Beruflich Dokumente
Kultur Dokumente
Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm
Review
Pharmacogenetics and Translational Genetics Center, Rappaport Faculty of Medicine & Research Institute, Technion-Israel Institute of Technology, Efron 1,
Haifa 31096, Israel
b
INSERM U974, CNRS UMR 7215, UPMC Univ Paris 6, AIM-Institute of Myology, Paris, France
c
Division of Neuroimmunology and Multiple Sclerosis Center, Carmel Medical Center, Haifa, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 July 2013
Accepted 2 December 2013
Myasthenia gravis (MG) is a rare autoimmune disease characterized by the production of autoantibodies
against proteins of the postsynaptic membrane in the neuromuscular junction. The estimated number of
MG patients is steadily increasing, and it had more than doubled in the last 20 years. Monozygotic MG
twin concordance is estimated to be about 35% supporting the central role of environmental factors in
MG etiology. Epigenetics, presume to be the mechanistic link between environmental and genetic risk
factors in disease development, provides support for specic microRNAs associated with MG. Genetic
studies have mainly pointed at specic HLA alleles implicated in MG susceptibility, however recently
both TNFAIP3-interacting protein 1 (TNIP1) and tyrosine phosphatase non-receptor 22 (PTPN22) were
indicated to be associated with MG in a GWAS study. A gender bias was observed for SNPs in the HLAlocus, suggesting female-specic alleles have an increase risk for MG. Moreover, sex hormones play a
pivotal role in the gender bias in autoimmunity in general and in MG in particular. Hence the genetic
basis of gender bias might be highly pertinent to MG and deserves further characterization. Pathwaybased analyses that combine information across multiple genes into a limited number of molecular
networks have been found to be a powerful approach. Both regulatory T-cell (Treg) differentiation and
NF-kB signaling pathway have been shown to have relevance to MG pathophysiology. Hence studies
centered around two pathways might be a fruitful approach to identify additional polymorphisms
associated with myasthenia gravis.
2013 Elsevier Ltd. All rights reserved.
Keywords:
Epigenetic
Genetics
Gender
Myasthenia gravis
NF-kB signaling pathway
TNIP1
thymoma). In early onset AChR MG patient, the thymus is characterized by the presence of anti-AChR autoreactive T cells and
autoantibody-producing B cells [4]. While the cause for AChR
autosensitization in the thymus is unclear, chronic inammation,
characterized by high expression of inammatory cytokines which
may increase AChR expression [6,7], and impaired regulatory Tcell(Treg)function [8,9], have been suggested to be involved in the
pathogenesis. The current hypothesis is that MG is a rare complex
disease with numerous genetic polymorphisms, each having a
small effect, contributing to MG predisposition. Because of it low
prevalence and disease complexity the genetic basis of MG remain
largely unknown.
1.1. Geo-epidemiology and prevalence
Current estimates place the MG prevalence at a high value of
about 3e30 per 100,000 persons depending on the study and
geographic location [10e13]. The estimated number of MG patients
is steadily increasing, and it had more than doubled in the last 20
147
2. Genetic susceptibility
2.1. Specic HLA alleles implicated in MG susceptibility
Like most autoimmune diseases, genetic studies have mainly
pointed at specic HLA alleles implicated in MG susceptibility. The
association of HLA A1-B8-DR3-DQ2 haplotype, also known as AH8.1
[29], with EOMG in the Caucasian population has been reproduced
by numerous groups [30e33]. Remarkably, AH8.1 haplotype has
been associated with other autoimmune diseases, such as celiac and
systemic lupus erythematosus (SLE), supporting the hypothesis of
shared genetic risk factors for several autoimmune diseases [34,35].
Other MHC variants have been described in Asiatic MG patients [36],
LOMG [37] and anti-MuSK patients [38]. Childhood-onset of
ocular MG in Southern Han Chinese is suggested to be a particular
subgroup with distinct genetic background since 90.1% of patients
were reported to be positively associated with DQ9 haplotype [36].
In contrast, in a northern Han Chinese population HLA-DRB1(*)09
allele was signicantly more prevalent among patients with MG
than among healthy controls [39]. DRB1*15:01, DQB1*05:02 and
DRB1*16 have been associated with increased risk for LOMG in
Norwegian and Italian cohorts [37,40]. Patients with MuSK-MG, a
rare and relatively newly described clinical entity, appear to be
associated with DQ5 alleles in populations with diverse ancestries
both from Southern and Northern Europe [38,41].
Tumor necrosis factor-alpha (TNF-a) is a potent proinammatory cytokine located within the HLA locus that is
tightly linked to AH8.1 haplotype. A functional SNP, rs1800629,
at 308 nucleotides upstream from the transcription initiation site
has been shown to affect TNF-a expression, with the 308A allelic
form having a two-fold greater level of transcription than the 308G
form [42]. The 308A allelic form was linked with elevated serum
levels of TNF-a and with a more severe disease outcome in several
diseases [43e46]. The A allele of this functional SNP has been
linked to higher expression level and higher serum level of TNF-a in
MG by several independent groups [47e49]. In a recently complete
EOMG association study rs1800629 was found to be the most
signicantly associated SNP, increasing the odd ratio (OD) to 2 in
males and to over 4 in females (submitted manuscript). All these
results suggest a physiological role of TNF-a polymorphism in MG
predisposition that needs to be further evaluated.
Table 1
Non-HLA genes associated with MG.
Locus symbol, gene product
Variant or marker
Mechanism
References
Cathepsin L2 (CTSL2)
Cellular tyrosine phosphatase 22 (PTPN22)
Cytotoxic T cell late antigen 4 (CTLA4)
Galectin-1 (LGALS1)
Unknown
Trp allele impairs binding to Csk kinase
Abnormal alternative splicing
Unknown
[104]
[60,61,65,105]
[70,71]
[106]
Unknown
[73]
Unknown
[106]
[107]
[108]
[109,110]
[79,81]
Intronic microsatellite
Unknown
[78]
Rs1800629(-308G<A)
rs2233290(Pro151Ala)
[45,47,48]
[54]
148
1966
Title
1971
1978
1984
1984
1986
1989
1989
1991
1994
1997
2004
2008
2011
Reference
Alter & Talbert, 1960 [111]
149
150
analysis [101]. TNIP1, that has been shown to promote proteasomedependent polyubiquitination degradation as well as VAV1, CD86,
and BAFF that were recently shown to be associated with EOMG
(submitted manuscript) are all part of NF-kB signaling pathway as
depicted in Fig. 1. Otherwise it was previously shown that Treg cells
from the thymus of MG patients are profoundly defective in their
suppressive activity [74]. Hence genes involved in these two
pathways, Treg differentiation and NF-kB signaling, are anticipated
to be associated with myasthenia predisposition. A candidate gene
association study centered on these two pathways might be a more
rewarding approach to identify additional polymorphisms associated with MG, a rare complex disease.
6. Concluding remarks
Understanding the molecular mechanisms involved in the
pathophysiology of autoimmune diseases is essential for the
introduction of effective, target-directed therapies. EOMG is one of
the most characterized autoimmune diseases with the pathogenic
autoantigen, AChR, identied more than four decades ago. Nevertheless, the genetic basis and the functional defects of the disease
remain largely unknown. The increased number of MG patients in
the last two decades makes the need for better prevention and
treatment even more essential. The detection of MG-specic
microRNAs and the study of their functions could provide
Fig. 1. TCR/CD28-mediated activation of the canonical NF-kB pathway in a PI3-K-dependent manner. The T-cell signalosome convey activation signals to the IL-2 gene promoter,
that bind multiple transcription factors, such as c-Jun, NF-KappaB, and NFAT. Cooperative interaction between these factors is required for efcient IL-2 gene expression. TCR/CD3
engagement induces activation of Src (Fyn and Lck), Syk, ZAP70 and Tec-family PTKs, leading to stimulation and membrane recruitment of PLC-Gamma1, PI3-K and Vav-1. Vav-1
induces the activation of the canonical p50/p65(RelA) NF-kB through a pathway involving Rac-1 and MEKK1. Vav-1 may also activate the alternative p52/p65(RelA) NF-kB pathway,
by recruiting and activating IKKa. TCR/CD28 costimulation with its CD80/CD86 ligands activates a transcriptional element that is a combinatorial binding site for NF-kB and
Activator Protein-1, SEK1 and IKKs. This activation signal proceeds through the synergistic activation of JNK by SEK1 and Ca2/Calcineurin signals. PI3-K e Phosphatidylinositiol-3Kinase, NF-kB eNuclear Factor-KappaB, NFAT e Nuclear Factor Of Activated T-Cells, PTKs e Protein Trosine Kinases, PLC-Gamma1 e Phospholipase-C-Gamma1, SEK1 e Activator
Protein-1, (SAPK/ERK Kinase-1), IKKs e I-KappaB Kinases. This image is a modication of QIAGENs original, copyrighted image by Dr. Nili Avidan. The original image may be found
at http://www.qiagen.com/products/genes%20and%20pathways/pathway%20details?pwid240; http://www.qiagen.com/products/genes%20and%20pathways/pathway%20details?
pwid235; http://www.qiagen.com/products/genes%20and%20pathways/pathway%20details?pwid361.
valuable information about MG pathogenesis and open new therapeutic avenues. In addition, comprehension of the interplays between genes, gender, and environmental factors that might
modulate disease development is highly pertinent to myasthenia.
Few important biological discoveries have been made in the last
ve years through GWASs, but only well powered GWASs using
thousands of patients samples produce reproducible association
[52,53]. Candidate gene approach requires a few hundred samples
to highlight modest genotype-risk effects with the caveat that it
requires some knowledge of disease pathophysiology, knowledge
that may be biased. Pathway-based gene selection, that combines
biological information into a limited number of molecular networks might be the optimal solution. Hence, candidate genes association study centered on these two pathways, Treg development
and regulation, and NF-kB signaling, might be a fruitful approach to
identify additional polymorphisms associated with myasthenia.
Acknowledgments
This work was supported by 7th Framework Program of the
European Union FIGHT-MG (grant no. 242210), the Association
Franaise contre les Myopathies (AFM) and the Sacta-Rashi
Foundation (N.A).
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