Galarza-Muñoz G, Briggs FB, Evsyukova I, Schott-Lerner G, Kennedy EM, Nyanhete T, Wang L, Bergamaschi L, Widen SG, Tomaras GD, Ko DC, Bradrick SS, Barcellos LF, Gregory SG, Garcia-Blanco MA. Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk. Cell. 2017 Mar 23;169(1):72-84.e13.
Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5′ UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.
There are about 150 known genes associated with susceptibility to MS. The major locus is the major histocompatilibility complex which is the one that gives you a DNA fingerprint but controls how your immune response recognises infections. The next set of discoveries found the interleukin 7 receptor.
The interleukin 7 protein acts because it binds to the interleukin-7 receptor. It is made up of two different smaller protein chains – i.e. it is a heterodimer, and consists of two subunits, interleukin-7 receptor-α (CD127) and common-γ chain receptor (CD132).The common-γ chain receptors is shared with various cytokines, including interleukin-2, -4, -9, and -15.Interleukin-7 receptor is expressed on various cell types, including naive and memory T cells and many others. Interleukin-7 receptor has been shown to play a critical role in the development of immune cells called lymphocytes – specifically in a process known as V(D)J recombination (important in antigen recognition) blocking apoptosis (cell death by cell suicide) is an essential function of this protein during differentiation and activation of T lymphocytes.
What about B cells?
IL-7R (CD127) is down regulated as B cells mature but it can be involved in immunoglobulin (antibody) VDJ re-arrangement and can promote B cell survival and proliferation.
It has been shown that Interleukin-7 (IL-7) promotes the maintenance and activation of peripheral T cells, whereas it does not act directly on mature B cells due to the lack of IL-7Rα expression on these. However, despite the insensitivity of B cells to IL-7, high concentration of IL-7 can lead to increased B cell survival and antibody production in the presence of T cells, without the use of any further B cell stimulatory signal. IL-7 promoted B cell activation through inducing CD70 expression on resting T cells, particularly on CD4+ memory cells. The interaction of CD70 molecules with the B cell costimulatory receptor CD27 led to B cell proliferation, the accumulation of CD38 + CD20- plasmablasts and antibody production. In addition, IL-7 treatment induced BAFF secretion from resting peripheral T cells thereby promoting B cell survival. IL-7 levels can increase in lymphopenic conditions, in autoimmune diseases or in patients receiving T cell regenerative IL-7 therapy. Based on our findings high IL-7 levels can lead to increased B cell activation by inducing the B cell regulatory proteins CD70 and BAFF in resting T cells. Such activity might be beneficial in short term immune-stimulatory IL-7 therapies; permanently increased IL-7 levels, on the other hand, can contribute to impaired B cell tolerance.
The IL-7R gene has 8 exons (coding bits of DNA),
Alternative splicing generates a soluble isoform lacking exon 6 and introducing a premature stop codon.
In this study they find that DDX39B also known as BAT-1,
RNA-dependent ATPases that mediate ATP hydrolysis during pre-mRNA splicing. The encoded protein is an essential splicing factor required for association of U2 small nuclear ribonucleoprotein with pre-mRNA, and also plays an important role in mRNA export from the nucleus to the cytoplasm. These genes are all within the human major histocompatibility complex class III region.
which favours the production of the splice variant with the exon 6 so favouring lack of soluble (sIL-7R) which is released from the cell into the solution (blood, fluid between cells=interstitial fluid) .
In this study they found that BAT-1 variants are also risk factors for MS and a vriant that has a different untranslated (DNA part of a gene not made into the protien) region (UTR) associated with risk
The 5′ untranslated region (5′ UTR) (also known as a Leader Sequence or Leader RNA) is the region of an mRNA that is directly upstream from the initiation codon. This region is important for the regulation of translation of a transcript. This region can regulate the translation of the main coding sequence of the mRNA. The 5′ UTR has been found to interact with proteins relating to metabolism; and proteins translate sequences within the 5′ UTR.
So the BAT-1 variant associated with MS risk makes less DDX39B meaning that more of the soluble IL7R is made and this is associated with MS risk.
BAT-1 variants show epistasis (The effect of one gene is dependent on the presence of one or more modifier gene) with the variants creating the alternatively spliced variant.
It has to be said although this study exposes how one MS susceptibility gene is acting, MS is polygenic and there are lots of genes and gene combinations leading to MS susceptibility. Each one confers only a minor risk and you can get MS without having the gene(s) and likewise you can have the genes and not get MS.