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Page 8 of 16 Weidner et al. J Transl Genet Genom 2019;3:2. I https://doi.org/10.20517/jtgg.2018.30

studies reviewed, a distinction between early onset and late onset allergic asthma cannot be distinguished.
Allergic asthma is usually described as a type 2 driven disease with increased type 2 cytokine production
such as IL-4, IL-5 and IL-13 and increased numbers of eosinophils as well as increased IgE levels. miR-155
[82]
has been shown to be down-regulated in allergic asthmatics in exhaled breath condensates . We observed
a similar downregulation of miR-155 in lymphocytes isolated from induced sputum from allergic asthmatics
[83]
in pollen season compared to out of season . miR-155, together with miR-18a, miR-126, let-7e and miR-
224, were also downregulated in nasal mucosa of allergic asthmatics compared to controls even when no
[85]
[84]
markers of type 2 inflammation were detected . Fekonja et al. utilized a different approach to examining
miRNAs by searching different databases to find asthma associated miRNAs and their target interactions.
They suggested 4 central molecules including miR-155, miR-21, IL-13 and Sma- and Mad-related protein 2 in
[85]
asthma, although they did not distinguish between asthma phenotypes . In contrast to miR-155, miR-19a
was found to be increased in BALF Th cells and was shown to promote type 2 cytokine production by direct
targeting of the inositol phosphatase PTEN, the signal inhibitor SOCS1, and the deubiquitinase A20 which
[86]
are inhibitors of nuclear factor NF-κB, signal transducer and activator of transcription and PI3K pathways .
miR-19a has also been described to enhance proliferation of bronchial epithelial cells in asthma by targeting
[87]
the transforming growth factor bR2 (TGFbR2) gene . Moreover, reduced miR-19a was shown to lead to
the constitutive high expression of protein arginine methyltransferase 1 in airway smooth muscle cells
[88]
leading to enhanced remodeling . Unfortunately, in the aforementioned study no description of the asthma
subtype was available. Furthermore, the three studies described above investigated different cell types, thus
it is unknown if these findings hold true throughout the body. Another important miRNA in allergic asthma
is miR-98 due to its ability to suppress thrombospondin 1 in B cells upon exposure to IL-1, which, in turn
[89]
impairs the immunosuppressive function of B cells on other effector immune cells . Additional miRNAs
reported to be upregulated in allergic asthma were miR-498, -187, -874, -886-3p, and -143 this time found in
[84]
nasal mucosa . In a more recent study, miR-143-3p was shown to control TGF-b1-induced cell proliferation
[90]
and extracellular matrix production in airway smooth muscle via negative regulation of the NFATC1 . In
both plasma and airway epithelial cells, miR-181b-5p was associated with airway eosinophilic inflammation
in asthma and was suggested to regulate proinflammatory cytokines expression by targeting osteopontin,
a multifunctional extracellular matrix protein. Plasma miR-181b-5p was increased after ICS treatment
and dexamethasone restored IL-13-induced miR-181b-5p down-regulation and suppressed IL-13-induced
[91]
osteopontin in epithelial cells .

As previously mentioned, miRNAs are emerging as biomarkers important in better understanding asthma
[92]
pathogenesis and aiding in the discrimination of various asthma phenotypes. Panganiban et al. performed
a study comparing differentially expressed miRNA in plasma samples from asthmatic patients, non-
asthmatic patients with allergic rhinitis (AR) and non-allergic non-asthmatic subjects to establish whether
miRNA could be used to characterize or subtype asthmatic patients. They reported 30 miRNAs out of 420
that were statistically different between the three groups which they then classified into five expression
pattern groups. Interestingly, group 2 miRNAs demonstrated expression differences that were unique to
asthmatic patients even though 83% of these patients were also allergic. They found that miR-16, -223-3p,
-148a and -146a were upregulated and miR-299-5p, -570 and -150 were downregulated among asthmatic
patients, but no difference was observed between AR and healthy subjects. Target pathways predicted
to be regulated by this group of miRNAs suggested the regulation of key components of inflammatory
pathways and focal adhesion pathways likely involved in airway basement membrane and airway smooth
[92]
muscle in asthmatic patients . The same group previously described the upregulation of miR-1248 and
the downregulation of miR-26a, let-7a, and let-7d in serum from allergic asthmatic patients compared to
controls. They also showed that miR-1248 interacted with IL-5 and served as a positive regulator, as opposed
[94]
[93]
to the deleterious effects seen by most miRNAs, by increasing IL-5 expression . Milger et al. utilized a
separate approach by first identifying murine miRNA candidates which later were studied in plasma samples
obtained from human allergic asthma patients. This study revealed three miRNAs common for both human