored the cytokine production of peripheral T cells in patients with AS (all B27⁺) and controls (B27⁺ and B27^-) and have identified a 'Th1 deficiency' phenotype in patients and in B27⁺ controls. The AS and control groups each included ~20 individuals and appropriate statistical analyses were applied. The stimulation of T cells with PMA and ionomycin is unphysiological; however, the technique probably reveals a genuine difference in T cell function in this study. This 'Th1 deficiency' can apparently be rectified, in B27⁺ subjects, by the presence of a rare TNF-a haplotype. However, the number of individuals with the rare genotype is small and this effect should be regarded as intriguing but inconclusive at this stage. Ideally, the differences in T cell cytokine production should be confirmed following physiological challenges, such as infection with influenza or tetanus toxoid vaccination.

Methods

Stimulation of T cells with phorbol myristate acetate (PMA)/ionomycin, FACS analysis with intracellular staining, amplification-refractory mutation system PCR