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Multiple Sclerosis
Figure 2: Receptors and Pathways in Which TSAd Has Been Implicated as a Participating Protein
pMHC
TGF EGF PDGF VEGF-A
Chemokine
Ligands
Cell membrane
TGFR EGFR PDGF VEGFR2 TCR GPCR
Gβ Receptors
Smad2 Src Grb2 PLCγ
TSAd interacting
Lck VCP
Smad3 MEKK2 P13K
proteins
Itk Rlk
Regulation of
cellular migration
Necessary for PDGF-
induced transcriptional
? ?
activation of AP-1
Necessary for acting Regulation of
reorganisation in proliferation and TSAd interacting proteins are depicted with open symbols.
endothelial cells differentiation References are given in the text.
cell, without the risk that Lck simultaneously phosphorylates bystander example of TSAd illustrates, a given protein may influence multiple
proteins in their vicinity. The SH2 domain of TSAd could provide the pathways, all of which may have relevance for the given disease. Such
necessary localisation information for the TSAd–Lck complex. However, pleiotropic function of a protein involved in disease susceptibility also
as yet only VEGFR-2 and valocin-containing protein (VCP) are known to increases the likelihood that certain combinations of genes and gene
bind to the TSAd SH2 domain.
32,39
It is highly likely that additional targets products present in a given individual may determine whether a
for the TSAd SH2 domain exist within T cells that may point to the more particular gene will contribute to disease risk or not. Consider the
precise role of TSAd in temporarily controlling Lck activity, but these hypothetical situation where the T-cell-regulatory function of TSAd
remain to be determined. Recently, TSAd was also found to be involved promotes development of autoimmune disease, whereas the effect of
in signalling from G-protein coupled receptors (GPCR)
48
(Berge, TSAd on endothelial cell function protects against disease. Under normal
submitted). Park and colleagues cloned the Gβ subunit of the conditions the protective effect of TSAd via endothelial cells could be
heterotrimeric G protein complex as a novel binding partner for TSAd dominant over the disease-promoting effect via T cells. However, in
and showed that TSAd is recruited to Gβ upon chemokine receptor combination with variants of particular genes that regulate T-cell
signalling.
48
Through its interaction with Itk, we have found that TSAd activation but not endothelial cell function, certain variants of TSAd may
promotes Itk activation and thereby regulates chemokine (i.e. CXCL12)- yield a high risk of disease. It must be stressed that at present it is totally
mediated T-cell migration by inducing actin cytoskeleton unknown whether epistatic interactions exist between TSAd variants
rearrangements (Berge, submitted). Taken together, attenuated TSAd and other MS susceptibility genes. The distribution of SH2D2A variants is
expression may thus potentially influence T-cell activation, T-cell the same in HLA-DR2-positive and -negative individuals.
23,26
However,
migration, and endothelial cell function, all of which could contribute to epistasis between genes is relevant for MS, as combinations of HLA-DR2
the pathogenesis of autoimmune disease (see Figure 1). with particular alleles of less effect within or outside of the HLA complex
may yield a considerable increase in disease risk,
49
or decrease the
Epistatic Interaction Between Susceptibility severity of the (experimental) disease.
50
Genes in Multiple Sclerosis and Possibility of
Novel Immune Therapies Conclusion
The association of SH2D2A with MS is an example among many, most of In conclusion, identification of susceptibility genes will have low
which are probably yet to be determined, where a gene provides a power in identifying people at risk of developing MS. However, their
moderate increase in risk of disease susceptibility. The mechanism by identification, the characterisation of their function and their possible
which these genes contribute to disease may be manifold, and it may be interactions with other susceptibility genes will point to pathways that
very difficult to pinpoint the exact mode of disease promotion. As the are putative targets for novel immune therapies in MS. n
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