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Journal of Autoimmunity 52 (2014) 146e153

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Genetic basis of myasthenia gravis e A comprehensive review

Nili Avidan a, *, Rozen Le Panse b, Sonia Berrih-Aknin b, Ariel Miller a, c

Pharmacogenetics and Translational Genetics Center, Rappaport Faculty of Medicine & Research Institute, Technion-Israel Institute of Technology, Efron 1,
Haifa 31096, Israel
INSERM U974, CNRS UMR 7215, UPMC Univ Paris 6, AIM-Institute of Myology, Paris, France
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.

Myasthenia gravis
NF-kB signaling pathway

1. Autoimmune myasthenia gravis (MG) a rare complex

Myasthenia gravis (MG) is a relatively rare autoimmune
neuromuscular disorder, clinically characterized by weakness and
fatigability of skeletal and extraocular muscles [1]. MG is a B-cell
driven, T-cell dependent, complement and antibody-mediated
disease, due to autoantibodies directed against molecules at the
neuromuscular junction, including antibodies against the acetylcholine receptor (AChR) (85% of patients), the muscle-specic kinase (MuSK) or the lipoprotein-related protein 4 (LRP4) [2e4]. The
binding of anti-AChR antibodies to their target impairs neuromuscular transmission by complement-mediated destruction of
the postsynaptic membrane [5]. About 80% of AChR-positive patients have thymic abnormalities (follicular hyperplasia or

* Corresponding author. Tel.: 972 4 8295358; fax: 972 4 8295436.

E-mail address: (N. Avidan).
0896-8411/$ e see front matter 2013 Elsevier Ltd. All rights reserved.

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

N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153

years in Western countries as well as in Japan and Taiwan [14e16].

This increase is probably due to improved diagnostic accuracy, the
improved efcacy of treatment and care, but also by the increasing
longevity of the population. MG shows a bimodal distribution with
two incidence peaks: Early-onset MG (EOMG) in the third decade
(strong female predominance) and late-onset MG (LOMG) in the
elderly (slight male predominance). The elderly-onset MG is the
major source of the overall increase and showed a 2.3-fold rise in
the last 20 years both in Western and in Asian countries [17,18]. The
reason for the increase is unclear and might be due to a better
awareness of neurologists to discriminate MG symptoms from
classical fatigue due to aging. However, the immunological background and the genetic basis are distinct from that in younger
patients. In contrast in China, the overall prevalence is similar to the
above reports, but with a younger age of onset and a ratio of 1:1
between male and female [19]. This geographic difference in
prevalence might reect difference in the methodology between
different studies or might be due to genetic and environmental
factors inuencing disease frequency.
1.2. Familial autoimmune MG is very rare
Familial autoimmune MG is mostly reported as rare case reports
[20e22]. A unique case of a Hungarian family was reported where
nine members from two generations develop MG [23,24]. Recently,
a sequence variant in the ecto-NADH oxidase 1 gene (ENOX1) was
strongly linked to EOMG in an Italian-American kinder with four
affected siblings [25]. The variant sequence was not found in 764
controls, in sporadic MG, or in other patients with familial autoimmune MG. The ENOX1 variant decreased ENOX1 levels in a
lymphoblastoid cell line in a dose-dependent manner, with a
reduction of mRNA levels of up to 80% compared with normal
variants. How ENOX1 could predispose to MG is unknown, but
immunological function studies could help elucidate its role in MG
pathogenesis. Although MG is rarely inherited within a family
occurrence of another autoimmune and immune-mediated diseases (AID) among myasthenic patients kins is relatively common
[26]. The most common concomitant AIDs being Rheumatoid
Arthritis (RA) and thyroid disorders [27,28]. This suggests that
common genetic and environmental factors might predispose to
autoimmune disorders and MG being one of them.


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



Cathepsin L2 (CTSL2)
Cellular tyrosine phosphatase 22 (PTPN22)
Cytotoxic T cell late antigen 4 (CTLA4)
Galectin-1 (LGALS1)

Association between rs4361859 with EO MG

Coding (Arg620Trp)
Two SNPs in the promoter region
Association with regulatory region
(rs4820293, rs4820294)
SNP in the intron region IVS9459
(A/G, rs2280883)
Association with regulatory region
(rs743777, rs228941)
Noncoding SNP (874A/T)
Coding I75V
50 anking sequence of the human IL-10 gene
(rs45552637 (A/C),
rs1800872 (T/C), and rs1800896 (A/G))
Upstream polymorphism (478A/G)

Trp allele impairs binding to Csk kinase
Abnormal alternative splicing






Putative NF-kB binding site

Reduced responsiveness to interleukin-4
Correlated with IL-10 protein production in vitro


Alters binding of IRF8


Intronic microsatellite




Higher secretion of TNF-alpha

Ubiquitin-dependent dysregulation of
NF-kappaB signaling


Fork head/winged-helix transcription

factor 3 (FOXP3)
Interleukin receptor 2b (IL2Rb)
Interferon-g (IFNG)
Interleukin-4 receptor a (IL4R)
Interleukin-10 (IL10)

Muscle nicotinic acetylcholine receptor

a-subunit (CHRNA1)
Muscle nicotinic acetylcholine receptor
d-subunits (CHRND)
Tumor necrosis factor alpha (TNF)
TNFAIP3-interacting protein 1 (TNIP1)


N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153

The four million base-pair HLA super locus contains a large

number of genes related to immune system function in humans.
However, the identication of the true predisposing gene(s) has
been handicapped by the strong linkage disequilibrium across the
region. A recent study renes the association signals for RA susceptibility in the HLA region to ve amino-acid positions encoded
in three HLA genes, all within peptide-binding grooves [50,51]. A
similar approach could be applied to identify functional variants in
MG with the rs1800629(-308 G > A) in the promoter of TNF-a gene
most likely being one of these functional variants.
2.2. Genome-wide association studies (GWAS) of EOMG
In the past ve years, important biologic discoveries have come
from genome-wide association studies (GWAS) aimed at unbiased
detection of variants at loci predisposing to complex traits [52,53].
GWAS of MG is quite a challenge because of its low prevalence and
the modest effect sizes anticipated. Recently, a GWAS with more than
600 patients from northern Europe has found that TNFAIP3interacting protein 1 (TNIP1) is associated with EOMG and conrms
the known association with HLA-B08 and protein tyrosine phosphatase non-receptor 22 (PTPN22) [54]. Imputation and conditional
analysis suggest an association with a putative functional amino acid
change in the TNIP1, rs2233290, a variant encoding a non-conservative Pro151Ala change. TNIP1 has been reported as a risk allele in
other autoimmune diseases, such as lupus and Sjogrens syndrome
[55,56] and has been implicated in chronic inammatory diseases
such as psoriasis and rheumatoid arthritis [57]. In vivo and in vitro
models strongly suggest that TNIP1 plays a crucial role in regulating
several cellular pathways involved in inammation and immunerelated disorders. TNIP1, also known as ABIN-1, is thought to be
involved in ubiquitin-dependent dysregulation of NF-kB signaling
[58,59] and co-repression of nuclear receptors such as retinoic acid
receptors and peroxisome proliferator-activated receptors [57].

in a Han Chinese population [73]. Pending validation of an additional

cohort, the biological relevance FOXP3 to MG is clear, since FOXP3
polymorphisms might inuence both the number and function of
CD4CD25 Tregs that is signicantly decreased in MG [74].
In addition to the loci shared by several AID, specic loci have
been associated with MG. the neuromuscular AChR complex consists of an alpha (CHNRA1), a beta (CHRNB1), a delta (CHRND) and
either a gamma subunit (CHRNG) in fetal muscle or an epsilon
subunit (CHRNE) in adults [75]. No association was found between
CHRNB1 or CHRNE and EOMG [76,77]. However polymorphisms in
CHNRA1 and CHRND have been shown to confer increased risk of
MG and are probably minor susceptibility genes for developing MG
[78e80]. Resequencing of the genomic region encompassing the
upstream regulatory and coding regions of CHRNA1 identied a
unique SNP, rs16862847, located in the CHRNA1 promoter region
that might disrupt a transcription binding motif. This SNP was
found to be more twice more frequent in MG cases versus control in
two different cohorts from France and UK [81].

3. Environmental and epigenetic implication

3.1. Twin studies in myasthenia
Comparison of disease concordance between monozygotic (MZ,
identical), and dizygotic (DZ, fraternal) twins has been used to estimate the contribution of genetics factors to disease risk [82]. Over
Table 2
Published Articles on MG monozygotic twins.


2.3. Non-HLA genes associated with MG


The non-HLA genes associated with MG are summarized in

Table 1. One of the best example of a non-HLA common susceptibility allele for autoimmunity is the association of PTPN22 with a
number of autoimmune diseases including MG [60e62]. PTPN22,
also name lymphoid-specic phosphatase (Lyp), is an intracellular
PTP and physically bound to c-src tyrosine kinase (Csk), and these
two proteins mediate T-cell activation [62]. Recent ndings have
revealed that the change of amino acid at position 620 from an
arginine (R) to a tryptophan (W) in PTPN22 disrupts the interaction
between PTPN22 and Csk. In vitro experiments have shown that the
T-allele of PTPN22 binds less efciently to Csk than the C-allele
does, suggesting that T-cells expressing the T-allele may be hyperresponsive, and consequently, individuals carrying this allele may
be prone to autoimmunity [63,64]. Indeed, The W620 variant was
signicantly overrepresented in MG patients [65], and a higher titer
of anti-AChR antibodies in W620 carriers were found [60].
Cytotoxic T lymphocyteeassociated antigen 4 (CTLA4) has also
been associated with several autoimmune diseases such as type 1
diabetes, celiac disease [66], RA [67], and Graves disease [68]. An
association between SNPs in the promoter region of CTLA4 and MG
has been found by several independent groups [69e71]. It has been
proposed that these SNPs might cause aberrant splicing of CTLA4
and/or cellular abnormalities of MG T-cells that contribute to disease pathogenicity.
Treg cell specic transcription factor, Fork head/winged-helix
transcription factor (FOXP3), has been shown to regulate both the
development and the function of Tregs [72]. Recently the frequency
of the FOXP3 IVS9459 G allele was associated with lower risk of MG


1960 Myasthenia gravis in one monozygotic

1966 Myasthenia gravis in identical twins









Alter & Talbert, 1960 [111]

Osborne & Simcock,

1966 [112]
A case of myasthenia gravis in identical Motoki et al., 1966 [113]
twin brothers
The familial occurrence of myasthenia
Herrmann, 1971 [114]
Myasthenia gravis occurring in twins
Namba et al., 1971b [84]
Michalski et al., 1978 [115]
Monozygotic twins with Klinefelters
snydrome discordant for systemic lupus
erythematosus and symptomatic
myasthenia gravis
Allen et al., 1984 [116]
Myasthenia gravis in monozygotic
twins. Clinical follow-up nine years
after thymectomy
Thymectomy for myasthenia in twin
Vasilev et al., 1984 [117]
Myasthenia gravis in identical twins
Murphy & Murphy,
1986 [118]
B cell and autoantibody repertoire in a Lefvert et al., 1989 [119]
pair of monzygotic twins discordant for
myasthenia gravis
Familial myasthenia gravis: a case
Dias-Tosta et al., 1989 [120]
report in identical twins
Grinlinton et al., 1991 [121]
A pair of monozygotic twins who are
concordant for myasthenia gravis but
became discordant for systemic lupus
erythematosus post-thymectomy
Theile and Kessler, 1994 [122]
Effect of heredity and environment in
immune diseases. Presentation of twin
Twin studies of myasthenia
Agafonov et al., 1997 [85]
Kakoulidou et al., 2004 [123]
The autoimmune T and B cell
repertoires in monozygotic twins
discordant for myasthenia gravis
Monozygous twins with neuromuscular Punga et al., 2009 [124]
transmission defects at opposite sides
of the motor endplate
Discordant thymectomy in identical
Riggs et al., 2011 [125]
twins concordant for myasthenia gravis

N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153

the last 50 years, MZ-MG twins have been reported in over 15

different publications summarized in Table 2, however because of
the small number of cases reported, the lack of adequate follow-up,
and unsatisfactory zygosity determination concordance rate estimated from these case reports should be view as a rough estimate.
Ramanujam et al. estimated MG concordance to be between 30 and
40% in monozygotic twins, compare to 4e5% in dizygotic twins
based on extensive literature search [83]. A recent survey set up by
the European network FIGHT-MG to identify and recruit MZ MG
twins throughout Europe and USA identied 14 MZ pairs (3 males
and 11 females aged between 11 and 85 years) for which 5 are
concordant and 9 discordant MG twins (unpublished data). The
concordance rate found in this survey is in the same range as
Multiple Sclerosis (MS) and similar to Ramanujam et al. publication
[82,83]. On one hand, this result emphasis the large contribution of
genetics to disease predisposition, on the other hand, the high
percentage of diseaseediscordant pairs in monozygotic twins
demonstrates the central role of environmental factors in the etiology of MG [84,85]. Indeed, despite the identical genetic material,
the share uterus environmental, and the common household
experience during the rst two decades of twin life, about two third
of MZ-MG twins are discordant.
3.2. MG and epigenetics
Epigenetics pertains to heritable alterations in gene expression
that do not involve modication of the underlying genomic DNA
sequence. Epigenetic patterning is modied by environmental exposures and may be a mechanistic link between environmental and
genetic risk factors in pathogenesis of diseases. Historically, the
study of epigenetic mechanisms has focused on DNA methylation
and histone modications, but the concept of epigenetics has been
more recently extended to include microRNAs as well. MicroRNAs
are small noncoding RNAs that inhibit sequence-specic translation and tag mRNA for degradation. Epigenetic modulation of
gene expression by specic microRNAs has been associated with a
variety of autoimmune diseases [86]. MicroRNAs appear to be new
key mediators in the immunoregulatory processes and excessive
activation of inammatory pathways [87]. In particular miR-155,
miR-146a, and miR-326 appear to be associated with several
autoimmune diseases and linked to T-cell response, immuneregulation, and inammation [88,89]. The aberrant expression of
several microRNA, including miR-320a and let-7c, were found in
lymphocytes from MG patients in comparison to controls [90,91].
Low-expression of miR-320a was correlated with over-expression
of pro-inammatory cytokines in MG patients presumably via the
NFkB pathway [90]. Inverse correlation between endogenous let-7c
and IL-10 expression was found in MG patients and it was shown
that IL-10 is negatively regulated by let-7c via a specic target site
within IL-10 30 UTR [91]. In an animal model for MG it was shown
that down-regulation of miR-145 promotes pathogenic Th17 cell
response [92]. The detection of myasthenia gravis-specic microRNAs and the study of their functions could provide valuable information about MG pathogenesis and open new therapeutic
4. Gender bias
4.1. The role of sex hormones in the MG gender bias
There are clear biological and physiological differences between
men and women, including differences in disease prevalence. For
instance, autoimmune diseases are known to be much more
prevalent in women while Coronary Artery Diseases are much more
prevalent in men. The immune, endocrine and nervous systems


communicate with each other through a myriad of molecules

including cytokines, hormones and neurotransmitters [93]. Sex
hormones play a pivotal role in the gender bias with a commonly
accepted view that androgens are protective. A number of studies
implicate estrogen as a primary mediator of MG disease [94]. Estrogen is known to modify both innate and adaptive immunity and
can promote production of antibodies by B lymphocytes as well as
inuence Treg function [95]. At elevated concentrations, estrogen
can enhance humoral immunity by inducing helper T cell responses
[95]. In addition, numerous HLA-region genes, including HLA-DRA
and TNF, contain estrogen response elements [96]. It has been
suggested that polymorphisms in these response elements might
inuence transcription in a gender specic manner.
The gut microbes can modulate, tune and tame the host immune response and disturbance in this population can incite
imbalance in immune system, leading to molecular mimicry and
therefore autoimmunity [97]. In an animal model for type 1 diabetes (T1D) hormone-dependent differences in microbiota
composition were found, and these differences conferred protection against T1D in males [98]. This result suggests that a core set of
microbial properties, functions, or genes, working in concert with
sex-hormones might inuence autoimmune disease predisposition. Hence, identication of the pathways and molecules from
both host and microbes that mediate susceptibility and to translate
this knowledge into the designing of new therapeutics might be a
new direction for autoimmune disease treatments.
4.2. Sex-specic genetic architecture modulate disease
Recent studies suggest that sex-specic genetic architecture
inuences human disease phenotypic traits and interplays between
genes, gender, and environmental factors to modulate disease
susceptibility. A systematically analysis for sex differences in genee
disease associations of seven common diseases identied several
SNPs that are signicantly associated with disease in only one sex
[99]. Gender-specic SNP associations have been also shown in a
meta-analysis for the regulation of hypothalamicepituitaryethyroid axis hormones [100]. In MG, in both a GWAS and in a genetic
association study of 35 candidate genes, a gender bias association
was observed for SNPs in the HLA locus [54]. This increased female
risk may reect hormonal effects, a female bias in environmental
exposure, or gender-related epigenetic changes playing a role in
disease risk. The results from these different studies suggest that
sexually dimorphic SNP-disease associations are relevant to understand the molecular mechanisms of autoimmune diseases and
the genetic basis of complex diseases in general and might be
highly pertinent to myasthenia.
5. The added value of network and pathway analyses
It has previously been observed that different genes harboring
causal mutations for the same Mendelian disease often physically
interact. The concept has been extended to complex diseases were
multiple loci contribute to disease predisposition. Pathway-based
analyses that combine information across multiple genes into a
limited number of molecular networks have been found to be a
powerful approach. This approach allows to gain further insights
into the biology of associated genes, to prioritize candidates for
subsequent genetic studies of complex traits, and to discover new
drug targets. GWAS associated genes were found to be more likely
to interact physically and to be enriched in specic pathways in
several autoimmune diseases [101e103]. Moreover, these networks
have been shown to have predictive power and to highlight relevant disease associated loci even before shown in extended GWAS


N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153

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

N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153

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.
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).
[1] Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging
clinical and biological heterogeneity. Lancet Neurol 2009;8:475e90.
[2] Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody
to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976;26:1054e9.
[3] Shigemoto K, Kubo S, Maruyama N, Hato N, Yamada H, Jie C, et al. Induction
of myasthenia by immunization against muscle-specic kinase. J Clin Invest
[4] Cavalcante P, le Panse R, Berrih-Aknin S, Maggi L, Antozzi C, Baggi F, et al. The
thymus in myasthenia gravis: site of innate autoimmunity? Muscle Nerve
[5] Engel AG, Fumagalli G. Mechanisms of acetylcholine receptor loss from the
neuromuscular junction. Ciba Found Symp 1982:197e224.
[6] Poea-Guyon S, Christadoss P, Le Panse R, Guyon T, De Baets M, Wakkach A,
et al. Effects of cytokines on acetylcholine receptor expression: implications
for myasthenia gravis. J Immunol 2005;174:5941e9.
[7] Cu P, Dragin N, Weiss JM, Martinez-Martinez P, De Baets MH, Roussin R,
et al. Implication of double-stranded RNA signaling in the etiology of autoimmune myasthenia gravis. Ann Neurol 2013;73:281e93.
[8] Le Panse R, Cizeron-Clairac G, Cuvelier M, Truffault F, Bismuth J, Nancy P,
et al. Regulatory and pathogenic mechanisms in human autoimmune
myasthenia gravis. Ann N Y Acad Sci 2008;1132:135e42.
[9] Masuda M, Matsumoto M, Tanaka S, Nakajima K, Yamada N, Ido N, et al.
Clinical implication of peripheral CD4CD25 regulatory T cells and Th17
cells in myasthenia gravis patients. J Neuroimmunol 2010;225:123e31.
[10] Querol L, Illa I. Myasthenia gravis and the neuromuscular junction. Curr Opin
Neurol 2013;26:459e65.
[11] Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of
population based epidemiological studies in Myasthenia Gravis. BMC Neurol
[12] Montomoli C, Citterio A, Piccolo G, Cioccale R, Ferretti VV, Fratti C, et al.
Epidemiology and geographical variation of myasthenia gravis in the province of Pavia, Italy. Neuroepidemiology 2012;38:100e5.
[13] Casetta I, Groppo E, De Gennaro R, Cesnik E, Piccolo L, Volpato S, et al.
Myasthenia gravis: a changing pattern of incidence. J Neurol 2010;257:
[14] Gattellari M, Goumas C, Worthington JM. A national epidemiological study of
myasthenia gravis in Australia. Eur J Neurol 2012;19:1413e20.
[15] Murai H, Yamashita N, Watanabe M, Nomura Y, Motomura M, Yoshikawa H,
et al. Characteristics of myasthenia gravis according to onset-age: Japanese
nationwide survey. J Neurol Sci 2011;305:97e102.
[16] Lai CH, Tseng HF. Nationwide population-based epidemiological study of
myasthenia gravis in Taiwan. Neuroepidemiology 2010;35:66e71.
[17] Pallaver F, Riviera AP, Piffer S, Ricciardi R, Roni R, Orrico D, et al. Change in
myasthenia gravis epidemiology in Trento, Italy, after twenty years. Neuroepidemiology 2011;36:282e7.
[18] Kalb B, Matell G, Pirskanen R, Lambe M. Epidemiology of myasthenia gravis:
a population-based study in Stockholm, Sweden. Neuroepidemiology
[19] Wang W, Chen YP, Wang ZK, Wei DN, Yin L. A cohort study on myasthenia
gravis patients in China. Neurol Sci 2013;34:1759e64.


[20] Lavrnic D, Nikolic A, De Baets M, Verschuuren J, Verduyn W, Losen M, et al.

Familial occurrence of autoimmune myasthenia gravis with different antibody specicity. Neurology 2008;70:2011e3.
[21] Corda D, Deiana GA, Mulargia M, Pirastru MI, Serra M, Piluzza MG, et al.
Familial autoimmune MuSK positive myasthenia gravis. J Neurol 2011;258:
[22] Feng HY, Liu WB, Luo CM, Yang LX, Fang W, Qiu L, et al. A retrospective
review of 15 patients with familial myasthenia gravis over a period of 25
years. Neurol Sci 2011;33(4):771e7.
[23] Li F, Szobor A, Croxen R, Anselmo V, Yuan QP, Lindblad K, et al. Dominantly
inherited familial myasthenia gravis as a separate genetic entity without
involvement of dened candidate gene loci. Int J Mol Med 2001;7:289e94.
[24] Szobor A. Familial myasthenia gravis: nine patients in two generations. Acta
Med Hung 1991;48:145e9.
[25] Landoure G, Knight MA, Stanescu H, Taye AA, Shi Y, Diallo O, et al.
A candidate gene for autoimmune myasthenia gravis. Neurology 2012;79:
[26] Mao ZF, Yang LX, Mo XA, Qin C, Lai YR, He NY, et al. Frequency of autoimmune diseases in myasthenia gravis: a systematic review. Int J Neurosci
[27] Nakata R, Motomura M, Masuda T, Shiraishi H, Tokuda M, Fukuda T, et al.
Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specic receptor tyrosine kinase-antibody-positive
myasthenia gravis. Eur J Neurol 2013;20:1272e6.
[28] Ramanujam R, Piehl F, Pirskanen R, Gregersen PK, Hammarstrom L.
Concomitant autoimmunity in myasthenia graviselack of association with
IgA deciency. J Neuroimmunol 2011;236:118e22.
[29] Horton R, Gibson R, Coggill P, Miretti M, Allcock RJ, Almeida J, et al. Variation
analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype
Project. Immunogenetics 2008;60:1e18.
[30] Vandiedonck C, Beaurain G, Giraud M, Hue-Beauvais C, Eymard B,
Tranchant C, et al. Pleiotropic effects of the 8.1 HLA haplotype in patients
with autoimmune myasthenia gravis and thymus hyperplasia. Proc Natl
Acad Sci U S A 2004;101:15464e9.
[31] Giraud M, Beaurain G, Eymard B, Tranchant C, Gajdos P, Garchon HJ. Genetic
control of autoantibody expression in autoimmune myasthenia gravis: role
of the self-antigen and of HLA-linked loci. Genes Immun 2004;5:398e404.
[32] Janer M, Cowland A, Picard J, Campbell D, Pontarotti P, Newsom-Davis J, et al.
A susceptibility region for myasthenia gravis extending into the HLA-class I
sector telomeric to HLA-C. Hum Immunol 1999;60:909e17.
[33] Suzuki S, Utsugisawa K, Nagane Y, Satoh T, Kuwana M, Suzuki N. Clinical and
immunological differences between early and late-onset myasthenia gravis
in Japan. J Neuroimmunol 2011;230:148e52.
[34] Candore G, Modica MA, Lio D, Colonna-Romano G, Listi F, Grimaldi MP, et al.
Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 inuences immunological parameters of healthy carriers of the haplotype. Biomed Pharmacother
[35] Candore G, Lio D, Colonna Romano G, Caruso C. Pathogenesis of autoimmune
diseases associated with 8.1 ancestral haplotype: effect of multiple gene
interactions. Autoimmun Rev 2002;1:29e35.
[36] Zhu WH, Lu JH, Lin J, Xi JY, Lu J, Luo SS, et al. HLA-DQA1*03:02/DQB1*03:03:02
is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese. J Neuroimmunol 2012;247:81e5.
[37] Maniaol AH, Elsais A, Lorentzen AR, Owe JF, Viken MK, Saether H, et al. Late
onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLoS One 2012;7:e36603.
[38] Bartoccioni E, Scuderi F, Augugliaro A, Chiatamone Ranieri S, Sauchelli D,
Alboino P, et al. HLA class II allele analysis in MuSK-positive myasthenia
gravis suggests a role for DQ5. Neurology 2009;72:195e7.
[39] Xie YC, Qu Y, Sun L, Li HF, Zhang H, Shi HJ, et al. Association between HLADRB1 and myasthenia gravis in a northern Han Chinese population. J Clin
Neurosci 2011;18:1524e7.
[40] Testi M, Terracciano C, Guagnano A, Testa G, Mara GA, Pompeo E, et al.
Association of HLA-DQB1 *05:02 and DRB1 *16 alleles with late-onset,
nonthymomatous, AChR-Ab-positive myasthenia gravis. Autoimmune Dis
[41] Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, et al.
Strong association of MuSK antibody-positive myasthenia gravis and HLADR14-DQ5. Neurology 2006;66:1772e4.
[42] Kroeger KM, Carville KS, Abraham LJ. The -308 tumor necrosis factor-alpha
promoter polymorphism effects transcription. Mol Immunol 1997;34:391e
[43] Rodriguez-Carreon AA, Zuniga J, Hernandez-Pacheco G, Rodriguez-Perez JM,
Perez-Hernandez N, Montes de Oca JV, et al. Tumor necrosis factor-alpha308 promoter polymorphism contributes independently to HLA alleles in
the severity of rheumatoid arthritis in Mexicans. J Autoimmun 2005;24:63e
[44] OKeefe GE, Hybki DL, Munford RS. The G>A single nucleotide polymorphism at the -308 position in the tumor necrosis factor-alpha promoter
increases the risk for severe sepsis after trauma. J Trauma 2002;52:817e25.
discussion 25e6.
[45] Elahi MM, Asotra K, Matata BM, Mastana SS. Tumor necrosis factor alpha
-308 gene locus promoter polymorphism: an analysis of association with
health and disease. Biochim Biophys Acta 2009;1792:163e72.


N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153

[46] Hong Y, Ge Z, Jing C, Shi J, Dong X, Zhou F, et al. Functional promoter308G>A variant in tumor necrosis factor alpha gene is associated with risk
and progression of gastric cancer in a Chinese population. PLoS One 2013;8:
[47] Huang DR, Pirskanen R, Matell G, Lefvert AK. Tumour necrosis factor-alpha
polymorphism and secretion in myasthenia gravis. J Neuroimmunol
[48] Skeie GO, Pandey JP, Aarli JA, Gilhus NE. TNFA and TNFB polymorphisms in
myasthenia gravis. Arch Neurol 1999;56:457e61.
[49] Zelano G, Lino MM, Evoli A, Settesoldi D, Batocchi AP, Torrente I, et al.
Tumour necrosis factor beta gene polymorphisms in myasthenia gravis. Eur J
Immunogenet 1998;25:403e8.
[50] Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, et al. Five
amino acids in three HLA proteins explain most of the association between
MHC and seropositive rheumatoid arthritis. Nat Genet 2012;44:291e6.
[51] Barrett JC. From HLA association to function. Nat Genet 2012;44:235e6.
[52] Hu X, Daly M. What have we learned from six years of GWAS in autoimmune
diseases, and what is next? Curr Opin Immunol 2012;24:571e5.
[53] Visscher PM, Brown MA, McCarthy MI, Yang J. Five years of GWAS discovery.
Am J Hum Genet 2012;90:7e24.
[54] Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, et al. Risk for
myasthenia gravis maps to a (151) Pro>Ala change in TNIP1 and to human
leukocyte antigen-B*08. Ann Neurol 2012;72:927e35.
[55] Adrianto I, Wang S, Wiley GB, Lessard CJ, Kelly JA, Adler AJ, et al. Association
of two independent functional risk haplotypes in TNIP1 with systemic lupus
erythematosus. Arthritis Rheum 2012;64:3695e705.
[56] Lessard CJ, Li H, Adrianto I, Ice JA, Rasmussen A, Grundahl KM, et al. Variants
at multiple loci implicated in both innate and adaptive immune responses
are associated with Sjogrens syndrome. Nat Genet 2013;45:1284e92.
[57] Ramirez VP, Gurevich I, Aneskievich BJ. Emerging roles for TNIP1 in regulating post-receptor signaling. Cytokine Growth Factor Rev 2012;23:109e18.
[58] Oshima S, Turer EE, Callahan JA, Chai S, Advincula R, Barrera J, et al. ABIN-1 is
a ubiquitin sensor that restricts cell death and sustains embryonic development. Nature 2009;457:906e9.
[59] Wagner S, Carpentier I, Rogov V, Kreike M, Ikeda F, Lohr F, et al. Ubiquitin
binding mediates the NF-kappaB inhibitory potential of ABIN proteins.
Oncogene 2008;27:3739e45.
[60] Lefvert AK, Zhao Y, Ramanujam R, Yu S, Pirskanen R, Hammarstrom L.
PTPN22 R620W promotes production of anti-AChR autoantibodies and IL-2
in myasthenia gravis. J Neuroimmunol 2008;197:110e3.
[61] Vandiedonck C, Capdevielle C, Giraud M, Krumeich S, Jais JP, Eymard B, et al.
Association of the PTPN22*R620W polymorphism with autoimmune myasthenia gravis. Ann Neurol 2006;59:404e7.
[62] Lee YH, Rho YH, Choi SJ, Ji JD, Song GG, Nath SK, et al. The PTPN22 C1858T
functional polymorphism and autoimmune diseasesea meta-analysis.
Rheumatology (Oxford) 2007;46:49e56.
[63] Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, et al.
A functional variant of lymphoid tyrosine phosphatase is associated with
type I diabetes. Nat Genet 2004;36:337e8.
[64] Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP,
Alexander HC, et al. A missense single-nucleotide polymorphism in a gene
encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004;75:330e7.
[65] Greve B, Hoffmann P, Illes Z, Rozsa C, Berger K, Weissert R, et al. The
autoimmunity-related polymorphism PTPN22 1858C/T is associated with
anti-titin antibody-positive myasthenia gravis. Hum Immunol 2009;70:540e
[66] Smyth DJ, Plagnol V, Walker NM, Cooper JD, Downes K, Yang JH, et al. Shared
and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J
Med 2008;359:2767e77.
[67] Kurko J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z. Genetics of
rheumatoid arthritis e a comprehensive review. Clin Rev Allergy Immunol
[68] Ploski R, Szymanski K, Bednarczuk T. The genetic basis of graves disease.
Curr Genomics 2011;12:542e63.
[69] Strobel P, Chuang WY, Chuvpilo S, Zettl A, Katzenberger T, Kalbacher H, et al.
Common cellular and diverse genetic basis of thymoma-associated myasthenia gravis: role of MHC class II and AIRE genes and genetic polymorphisms. Ann N Y Acad Sci 2008;1132:143e56.
[70] Wang XB, Pirskanen R, Giscombe R, Lefvert AK. Two SNPs in the promoter
region of the CTLA-4 gene affect binding of transcription factors and are
associated with human myasthenia gravis. J Intern Med 2008;263:61e9.
[71] Gu M, Kakoulidou M, Giscombe R, Pirskanen R, Lefvert AK, Klareskog L, et al.
Identication of CTLA-4 isoforms produced by alternative splicing and their
association with myasthenia gravis. Clin Immunol 2008;128:374e81.
[72] Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531e64.
[73] Zhang J, Chen Y, Jia G, Chen X, Lu J, Yang H, et al. FOXP3-3279 and IVS9459
polymorphisms are associated with genetic susceptibility to myasthenia
gravis. Neurosci Lett 2013;534:274e8.
[74] Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional
defect of regulatory CD4()CD25 T cells in the thymus of patients with
autoimmune myasthenia gravis. Blood 2005;105:735e41.
[75] Itier V, Bertrand D. Neuronal nicotinic receptors: from protein structure to
function. FEBS Lett 2001;504:118e25.

[76] Bonifati DM, Willcox N, Vincent A, Beeson D. Lack of association between

acetylcholine receptor epsilon polymorphisms and early-onset myasthenia
gravis. Muscle Nerve 2004;29:436e9.
[77] Djabiri F, Gajdos P, Eymard B, Gomez L, Bach JF, Garchon HJ. No evidence for
an association of AChR beta-subunit gene (CHRNB1) with myasthenia gravis.
J Neuroimmunol 1997;78:86e9.
[78] Giraud M, Eymard B, Tranchant C, Gajdos P, Garchon HJ. Association of the
gene encoding the delta-subunit of the muscle acetylcholine receptor
(CHRND) with acquired autoimmune myasthenia gravis. Genes Immun
[79] Heckmann JM, Morrison KE, Emeryk-Szajewska B, Strugalska H, Bergoffen J,
Willcox N, et al. Human muscle acetylcholine receptor alpha-subunit gene
(CHRNA1) association with autoimmune myasthenia gravis in black, mixedancestry and Caucasian subjects. J Autoimmun 1996;9:175e80.
[80] Wilisch A, Gutsche S, Hoffacker V, Schultz A, Tzartos S, Nix W, et al. Association of acetylcholine receptor alpha-subunit gene expression in mixed
thymoma with myasthenia gravis. Neurology 1999;52:1460e6.
[81] Giraud M, Taubert R, Vandiedonck C, Ke X, Levi-Strauss M, Pagani F, et al. An
IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous
expression in thymus. Nature 2007;448:934e7.
[82] Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA,
Selmi C, et al. Twin studies in autoimmune disease: genetics, gender and
environment. J Autoimmun 2012;38:J156e69.
[83] Ramanujam R, Pirskanen R, Ramanujam S, Hammarstrom L. Utilizing twins
concordance rates to infer the predisposition to myasthenia gravis. Twin Res
Hum Genet 2011;14:129e36.
[84] Namba T, Shapiro MS, Brunner NG, Grob D. Myasthenia gravis occurring in
twins. J Neurol Neurosurg Psychiatr 1971;34:531e4.
[85] Agafonov BV, Tsuman VG, Shagal DI, Sidorova OP, Sibiriakova LG,
Lebedeva LL, et al. Twin studies of myasthenia. Zh Nevrol Psikhiatr Im S S
Korsakova 1997;97:18e21.
[86] Singh RP, Massachi I, Manickavel S, Singh S, Rao NP, Hasan S, et al. The role of
miRNA in inammation and autoimmunity. Autoimmun Rev 2013;12:1160e5.
[87] Le Panse R, Berrih-Aknin S. Autoimmune myasthenia gravis: autoantibody
mechanisms and new developments on immune regulation. Curr Opin
Neurol 2013;26:569e76.
[88] De Santis M, Selmi C. The therapeutic potential of epigenetics in autoimmune
diseases. Clin Rev Allergy Immunol 2012;42:92e101.
[89] Hedrich CM, Tsokos GC. Epigenetic mechanisms in systemic lupus erythematosus and other autoimmune diseases. Trends Mol Med 2011;17:714e24.
[90] Cheng Z, Qiu S, Jiang L, Zhang A, Bao W, Liu P, et al. MiR-320a is downregulated in patients with myasthenia gravis and modulates inammatory
cytokines production by targeting mitogen-activated protein kinase 1. J Clin
Immunol 2013;33:567e76.
[91] Jiang L, Cheng Z, Qiu S, Que Z, Bao W, Jiang C, et al. Altered let-7 expression in
myasthenia gravis and let-7c mediated regulation of IL-10 by directly targeting IL-10 in Jurkat cells. Int Immunopharmacol 2012;14:217e23.
[92] Wang J, Zheng S, Xin N, Dou C, Fu L, Zhang X, et al. Identication of novel
microRNA signatures linked to experimental autoimmune myasthenia gravis
pathogenesis: down-regulated miR-145 promotes pathogenetic Th17 cell
response. J Neuroimmune Pharmacol 2013;8(5):1287e302.
[93] Mays J, Butts CL. Intercommunication between the neuroendocrine and
immune systems: focus on myasthenia gravis. Neuroimmunomodulation
[94] Nancy P, Berrih-Aknin S. Differential estrogen receptor expression in autoimmune myasthenia gravis. Endocrinology 2005;146:2345e53.
[95] Delpy L, Douin-Echinard V, Garidou L, Bruand C, Saoudi A, Guery JC. Estrogen
enhances susceptibility to experimental autoimmune myasthenia gravis by
promoting type 1-polarized immune responses. J Immunol 2005;175:5050e7.
[96] Kaur M, Schmeier S, MacPherson CR, Hofmann O, Hide WA, Taylor S, et al.
Prioritizing genes of potential relevance to diseases affected by sex hormones: an example of myasthenia gravis. BMC Genomics 2008;9:481.
[97] Sathyabama S, Khan N, Agrewala JN. Friendly pathogens: prevent or provoke
autoimmunity. Crit Rev Microbiol 2013. Ahead of Print: Pages 1e8.
[98] Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al.
Gender bias in autoimmunity is inuenced by microbiota. Immunity
[99] Liu LY, Schaub MA, Sirota M, Butte AJ. Sex differences in disease risk from
reported genome-wide association study ndings. Hum Genet 2012;131:
[100] Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, et al. A metaanalysis of thyroid-related traits reveals novel loci and gender-specic differences in the regulation of thyroid function. PLoS Genet 2013;9:e1003266.
[101] Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y, et al. Proteins
encoded in genomic regions associated with immune-mediated disease
physically interact and suggest underlying biology. PLoS Genet 2011;7:
[102] Consortium IMSG. Network-based multiple sclerosis pathway analysis with
GWAS data from 15,000 cases and 30,000 controls. Am J Hum Genet
[103] Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Hostmicrobe interactions have shaped the genetic architecture of inammatory
bowel disease. Nature 2012;491:119e24.
[104] Viken MK, Sollid HD, Joner G, Dahl-Jorgensen K, Ronningen KS, Undlien DE,
et al. Polymorphisms in the cathepsin L2 (CTSL2) gene show association with

N. Avidan et al. / Journal of Autoimmunity 52 (2014) 146e153








type 1 diabetes and early-onset myasthenia gravis. Hum Immunol 2007;68:

Provenzano C, Ricciardi R, Scuderi F, Maiuri MT, Maestri M, La Carpia F, et al.
PTPN22 and myasthenia gravis: replication in an Italian population and
meta-analysis of literature data. Neuromuscul Disord 2012;22:131e8.
Pal Z, Antal P, Millinghoffer A, Hullam G, Paloczi K, Toth S, et al. A novel
galectin-1 and interleukin 2 receptor beta haplotype is associated with
autoimmune myasthenia gravis. J Neuroimmunol 2010;229:107e11.
Yilmaz V, Tutuncu Y, Baris Hasbal N, Parman Y, Serdaroglu P, Deymeer F,
et al. Polymorphisms of interferon-gamma, interleukin-10, and interleukin12 genes in myasthenia gravis. Hum Immunol 2007;68:544e9.
Pal Z, Varga Z, Semsei A, Remenyi V, Rozsa C, Falus A, et al. Interleukin-4
receptor alpha polymorphisms in autoimmune myasthenia gravis in a
Caucasian population. Hum Immunol 2012;73:193e5.
Alseth EH, Nakkestad HL, Aarseth J, Gilhus NE, Skeie GO. Interleukin-10
promoter polymorphisms in myasthenia gravis. J Neuroimmunol 2009;210:
Zagoriti Z, Georgitsi M, Giannakopoulou O, Ntellos F, Tzartos SJ, Patrinos GP,
et al. Genetics of myasthenia gravis: a case-control association study in the
Hellenic population. Clin Dev Immunol 2012;2012:484919.
Alter M, Talbert OR. Myasthenia gravis in one monozygotic twin. Neurology
Osborne D, Simcock J. Myasthenia gravis in identical twins. Br Med J 1966;1:
Motoki R, Harada M, Chiba A, Honda K. A case of myasthenia gravis of
identical twin brothers. Int Surg 1966;45:674e7.
Herrmann Jr C. The familial occurrence of myasthenia gravis. Ann N Y Acad
Sci 1971;183:334e50.


[115] Michalski JP, Snyder SM, McLeod RL, Talal N. Monozygotic twins with Klinefelters syndrome discordant for systemic lupus erythematosus and
symptomatic myasthenia gravis. Arthritis Rheum 1978;21:306e9.
[116] Allen N, Kissel P, Pietrasiuk D, Perlow MJ. Myasthenia gravis in monozygotic
twins. Clinical follow-up nine years after thymectomy. Arch Neurol 1984;41:
[117] Vasilev VN, Sirotina VV, Shabanova LF, Egorova IE. Thymectomy for myasthenia in twin sisters. Vestn Khir Im I I Grek 1984;133:75e6.
[118] Murphy J, Murphy SF. Myasthenia gravis in identical twins. Neurology
[119] Lefvert AK, Pirskanen R, Eng H, Sundewall AC, Svanborg E. B cell and autoantibody repertoire in a pair of monozygotic twins discordant for myasthenia gravis. Clin Immunol Immunopathol 1989;53:161e70.
[120] Dias-Tosta E, Aguiar MF, Barbosa H, Vilela SS. Familial myasthenia gravis: a
case report in identical twins. Arq Neuropsiquiatr 1989;47:248e53.
[121] Grinlinton FM, Lynch NM, Hart HH. A pair of monozygotic twins who are
concordant for myasthenia gravis but became discordant for systemic lupus
erythematosus post-thymectomy. Arthritis Rheum 1991;34:916e9.
[122] Theile U, Kessler S. Effect of heredity and environment in immune diseases.
Presentation of twin data. Med Klin (Munich) 1994;89:312e8.
[123] Kakoulidou M, Ahlberg R, Yi Q, Giscombe R, Pirskanen R, Lefvert AK. The
autoimmune T and B cell repertoires in monozygotic twins discordant for
myasthenia gravis. J Neuroimmunol 2004;148:183e91.
[124] Punga AR, Nygren I, Askmark H, Stalberg EV. Monozygous twins with
neuromuscular transmission defects at opposite sides of the motor endplate.
Acta Neurol Scand 2009;119:207e11.
[125] Riggs KR, Gutmann L, Riggs JE. Discordant thymectomy in identical twins
concordant for myasthenia gravis. Ann Intern Med 2011;155:478e9.