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The SH2D2A Gene – Contributions to Our Future Understanding of Multiple Sclerosis
the development of MS. This is exemplified by mice that have altered Figure 1: The Sequence of Events from Activation of
susceptibility to spontaneous or induced experimental autoimmune
T cells to Autoimmune Tissue Damage
diseases due to dysregulation of the T-cell activation process
,
14,15
chemokine-regulated cellular migration,
16,17
or altered blood–brain
Lymph node
Blood
CNS
barrier function.
18
In the search for novel candidate genes in MS that are
expressed in activated T-cells, we previously identified and cloned the
T cell
3
TSAd encoded by the
TCR
SH2D2A gene.
19
Microglia
1 aT aT 4
The SH2D2A Gene Is Located in a
Chromosomal Region Regulating TCR
HLA
Experimental Demyelinating Disease
The
HLA
SH2D2A gene in the mouse is located within Eae3, a chromosomal
Proliferation
region that has been implicated in genetic susceptibility to EAE in the
Cytokine production
mouse.
20,21
Professional
Eae3 harbours multiple genes of immunological relevance,
APC
including SH2D2A. However, as yet the susceptibility gene within Eae3
has not yet been identified.
2
Polymorphisms in the
Endothelial cell
SH2D2A Gene
A potentially auto-aggressive T cell is activated by presentation of antigen on a professional
There are several potentially functionally relevant polymorphisms within
antigen presenting cell (APC) in the lymph node (1). The activated T cell migrates into the
the
bloodstream (2) and may cross the blood–brain barrier into the brain (3). In the target tissue
SH2D2A gene. In the SH2D2A promoter, there is a highly polymorphic
the T cell may eventually re-encounter the initial or a very similar peptide–human leukocyte
dinucleotide (GA) repeat located -345 basepairs (bp) upstream of the
antigen (HLA) complex presented by microglia and thus become re-activated to proliferate
first coding ATG.
22
Genotypes homozygous for short alleles of this GA
and secrete potentially harmful cytokines (4). aT = activated T-cell; CNS = central nervous
system; TCR = T-cell receptor.
repeat appear to be associated with reduced expression of TSAd in
activated primary CD4
+
T cells.
23
In the coding sequence of the SH2D2A activated T cells to undergo apoptosis.
29
Accumulating evidence
gene there is a non-synonymous single nucleotide polymorphism (SNP) implicates a failure of myelin-reactive immune cells to undergo
that results in an amino acid change from serine to asparagine (S52N). apoptosis in the pathological events contributing to MS.
30
Thus,
The frequency of the minor allele (A) of this SNP (rs926103) has been members of the inhibitor of apoptosis (IAP) family of anti-apoptotic
found to range from 0.125 to 0.767 in different populations, with Africans genes have been found to be elevated in peripheral blood monocytes
south of the Sahara displaying the highest and Asians the lowest and T-cells of patients with aggressive forms of MS.
31
TSAd was recently
frequencies. The serine in position 52 is a potential phosphorylation site, found to regulate neoangiogenesis in experimental tumours. In mice
located N-terminal to the SH2 domain of TSAd. It has previously been lacking TSAd, tumours grew more slowly and contained fewer vessels
shown that phosphorylation of a serine N-terminal to an SH2 domain than tumours grown in wild-type mice.
32
Interestingly, neovascularisation
may influence the specificity of the SH2 domain for its tyrosine may represent a pathological mechanism contributing to sustained
phosphorylated ligands.
24
An intriguing possibility is thus that the S52N autoimmune disease.
33,34
Vascular endothelial growth factor has also
polymorphism might affect the function of TSAd through modulation of been implicated in various autoimmune diseases including MS
its SH2 domain specificity. (reviewed in reference 35). Although mice lacking TSAd display several
abnormal features that are also observed in MS patients, it remains to
SH2D2A Is Associated with Multiple Sclerosis be clarified whether mice lacking SH2D2A gene expression have altered
Initially, the GA repeat polymorphism in the human SH2D2A gene susceptibility to EAE.
promoter was found to be associated with MS
23
and juvenile rheumatoid
arthritis.
25
A further assessment of this association in MS patients from The SH2D2A-encoded Protein TSAd Regulates
Scandinavian populations revealed that a haplotype of the GA16 repeat T-cell Activation and Cellular Migration
allele in the SH2D2A promoter and the N52 allele of SNP rs926103 was Since its discovery in 1998, TSAd has been found to be involved in
associated with MS among Norwegians and possibly also among multiple signalling pathways, e.g. those of the TCR,
28,36–40
vascular
Danes.
26
A meta-analysis of all published gene expression studies in MS endothelial growth factor receptor-2 (VEGFR-2),
32,41
epidermal growth
patients and controls compared with available linkage data revealed factor receptor (EGFR),
42
platelet-derived growth factor receptor
that SH2D2A gene expression in peripheral blood lymphocytes has been (PDGFR)
43
and transforming growth factor beta receptor (TGFβR)
44
found to be reduced in MS patients.
27
Thus, alteration in SH2D2A gene (see Figure 2). TSAd participates in these pathways by interacting with a
expression or function may be involved in MS. number of different signalling molecules, including members of the Src
and Tec kinase family members, i.e. Lck, Src, Itk and Rlk,
36,37,45–47
the
Mice Lacking the SH2D2A Gene serine/threonine kinase MEKK2
42
and the adapter protein Grb2.
43
The role
Show Aberration in T-cell and of TSAd as an adapter protein is still not well characterised. TSAd has
Endothelial Cell Function several binding sites for the Lck SH2 and SH3 domains, and also three
Mice with a disrupted SH2D2A gene (TSAd knock-out [KO]) appear tyrosines located within a 25-amino-acid stretch that can be
normal, but T cells from these mice migrate poorly in response to phosphorylated by Lck. This conformation of TSAd may explain how
CXCL12/SDF-1α (Berge, submitted) and activated T cells produce less of TSAd can modulate Lck activity.
36,45
TSAd binds to Lck and is
the T-helper type 1 (Th1) cytokines interleukin 2 (IL-2) and interferon phosphorylated by Lck through a process whereby the substrate
gamma (IFN-γ) than T cells from normal mice.
28
With age, TSAd KO mice remains bound to the enzyme throughout the phosphorylation cycle.
47
spontaneously develop a lupus-like autoimmune disease characterised Thus, TSAd has a chaperone-like function for the tyrosine kinase activity
by the presence of antinuclear antibodies and an apparent failure of of Lck. In this way, TSAd may bring Lck to particular locations within the
EUROPEAN NEUROLOGICAL REVIEW 69