Sassari - A gene variant that leads to increased production of the cytokine BAFF could explain why an unusually high number of people in Sardinia develop multiple sclerosis. According to the study in the New England Journal of Medicine (), quarter of the population of the Mediterranean island are carriers of the gene variant that may have protected them from malaria in the past.
Despite the favorable geographical location - the frequency usually increases the MS with its proximity to the Poles - Sardinia has one of the world's highest incidence rates of multiple sclerosis (MS). Systemic lupus erythematosus (SLE) is also unusually common in the population.
A team led by Francesco Cucca from the Istituto di ricerca genetica e biomedica (IRGB) is looking for the reasons in genome-wide association study Signal encountered in the TNFSF13B gene. Carriers of the variants had an increased risk of developing MS or SLS. Both belong to the group of autoimmune diseases, in which the immune system attacks the body's own tissue after the formation of specific antibodies.
That Gene TNFSF13B contains the information for the cytokine Baff ("B cell activating factor of the TNF family"). BAFF is produced by monocytes and neutrophils. It acts as an important survival factor for B cells. This makes BAFF an interesting target for immunosuppressive agents. The monoclonal antibody belimumab has been approved for the treatment of SLE in Germany since 2011. It is not (so far) used in MS.
Closer genetic analysis showed that the TNFSF13B variant contained so-called "indel". The sequence GCTGT was replaced by A (the letters denote the four nucleobases Adenine, cytosine, guanine and thymine, the sequence of which forms the genetic alphabet. The result of the Indel is that modified messenger RNA is formed. This messenger RNA is beyond the control of microRNA and as result, more BAFF is formed.
The increased BAFF production increases the number of B cells that make more antibodies, including in some people those involved in the pathogenesis of SLE or MS. The results make plausible arguments for the Use of belimumab in multiple sclerosis. However, success cannot be predicted. Clinical studies with belimumab have apparently not been carried out to date. A phase 2 study with the fusion protein atacicept, which is also used in addition to BAFF h blocks the cytokine APRIL, had to be stopped early because there were twice as many relapses in the treatment group as in the placebo group (Lancet Neuroogy 2014; 13: 353-363).
The researchers also found that 26.5 percent of the Sardinian population are carriers of the Indel variant of the TNFSF13B gene. That is more than coincidence could explain. Cucca suspects that the variant protected the population from malaria in the past. The disease was widespread in Sardinia until the 1950s. This hypothesis is supported by animal studies, in which an increased formation of BAFF mice protected against infection with Plasmodia.