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Page 281 Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32

Type 1 interferonopathies
Interferons (IFNs) are crucial for innate immune defense, interfering with viral replication and
dissemination. Any cells can produce IFNs upon the invasion of microbes. However, some innate immune
cells, such as plasmacytoid dendritic cells, produce large amounts of type 1 and type 3 IFNs, while type 2
IFN (IFN-γ) is mainly produced by type 1 T-helper (Th1) cells . IFNs are potent activators of macrophage
[62]
and monocyte lineage cells, and dysregulated signaling through IFNs can lead to macrophage activation
syndrome, a potentially lethal condition affecting multiple organs . The COVID-19 pandemic showed
[62]
what a crucial role that IFNs can play. It is now known that severe COVID-19 disease in elderly subjects is
partly attributed to the production of autoantibodies against type 1 IFNs . On the other hand,
[63]
uncontrolled production of type 1 IFNs or dysregulated signaling via IFNs in innate immune cells leads to
autoinflammatory conditions, now referred to as type 1 interferonopathies .
[64]

(1) Clinical presentation: Various variants of multiple genes are now recognized to cause overproduction of
[65]
IFNs or dysregulated activation of type 1 IFN signaling pathways . This leads to uncontrolled activation of
the downstream innate immune signaling pathways, polyclonal B cell activation, and subsequent
autoinflammatory and autoimmune conditions . One of the striking features of interferonopathies is
[66]
neuroinflammation. Aicardi-Goutières syndrome, the prototype of interferonopathies, is known to present
with symptoms caused by severe neuroinflammation in early infancy, resembling clinical features of
congenital infectious encephalopathy and subsequent progressive loss of cognitive functioning .
[64]
Neuroinflammation in type 1 interferonopathies is, in part, attributed to uncontrolled activation of
microglial cells as seen in patients with macrophage activation syndrome (MAS) or hemophagocytic
lymphohistiocytosis (HLH) . Type 1 IFNs also affect other neuronal cells, causing profound effects on the
[66]
CNS through multiple mechanisms [66,67] . Although the number of subjects, with each of the gene variants
reported to cause type 1 interferonopathies, is not large, more and more genes are being reported to be
[68]
associated with interferonopathies and many of them are inherited in an AD manner . Therefore, this
condition may be more likely to be frequently encountered as IEIs.

(2) Treatment measures: Since interferonopathies are caused by pathogenic variants of multiple genes,
therapeutic approaches will be influenced by which genes are affected and what effects are exerted by other
[62]
epigenetic factors , as evidenced by the markedly variable clinical presentations seen. It has been reported
that patients with type 1 interferonopathies are generally resistant to the first-line treatment measures
typically used for autoimmune conditions like lupus; efficacies of high dose IV bolus of methylprednisolone
and/or IVIg for controlling the acute phase of symptoms are suboptimal at best [66,69] .

Downstream signaling of type 1 IFNs involves Janus kinases (JAKs), which act as signal transducers, and
four mammalian members of JAKs are identified: JAK1, JAK2, JAK3, and TYK2 [70,71] . All JAKs, except for
JAK3 that is expressed only in hematopoietic and lymphoid cells, are expressed ubiquitously and play a
crucial role in the JAK-STAT (signal transducers and activators of transcription) pathway . The JAK-
[71]
STAT pathway transduces signaling from multiple cytokine receptors. JAK3 mediates signals from type 1
cytokines and thus the deficiency of JAK3 leads to SCIDS . On the other hand, dysregulated activation of
[72]
the JAK-STAT pathway will lead to chronic inflammatory conditions, implicated in the pathogenesis of
autoimmune, allergic, and autoinflammatory conditions . In patients with type 1 interferonopathies, type 1
[73]
IFN signaling involving JAK1/JAK2 and TYK2 has been proposed as therapeutic targets for these
patients . In clinical trials of small numbers of monogenic type 1 interferonopathies, improvement of
[66]
clinical symptoms and inflammatory markers are reported with the use of JAK inhibitors, including
baricitinib and tafacitinib [66,74-76] . Other types of treatment measures targeting the production and/or actions
of type 1 IFNs have been proposed, but not widely used compared to JAK inhibitors [66,77,78] .