Genetics and T cells

G
Thessen Hedreul M, Möller S, Stridh P, Gupta Y, Gillett A, Beyeen AD, Ockinger J, Flytzani S, Diez M, Olsson T, Jagodic M Combining genetic mapping with genome-wide expression in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and candidate genes regulating autoimmunity. Hum Mol Genet. 2013 [Epub ahead of print]

The experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system commonly used to study multiple sclerosis (MS). We combined clinical EAE phenotypes with genome-wide expression profiling in spleens from 150 backcross rats between susceptible DA and resistant PVG rat strains during the chronic EAE phase. This enabled correlation of transcripts with genotypes, other transcripts and clinical EAE phenotypes and implicated potential genetic causes and pathways in EAE. We detected 2285 expression quantitative trait loci (eQTLs). Sixty out of 599 cis-eQTLs overlapped well-known EAE QTLs and constitute positional candidate genes, including Ifit1 (Eae7), Atg7 (Eae20-22), Klrc3 (eEae22) and Mfsd4 (Eae17). A trans-eQTL that overlaps Eae23a regulated a large number of small RNAs and implicates a master regulator of transcription.We defined several disease-correlated networks enriched for pathways involved in cell-mediated immunity. They include C-type lectins, G protein coupled receptors, mitogen-activated protein kinases, transmembrane proteins, suppressors of transcription (Jundp2 and Nr1d1) and STAT transcription factors (Stat4) involved in interferon signaling. The most significant network was enriched for T cell functions, similar to genetic findings in MS, and revealed both established and novel gene interactions. Transcripts in the network have been associated with T cell proliferation and differentiation, the TCR signaling and regulation of regulatory T cells. A number of network genes and their family members have been associated with MS and/or other autoimmune diseases. Combining disease and genome-wide expression phenotypes provides a link between disease risk genes and distinct molecular pathways that are dysregulated during chronic autoimmune inflammation..

This study shows how genetical complex event a simple model is. MS adds another level of complexity




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MouseDoctor

5 comments

Leave a Reply to Helen Scott Cancel reply

  • Does using specimens from an imperfect model of MS, that is EAE, somehow lessen the importance of the data. Would it not be more informative to use specimens from human MS patients?

    • It depends on what you are trying to answer and say

      For some things EAE is perfect….

      Would it be more informative to use human specimens, sure it could be but not many people offer to give researchers their brains if they are living.

      MS is a dynamic process but often you only get to study it at one point in time at post-mortem.

      Also look at how many thousands of MSers have been used to study the genetics of MS, yet we still don't properly understand the complexity of the first gene cluster found (In the HLA-MHC region), which was known before the millions spent on studying genetics. They have found over 100 gene variants how do they interact to give MS?.

  • Wait until our review paper comes out, it was accepted yesterday. (There….11 words)

    or wait until our research paper gets accepted….. at this rate sometimes next year 🙁

    If you look there are a fair few posts of microRNA (This is because this is where our studies have focussed). I'll keep an eye out, but to try an explain these posts properly takes quite a bit of work as you need to explain the science behind paper

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