Page 105 - GPD-4-3

Gene & Protein in Disease Monogenic lupus and interferonopathies

Table 1. Pathogenic genetic variants of our patients with monogenic lupus
Patient Gene Mechanism Mutation Zygosity Inheritance
Patient 1 DNase II Loss of function NM_001375:c. 902C>T (p.S301P) Homozygous Recessive
Patient 2 ISG15 Loss of function NM_005101: c. 4-1G˃A Homozygous Recessive

described SAIDs, including actinopathies, nuclear factor
kappa B-mediated conditions, and interferonopathies,
often deviate from the typical features of the classic SAIDs,
particularly inflammasomopathies. Patients with these
conditions are more likely to experience a progressive
disease course rather than periodic attacks, and they often
present with autoimmune phenomena such as the presence
of autoantibodies, further demonstrating the inseparable
division between innate and adaptive immunity. 6,7,22,23
Monogenic lupus variants affecting the interferonopathy
pathway are often associated with autoinflammatory
clinical and laboratory features, whereas variants involving
Figure 2. Brain magnetic resonance imaging showing multiple scattered B-cell and T-cell dysfunction tend to present with
hyperintense lesions in the bilateral cerebral white matter autoimmune characteristics (Figure 3).

Both patients were treated with systemic corticosteroids, Our first patient, with a loss-of-function variant
starting with methylprednisolone pulse therapy for 3 days, in the DNase II gene mirrors cases described by
24
followed by tapered maintenance dosages (1 mg/kg/day), Rodero et al., who identified a type I interferonopathy
hydroxychloroquine (200 mg daily), mycophenolate in humans caused by DNase II deficiency. This deficiency
mofetil (500 mg twice daily), and belimumab impairs the clearance of apoptotic, necrotic, and
(10 mg/kg/dose) infusion. Notably, they were eventually neutrophil extracellular traps, which are primary sources
able to discontinue corticosteroid use. Table 2 outlines the of self-dsDNA. The accumulation of self-dsDNA can
clinical and laboratory features, as well as the treatment stimulate autoreactive B cells to produce autoantibodies
regimens, for these two patients with monogenic lupus. in conjunction with autoreactive T cells. The resulting
Unfortunately, the interferon signature analysis was not dsDNA immune complexes trigger phagocytes and
performed for either patient due to its unavailability at plasmacytoid dendritic cells to produce substantial
our institution. amounts of IFN-I through various intracellular DNA
sensors. 24,25
4. Discussion The second patient was confirmed to have a loss-of-

We present two patients who fulfilled the recently function variant in ISG15. The deficiency in ISG15 leads
validated EULAR/ACR 2019 classification criteria for to unstable levels of ubiquitin-specific peptidase 18, a
monogenic lupus. Monogenic lupus is a complex negative regulator of IFN-I signaling. Consequently,
15
construct characterized by a wide range of phenotypes and the absence of ISG15 results in persistent expression
a paradoxical combination of immune dysregulation and of interferon-stimulated genes, presenting with severe
autoimmunity, caused by various pathogenic mechanisms inflammatory phenotypes that include autoimmune and
linked to pathogenic genetic variants. At present, about 35 autoinflammatory features. 17,26
18
genes have been identified as predisposing to monogenic In light of the significant role of IFN-I in the
lupus. 13,18-20 Recent studies have identified that the second pathogenesis of monogenic lupus, it is important to
most prevalent cause of monogenic lupus involves acknowledge the complex immunological networks that
variants in genes related to IFN-I signaling, which lead to further amplify inflammatory responses. Recent studies
significant IFN-I hyperactivation. 7,21,22 In addition, many suggest a critical interaction between IFN-I signaling,
newly identified SAIDs are primarily driven by various Th17 cells, and soluble HLA-G (sHLA-G), which together
innate immune pathways beyond the interleukin (IL) contribute to immune dysregulation in chronic immune-
family (e.g., IL-1 and IL-18), or inflammasome-mediated mediated diseases. Th17 cells, known for their role in
disorders, and are characterized by elevated IFN-I mucosal immunity and inflammation, are influenced by
production. The phenotypic features of these recently the IFN-I axis, with evidence indicating enhanced Th17
7

Volume 4 Issue 3 (2025) 3 doi: 10.36922/GPD025080019