The IL-17 family includes structural related cytokines, of which IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F are identified. These family members can induce the expression of proinflammatory cytokines such as tumor necrosis factor (TNF)-α
to promote neutrophil migration, so they play inflammatory roles in the development of diseases [20
]. IL-22 can be secreted by Th22 cells as well as Th17 cells, γδ
T cells, and NK cells [11
]. IL-22 has high similarities in the structure of encoding genes and protein with IL-10 [21
]. In contrast to the anti-inflammatory properties of IL-10, however, IL-22 shows proinflammatory properties [22
GBS is classically regarded as T helper (Th)1 cells-mediated autoimmune inflammatory disease. Whereas, some changes in experimental autoimmune neuritis (EAN), an animal model of human GBS could not be explained by this opinion perfectly. Zhang et al. found that IFN-γ
knockout mice were also susceptible to EAN [23
], this indicated other factors and mechanisms are involved. Moreover, IL-17A positive cells in cauda equina (CE) infiltrating cells, and the levels of IL-17A in sera were increased in IFN-γ
knockout mice [23
]. IL-17 was found in sciatic nerves of EAN, and the accumulation of IL-17 was correlated with the severity of neurological signs [24
], which suggested a pathological contribution of IL-17 to the development of EAN. The frequency of Th17 cells in CSF and the level of IL-17 in plasma were significantly higher in active chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [25
]. There was strong evidence for proving that IL-17 had some correlation with GBS.
Our data showed that levels of IL-17 and IL-22 in CSF and plasma of GBS patients were obviously elevated compared with HC. This is the first human study reporting an elevation of IL-17 and IL-22 levels in GBS, although the functional roles of IL-17 and IL-22 in GBS require further investigation. In previous studies, IL-6 in the presence of transforming growth factor (TGF)-β
1, and IL-6, IL-23 in combination with IL-1β
had been proved to be the effective factors responsible for the differentiation of Th17 cells and the production of IL-17; these cytokine milieux may also facilitate the expression of IL-22 [26
]. IL-6, IL-1β
, IL-23, and TNF-α
are all proinflammatory cytokines and have an important role in the pathogenesis of GBS [28
]. Therefore, it is safe to conclude in our study that the extensive network of IL-17 and IL-22 in coordination with these inflammatory cytokines is associated with the pathogenesis of GBS. The elevated levels of IL-17 and IL-22 in plasma reflect the activation of Th17 and Th22 cells in the systemic auto-immune responses of GBS patients. Therefore, IL-17 and IL-22 might be important effectors in addition to Th1 cells and Th1 cytokines in autoimmune-mediated responses in GBS. The male-to-female ratio in our study was 1.75
1, which was in line with some previous reports [29
], and this confirmed that GBS might be a kind of male-vulnerable autoimmune disease. We presume that estrogen and testosterone may influence the production of inflammatory cytokines, such as IL-17 and IL-22. But the exact mechanisms are still unknown and need further researches.
Our data showed that GBS patients had increased IL-17 and IL-22 concentrations in CSF. In addition, in line with previous studies, Qalb, the total protein and albumin level of CSF were remarkably higher in GBS patients [30
]. CSF is considered to reflect events within the blood-nerve barrier (BNB), and it is more approximate to target organs of GBS than the peripheral blood. Kieseier reported that immune-mediated disorders of the peripheral nervous system (PNS) are pathologically characterized by the breakdown of the BNB, accumulation of activated T cells and macrophages in the PNS, and demyelination of peripheral nerves [31
]. Human Th17 cells could disrupt the tight junctions of blood-brain barrier (BBB) by direct effects of IL-17A and IL-22 on endothelial cells [32
]. GBS is a reported autoimmune demyelination disease affecting both the central nervous system (CNS) and PNS [33
], meanwhile, our data of the elevated IL-17 and IL-22 levels in CSF and plasma of GBS confirmed this respect. We presume several potential mechanisms of the origin in CSF and plasma of these cytokines: (i) IL-17 and IL-22 in peripheral blood could penetrate the BBB, so the levels of them in CSF are also elevated; (ii) the elevation of IL-17 and IL-22 in CSF and plasma might be related to the local inflammation of spinal roots and peripheral nerves that causes demyelination and axon degeneration; (iii) reactive Th17 and Th22 cells in peripheral blood may cross the BBB/BNB and secret relative cytokines.
We also found that the CSF levels of IL-17 and IL-22, respectively, were correlated with GDSs at the acute phase of GBS, and there was a positive correlation between them. Nevertheless, the levels of IL-22 in CSF and plasma also had a positive correlation. This indicates that the elevation of IL-17 and IL-22 in CSF is related to the severity of inflammation in the spinal roots. Since their elevations in CSF are synchronous, IL-17 and IL-22 may coordinate in the pathogenesis of the disease and may be a biomarker for indicating disease severity or prognosis, which, however, should be confirmed in future studies with a larger sample size.
There are limitations in our study. Due to the low incidence of GBS in the whole population [3
], the sample size is relatively small. Although paired samples of CSF and plasma were collected, the time-points of lumbar puncture with regard to disease onset varied among GBS patients. These limitations may influence the statistical power of the data analysis.
In summary, this study showed increased CSF and plasma levels of IL-17 and IL-22 in GBS patients compared with HC. We also demonstrated that the levels of IL-17 and IL-22 in CSF are correlated with GBS severity. Nevertheless, the level of IL-17 was correlated with that of IL-22 in CSF. Meanwhile, the levels of IL-22 in CSF and plasma also had a positive correlation. Further studies are warranted to confirm the immunological mechanisms of the elevated IL-17 and IL-22 levels in GBS.