In this study, we followed up two girls with RAC2 gain-of-function mutations and identified novel autoinflammatory phenotypes that included juvenile idiopathic arthritis and severe uveitis, and vasculitis and leg ulcers. Our report extends the spectrum of the clinical presentation of GOF variants in RAC2 to include novel unusual phenotypes. The results highlight that such mutations can cause immunodeficiency with autoinflammatory manifestations.
The term hereditary monogenic autoinflammatory diseases (AIDs) was coined to describe a group of rheumatologic diseases caused by dysregulation of the innate immune system in the absence of detectable B or T cell autoreactivity [27]. The molecular mechanisms underlying AIDs are linked to different pathogenic defects in dysregulated inflammasome-mediated, NF-κB-mediated, or IFN-mediated inflammatory signaling pathways, the actin cytoskeleton, proteasome complexes, various enzymes, cytokine receptors, and intracellular stress [28, 29]. These disorders are mediated by continuous overproduction and release of pro-inflammatory mediators such as type I interferon (IFN), IL-1, IL-6, and tumor necrosis factor alpha (TNF-α), and increased levels of inflammatory components such as S100 proteins, IL-18, or serum amyloid A; these mediators trigger persistent or recurrent sterile systemic or organ-specific inflammation [30, 31]. Typical AIDs usually present during infancy or childhood, and show a broad spectrum of manifestations such as recurrent episodes of fever, abdominal pain, arthritis, ocular involvement (including conjunctivitis and uveitis), vasculitis or vasculopathy, serositis, rash, hepatosplenomegaly, lung disease, neutropenia, anemia, or other disease-specific patterns of organ inflammation and hematological alterations, as well as laboratory signs of systemic inflammation such as elevated pro-inflammatory mediators, inflammatory biomarkers, CRP, ESR, and ferritin [32–35]. Our report of autoinflammatory phenotypes, presenting as vasculitis and leg ulcers proceeded by livedo reticularis, as well as juvenile idiopathic arthritis and severe uveitis, is consistent with the nature and characteristics of AIDs, notwithstanding with less severity of clinical symptoms than typical AIDs.
There is a direct link between RAC2 and production of ROS, TNF-α, IL-1, IFN, and NF-κB signaling [36–39]; indeed, neutrophils are a key component of the pathogenesis of AIDs, found mainly in affected tissues such as the inflamed joints, skin lesions, vasculitis and uveitis [40–43], and the markers of neutrophilic inflammation, such as S100A12, S100A8, and S100A9, are eleveted in juvenile idiopathic arthritis and AIDs [44–46], which was also seen in our patient 1 by single-cell RNAseq [23]; RAC2 recruits neutrophils to inflamed tissues, including the joints in those with rheumatoid arthritis or the blood vessels in those with vasculitis [47]. Furthermore, a dysregulated phenotype in T lymphocytes skews the immunoprofile toward Th1/17 subsets, which were also detected in our patients [9, 10]. This skewing can trigger pathogenesis of juvenile idiopathic arthritis, uveitis, and vasculitis [48–50]. Finally, it is interesting that GOF RAC2 mutations can over-activate the phospholipase C (PLC) isoform PLCγ, and phosphatidylinositol 3 kinase (PI3K) [51–53], and that patients carrying GOF heterozygous mutations of both are characterized by uveitis, skin lesions, vasculitis, and arthritis [54–57]. Taken together, these data indicate that RAC2 GOF mutations may also show autoinflammatory manifestations. However, the exact pathogenesis remains poorly understood, and further detailed research is warranted.
Immediate attention should be paid to the fact that reports suggest that in those with RAC2 GOF mutations, lung damage can be virulent, thereby increasing morbidity and mortality; historically, this lung damage was attributed to recurrent infections caused by inborn errors of immunity [58, 59]. Gradually, more attention is being paid to the inflammatory pathways that lead to pathologic pulmonary damage and disease [60, 61], and the contribution of overactivated RAC2 has been recognized [62–65]. A lack of knowledge and awareness meant that we did not promptly or strongly recommend systemic use of glucocorticoids, immunosuppressive agents, biological agents, or pharmacological inhibitors of RAC2 to prevent occurrence and progress of the complications listed above; a lesson that our group has learned from studying these rare cases.