SOLUBLE INTERLEUKIN-1 RECEPTOR ANTAGONIST INTRON 2 POLYMORPHISM: FUNCTIONAL ROLE AND RELEVANCE IN MULTIPLE SCLEROSIS

Soluble interleukin I receptor-antagonist (sIL-1ra) antagonizes interleukin-1 {IL-1) by binding both IL- 1 receptors with comparable affinity, but failing to trigger any intracellular signal. The IL-ira gene is polymorphic: the intron 2 contains a 2 to 6 repeats of an 86 b9 sequence. The A2 allele (2 repeats) has been associated with the occurrence of autoimmune inflammatory disease. We analyzed the intron 2 allele frequency in 353 patients affected by multiple sclerosis (MS) and in 263 healthy controls (HC). Although no association was found with the occurrence of MS, course of disease and sex, a significant increase of A2 frequency was found in those MS patients with a particularly benign course of disease [i. e.; at least 10 years from diagnosis and expanded disability status scale (EDSS>3) compared to the remaining MS patients with aggressive course of disease (EDSS>3) (p=0.026}. The functional role of this polymorphism on the sIL-1ra expression was then investigated at mRNA and protein levels in myelomonocytic cell lines and in blood cells and sera from MS patients and healthy controls. The carriage of A2 allele was significantly associated with higher levels of sIL-1ra mRNA and mature protein. We conclude that IL-1ra A2 allele is associated with an elevated production of sIL-1ra which might determine relatively milder inflammation during auuoimmune diseases. This allele seems to be a modifier of the natural hystory of MS.