CP is the most common physical disability of childhood and is a heterogeneous condition resulting from damage to the developing brain . CP has no curative therapy and few disease-modifying interventions . Earlier and accurate diagnosis of CP has become highly desirable because it allows earlier initiation of treatments that may improve long-term outcomes during periods of rapid brain growth and neuroplasticity, which suggests the importance of uncovering the etiology of CP. However, these known CP causes, such as periventricular leukomalacia (PVL), NE, infarct, and premature delivery, account for only a minority of the total cases . The pathogenesis of CP is largely unknown and needs further study.
Cytokines coordinate the host response to infection and mediate normal, ongoing signaling between cells of nonimmune tissues, including the CNS . Cytokines can profoundly impact fetal neurodevelopment in response to maternal infection or prenatal hypoxia . CP has been linked to early life immune activation and inflammation [35, 36], and several cytokines, including IL-6, IL-8, IL-10, IL-17 and IL-23R, have been proven to be related to CP [18, 33, 37, 38]. IL-2 is a pleiotropic cytokine produced after antigen activation. IL-2 can promote CD8+ T cell and natural killer cells cytolytic activity, modulate T-cell differentiation programs in response to antigens and control the development and maintenance of Treg cells to mediate immune responses and maintain self-tolerance by the IL-2/IL2R complex signaling pathway . IL2RA provides a higher affinity to the IL2R complex and a more stable state through which to transmit signals. Studies have shown that the expression of the anti-inflammatory cytokine IL-2 is decreased in infants with CP [40, 41], which implies that the IL2/IL2R complex pathway is related to CP. Here, we first investigated the relationship between CP and IL2RA by a case-control study in Han Chinese individuals and found that IL2RA was associated with an increased risk of CP.
Several kinds of immune-activated cells have been shown to secrete IL-2, including T cells, natural killer cells, dendritic cells (DCs) and mast cells . During immune activation, IL-2 expression increases rapidly. Activated DCs secrete low levels of IL-2 as an early source, thereby stimulating T cell activation . Activated T cells (including CD4+ and CD8+ T cells) begin to secrete large amounts of IL-2 for their own use and stimulate adjacent IL2R+ cells by paracrine signaling [39, 44, 45]. After IL-2 binds to the IL2R complex, signal transduction occurs through three main pathways: (i) Janus kinase (JAK)-signal transducer and activator of transcription (STAT), (ii) the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR)-p70 S6 kinase pathway and (iii) mitogen-activated protein kinase (MAPK). Phosphorylated STAT5A and STAT5B then oligomerize to form STAT5 dimers and tetramers before undergoing nuclear translocation, where they bind to key target genes (including IL2RA) responsible for cell activation, differentiation, and proliferation, while mTOR and MAPK promote cell growth and survival [22, 39, 44]. It is reasonable to hypothesize that IL2/IL2R complex signaling pathways are disturbed by functional genetic variants, immune cells are unable to proliferate and differentiate normally and the immune system cannot respond optimally to antigen stimulation, causing damage to the developing brain (CP).
Previous studies have shown that disruption of IL2/IL2R complex signaling pathways can lead to adverse cerebral events. In IL-2 knockout (IL-2 KO) mice, brain IL2R complexes are enriched in hippocampal formation, and loss of IL-2 results in cytoarchitectural alterations in the hippocampus and septum. These alterations include decreased cholinergic somata in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) and decreased distance across the infrapyramidal (IP) granule cell layer (GCL) of the dentate gyrus (DG) . The deletion of IL-2 alters the neuroimmunological status of the mouse hippocampus through dysregulation of cytokines produced by CNS cells . A study in 2015 suggested that complex interactions between IL2 deficiency in the brain and the immune system may modify brain processes involved in different modalities of learning and memory . In this study, we analyzed the correlation between five SNPs of IL2RA and CP and finally ascertained the association of IL2RA with CP. The results of our study showed that there might be an association between IL2RA and susceptibility to CP, implying that SNPs in the IL2RA gene might be involved in the occurrence and development of CP.
Our study has several limitations. First, our study was based on a single gene for susceptibility to CP. Given the genetic heterogeneity and gene-gene interactions related to CP etiology, other candidate genes that are part of the IL2/IL2R complex signaling pathway should also be analyzed. Second, we were unable to examine IL2RA protein expression in the brains of the subjects in the current study. Future studies are encouraged to measure inflammatory cytokine alterations in the brain. Third, although our study demonstrated an association between IL2RA and CP, further functional studies are necessary to verify the results.