Jul 20, 2017 Last Updated 12:22 PM, Jul 17, 2017

Overexpression of the Cytokine BAFF and Autoimmunity Risk

Published in Head news
Read 250 times
Rate this item
(0 votes)

In this beautiful paper, published just last week on NEJ, Dr Steri, Orrù and Idda et al. were able to identify in a variant of the TNFSF13B gene, which encode for B-cell activating factor (BAFF), a very important risk factor for multiple sclerosis as well as for lupus. 

 

 

BACKGROUND

Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways.

METHODS

Using case–control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus–specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated.

RESULTS

A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertiondeletion variant, GCTGTA (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria.

CONCLUSIONS

A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.)

 Link to New England Journal

 Link to the original paper news (only for registered users)

Last modified on Thursday, 11 May 2017 07:05
Login to post comments

Registered area

Thanks to the support of
merck serono biogen sanofi

JNIInternational Brain Research Organization
Bringing Neuroscience to the World
JNIJournal of Neuroimmunology
Studies on all branches of neurosciences covering both research and clinical problems of neuroscientific interest.

This website or its third party tools use cookies, which are necessary to its functioning and required to achieve the purposes illustrated in the cookie policy. If you want to know more or withdraw your consent to all or some of the cookies, please refer to the cookie policy. By closing this banner, scrolling this page, clicking a link or continuing to browse otherwise, you agree to the use of cookies. To find out more about the cookies we use and how to delete them, see our Cookie Policy