Unlike other forms of JIA, SJIA is an uncommon condition with unique characteristics. Both HLA and non-HLA susceptibility genes are implicated in SJIA genetic findings, indicating the role of adaptive immunological cell-mediated immunity. Simultaneously, phenotypic data suggests autoinflammatory mechanisms are involved. Thus, the illness impacts both innate and adaptive immune responses [11].
Acute medium-vessel vasculitis, known as KD, primarily affects infants older than six months and children under five years old. It is the leading cause of acquired heart disease in children and predisposes them to the formation of coronary artery aneurysms[12]. Clinical signs of KD and SJIA are comparable, indicating similar underlying immunopathogenic mechanisms. These signs include joint swelling and discomfort, a persistently high fever, and even cardiovascular problems. Clinical parallels and hints about the IL-1β pathway between research on humans and mice point to a shared immune biology underpinning SJIA and KD[13]. Therefore, it is essential to investigate the evidence and significance of any potential link between SJIA and KD, regardless of whether it's based on clinical practice or molecular mechanism study. In order to identify putative genes for interaction between SJIA and KD and to further explore their potential clinical utility and latent relationship with immune cells, our research merged the transcriptomes from the public database for the first time.
The majority of the SDEGs in our analysis are genes associated with extracellular proteins. Extracellular proteins can influence a greater variety of biological processes. This is also consistent with the theory that SJIA and KD are related to immune system illnesses, where cellular secretions play a significant role[11, 14]. The biological processes of cell killing in the innate immune response, neutrophil degranulation, and several signalling pathways, including the TNF and NF-kappa B signalling pathways, were all significantly impacted by up-regulated SDEGs.
The TFs were found in the SDEGs, and the major TFs were those that had the greatest number of putative target genes in the SDEGs. The functional studies revealed that the majority of TFs that target SDEGs are enriched in words that correspond with SDEGs, indicating a potential involvement for important TFs (EGR1, BCL6, FOS, and NFE2) and their regulatory networks in the pathophysiology that is jointly linked to SJIA and KD. It also suggests that the critical transcription factors might be possible therapeutic targets.
Early Growth Response1, or EGR1, is a zinc-finger transcription factor controling
several target genes’ transcription. As a result, it is involved in controlling the body's response to ischemia, growth hormones, and DNA damage. Through animal research, Miura et al. discovered that overexpression of EGR1 increased the expression of TNFα, RANKL, and sclerostin in osteocytes, contributing to the development of osteoporosis in rheumatoid arthritis[13]. EGR1 strongly correlates with the progression of inflammatory and cardiovascular illnesses[15]. Since clinical studies have demonstrated that TNF-α antagonist etanercept can improve coronary artery dilatation and research has confirmed that blocking TNF-α is essential to obtaining anti-inflammatory effects in children with KD, it is hypothesized that TNF-α may play a significant role in the onset and progression of coronary artery inflammation in Kawasaki disease[16, 17]. While TNF is an endogenous pyrogen that produces fever and drives liver cells to produce acute-phase proteins, SJIA is characterized by recurring fever. Fever generated by TNF can be attributed to many factors, such as activation of the hypothalamus thermoregulatory centre, stimulation of IL-1 release from macrophages, and stimulation of IL-1 and TNF-α to boost the production of IL-6 in other cells[18]. The primary immunological characteristics in the early stages of SJIA illness include excessive production of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and IL-18, as well as inappropriate activation of the innate immune system[19]. These findings raise the possibility that EGR1 plays a role in the pathophysiology of SJIA. In summary, EGR1 plays an important regulatory role in both SJIA and KD.
BCL6, or B cell lymphoma, is a transcription inhibitor with a zinc finger structure found on chromosome 3q27. It is the source of B cell germinal centres and is involved in inflammatory processes, cell proliferation, differentiation, apoptosis, DNA damage repair, and other processes. It is particularly involved in the immune system's inflammatory response[20]. Prior research has indicated a favourable relationship between BCL6 and the level of disease activity as well as the synovitis pathological score in individuals with rheumatoid arthritis (RA). The level of BCL6 can be used as a clinical diagnosis of RA and an auxiliary examination to assess the illness. It can also be used to measure synovial pathology and RA activity[21]. Both SJIA and rheumatoid arthritis share comparable physiological and pathological causes, including joint effusion, synovial hyperplasia, and a highly inflammatory state. Thus, we hypothesize that BCL6 also has a role in the pathophysiology of SJIA. Studies on gene expression in naïve CD4 T cells with Granulomatosis with polyangiitis (GPA) showed dysregulation of the IL-2 receptor β/JAK-STAT signalling pathway and increased expression of BCL6 and BCL6-regulated genes[22]. Since both KD and GPA are vasculitis, and considering KD vasculitis is associated with CD4 T cells, we may assume that BCL6 plays a role in the pathophysiology of KD as well. So, we speculate that BCL6 may have a certain regulatory role in both SJIA and KD.
FOS (Fos proto-oncogene, activator protein 1 (AP-1) transcription factor subunit) encodes leucine zipper proteins and is linked to the regulation of cell division, transformation, proliferation, and inflammatory response[23]. According to Alberto Floris et al., FOS may have a role in the pathogenesis of psoriatic arthritis (PsA) via coordinating inflammation and bone metabolism processes[24]. Matsuoka K et al. discovered that as the illness progressed, the number of FOS-positive chondrocytes increased in both human and mouse OA cartilage[25]. Pro-inflammatory factors and immune cells create an inflammatory milieu that triggers osteoclast activation, cartilage stress, and bone loss, which is how SJIA begins. FOS may also have a role in the pathophysiology of SJIA.
Furthermore, a number of studies have demonstrated that endothelial dysfunction and an overabundance of inflammatory immune response may play a significant role in the development of KD. In KD subacute chronic arteritis, the inflammatory infiltrate comprises CD8 + T cells, IgA + plasma cells, monocytes, and macrophages. Hypoxia stress can cause inflammatory damage to artery endothelial cells, influence downstream inflammatory molecules like IL-18, and cause the Fos gene to be expressed in endothelial progenitor cells. In a similar vein, FOS could contribute to KD's coronary artery damage process. More studies are required on this particular mechanism.
The protein coding gene NFE2 (Nuclear factor, Erythroid2) is expected to function either upstream or within many processes, such as the growth of blood vessels in the labyrinthine layer, the negative control of bone mineralization, and the negative regulation of plasma membrane fusion-induced syncytium formation. The risk of myeloproliferative neoplasms has been linked to NFE2[26, 27]. It has yet to be documented whether NFE2 plays a role in the pathophysiology of KD and SJIA; hence, further thorough research is required.
Thirty years ago, it was found that NF-kB is a rapidly inducible transcription factor with multidirectional regulatory effects. It plays a significant role in immunological regulation, inflammation, stress response, and cell death, in addition to regulating the expression of several other factors[28]. Previous studies have shown that NF-kB was highly expressed in peripheral blood CD4 positive mononuclear macrophages and CD3 positive T cells in children with acute Kawasaki disease[29]. This suggests that NF-kB may act upstream of the initial inflammatory response, bind to corresponding target genes after activation, regulate a series of cytokine expression, and ultimately lead to inflammatory pathological damage. Thus, we hypothesized that NF-kB activation would be a part of the vascular inflammatory damage pathophysiology in KD. Previous studies have confirmed that NF-KB is involved in the occurrence and development of SJIA and SJIA-associated macrophage activation syndrome(SJIA-MAS), and the possible mechanisms are: The expression of TNF- α is regulated by NF-kB. Activated NF-kB and TNF-α combining and enhance TNF-α gene transcription and protein synthesis through positive feedback, further amplifying inflammatory signals. In addition, TNF-α can also enhance the cytokine waterfall effect, promote granulocyte colony stimulating factor (G-CSF), and IL-1 β And IL-6 expression. Moreover, the above inflammatory factors are highly expressed in SJIA, so we speculate that the NK-kB signalling pathway is involved in the occurrence and development of SJIA.
Additionally, we discovered that neutrophil degranulation contributes significantly to the common pathophysiology of KD and SJIA. Neutrophils are the most abundant white blood cells in peripheral blood circulation and an essential component of innate immunity. Neutrophil degranulation is closely related to the activation of neutrophils, which release granular substances from cells to destroy and eliminate extracellular pathogens[30]. However, an overabundance of neutrophils may cause several illnesses, including systemic lupus erythematosus, asthma, rheumatoid arthritis, ischemia-reperfusion injury, and vascular injury, among other tissue damage and disorders[31, 32]. Neutrophils significantly increase during the acute phase of KD and damage endothelial cells by secreting oxygen free radicals and elastases in children with acute KD, and was also associated with the development of coronary and myocardial disorders[12]. In a similar vein, neutrophil self-activation levels rise markedly in SJIA and then fall throughout the remission phase in accordance with the illness[33]. This implies that studies on neutrophils not only provide light on the pathophysiology of the condition, but that using this indicator in clinical settings will aid in diagnosis, therapy, and patient outcome improvement.