Discussion
Clinical primary immunodeficiency cases caused by TYK2 mutations
are very rarely reported. To our best knowledge, there are 13 cases in
total in English literature not including ours. Because of this, the
exact roles of TYK2 in the development, function and regulation of
immune cells in human remain largely unknown. In clinical setting, it is
extremely difficult to raise a specific suspicion of TYK2 deficiency
when there is no clear full picture of its clinical manifestations which
are closely related to the roles TYK2 plays in various immunologic
processes. A recent study showed the P1104A TYK2 common variant
predisposes host to mycobacteria infection by selectively disrupting
IL-23–dependent antimycobacterial IFN-γ immunity, which also
contributed to our understanding of TYK2 function[19]. In this study, we presented five more cases
of TYK2 deficiency and investigated many aspects of the effects TYK2
deficiency brings, which we think would further improve our
understanding of TYK2 deficiency.
The first TYK2-deficient patient to be described was Japanese and had
HIES as the main clinical feature, associated with numerous
intracellular infections. Since then, TYK2 deficiency was considered a
subset of AR-HIES. However, newly identified TYK2 deficient patients did
not necessarily present with hyper-IgE. A comprehensive comparison of
various immunologic defects between the first reported patient and seven
patients without hyper-IgE was reported, which proposed that intact
IL-6/STAT3 signaling in patients without hyper-IgE might be responsible
for this phenotypic difference [4]. As defects in
STAT3-mediated signaling play a key role in the development of HIES[20] and IL-6 signaling is TYK2 independent in
mice [21]. Another TYK2 deficient patient without
HIES was also reported to show normal IL-6 signaling[6] and a TYK2 deficient patient with HIES showing
impaired IL-6 signaling was reported [5] (Table
1). Recently, autosomal recessive and dominant mutations inIL6ST, which encodes gp130, a subunit of cytokine receptor for
IL-6, IL-11, IL-27 and some others, have been reported in patients with
HIES [22,23]. Thus, this idea seems to be
plausible according to these previously reported cases. Surprisingly,
however, our data did not support this hypothesis. As shown in Fig. 3,
PBMC from P1 with mildly elevated IgE and P3 with low IgE both responded
to IL-6 treatment normally in terms of STAT3 activation. Furthermore,
PBMC from P2 with normal IgE level showed impaired response to IL-6
treatment. These findings strongly suggest the relation between
hyper-IgE and TYK2 deficiency cannot be explained by dysregulated
IL-6/STAT3 signaling.
Actually, mechanisms underlying increased IgE production are variable
and complicated [24]: a) enhanced class switching
to IgE and the Th2 bias. B cell class switching to IgE is tightly
regulated by interaction with CD4 T cells and the cytokine
microenvironment. It is well established that IL-4 and IL-13, cytokines
produced by Th2 cells and B cells, promote isotype class switching to
IgE in B cells. Meanwhile, IL-10 and IL-21 act directly upon activated B
cells to reduce the efficiency of class switching towards IgE. In
addition, the engagement of CD40 on B cells by CD40L provides a second
signal for IgE class switching [25]. Th bias
towards a Th2 phenotype can indirectly promote a cytokine milieu capable
of enhancing IgE production. b) defects in general tolerance, meaning
the Th2 response is increased concurrently with Th1 and Th17 responses
in cases of cataclysmic tolerance failure, which is seen in IPEX[26]. Intriguingly, P1, P2 and P3 in our cohort
all showed Th1 bias instead, with variable IgE levels, indicating
involvement of other mechanisms. c) defects in barrier. While the
majority of patients with atopy begin with elevated IgE, a minority of
patients develop atopic dermatitis with normal IgE levels but experience
elevated IgE after prolonged disease, indicating increased IgE levels
can be a result of disrupted barriers. So, it seems that in the case of
TYK2 deficiency, disrupted cytokines signaling network is key to the
normal, increased or decreased IgE levels.
The viral infections can probably be accounted for by defects of
IFN-α/β/γ signaling. Similar to the first described TYK2 deficient
patient, P1 in our cohort suffered repeated viral infection possibly due
to abolished responses to IFN-α/β. Although impaired but not abolished
IFN signaling does not necessarily lead to severe viral infection as the
case of P2 (Table 1) and previously reported cases[4]. The explanation for this might be that TYK2
plays important roles in various immune cells. Mutation of P2 may
affected innate immune cells but not adaptive immune cells such as B
cells, which also play critical role in restricting viral infection.
IL-12 signaling induced IFN-γ production is believed to be responsible
for the susceptibility to intracellular bacterial infection in TYK2
deficient patients, while IL-23 signaling induced IL-17 production for
extracellular bacterial infection [3]. However,
again our data present challenges to this notion as P3 showed no
evidence of intracellular bacterial infection such as mycobacteria and
salmonella in spite of impaired IL-12 signaling and P2 and P3 showed no
evidence of extracellular bacterial infection such as S. aureusin spite of impaired IL-23 signaling. Similar to diverse
responses to interferons, restricting extracellular or intracellular
bacteria can be achieved by multiple cellular mechanisms.
Cytokine signaling not only affects the function of various immune cells
but also plays essential roles in regulating homeostasis of immune
system [18]. The effects of TYK2 deficiency on the
homeostasis of lymphocytes compartment is unclear. In investigating
this, we noticed that patients with elevated IgE (P1, P4 and P5) levels
shared similar profile of disrupted T and B cell compartment and patient
with normal IgE level (P2) shared similar profile of T cell compartment
but distinct profile of B cell compartment with patient with low IgE
level (P3).
The divergent cellular responses
to cytokines, which is probably responsible for the divergent clinical
phenotypes, might be resulted from residual expression of mutant TYK2.
Another possibility is that the presence/absence of the cell population
that should respond caused these divergent cellular responses as the
experiments in our study are done on heterogeneous cell populations. The
effects of these mutations on TYK2 protein stability could be due to
disrupted post-translation modification of the protein.
In summary, we presented five more TYK2 deficiency cases caused by
different novel mutations displaying divergent cellular defects and
variable clinical phenotypes, which demonstrated that the correlation of
cellular defects and clinical phenotypes is far more complicated than
previously thought. In view of this, here we propose a new model that
TYK2 works as a multi-tasker in orchestrating various cytokines
signaling pathways, differentially combined defects of which account for
the expressed clinical manifestations. Furthermore, we speculated that
the discrepancies in cellular defects could at least partially be
explained by different mutational effects to TYK2 protein, which needs
to be investigated in the future. Nevertheless, our findings might lead
us further towards more accurate understanding of TYK2 function in human
immune system and a more timely diagnosis of TYK2 deficient patients.