CCL21/CCR7 Chemokine Axis and SS
The main pathological manifestations of SS are dry eyes and xerostomia caused by the infiltration of lymphocytes into lactear and salivary glands. The pathogenesis of SS is based on the dysfunction and infiltration of lymphocytes, accompanied by the production of auto-antibodies and hypergamma globulinemia. The study found that the expression of CCR7 was detected on the surface of CD4+ and CD8+ T cells in the peripheral blood of patients with SS. Compared with the CD4+ and CD8+T cells in the normal control, the expression of CCR7 was significantly increased in SS. Compared with peripheral blood T cells in SLE patients, CD4+ T cells in SS patients express more CCR7, suggesting that CCR7+ CD4+ T cells may play a key role in the pathogenesis of SS (Argyropoulou et al., 2018). Transwell showed that under the action of CCL21, the migration number of CD4+ T cells in peripheral blood of SS patients was significantly higher than that of the normal control, and the number of CCR7+CD4+ T cells was significantly higher than that of CCR7+CD8+ T cells, indicating that CCL21 can significantly improve the migration ability of CD4+ T cells in SS patients, and the chemotaxis ability of CCL21 to CD4+ T cells may be stronger than CD8+ T cells. This is because the combination of CCL21 and CCR7 induces actin aggregation and pseudopodia formation in CCR7-expressing cells and promotes the migration of CCR7+ cells along the ligand concentration gradient, which leads to the increase of CD4+T cell migration in the peripheral blood of SS patients. This may be the mechanism by which the CCL21/CCR7 chemokine axis in SS participates in the migration and infiltration of a large number of lymphocytes, especially CD4+ T cells. Previous studies have been reported that the chemotaxis index of CD4+ T cell in SS patients decreased significantly after anti-CCR7 monoclonal antibody treatment. Correlation analysis showed that there was a significant correlation between the chemotactic index and CCR7 expression on CD4+ T cells in peripheral blood of SS patients. These results further confirm that CCR7 plays a crucial role in the migration of CCL21 chemotactic lymphocytes to specific tissues (Rischmueller et al., 2016). Analysis of CD4+ T cell migration in SS patients and clinical data showed that the chemotactic index of CD4+T cell was positively correlated with disease activity index, but there was no significant correlation with the disease damage index. The results indicated that the increased expression of CCR7 on the surface of CD4+ T cells in the peripheral blood of SS patients promoted the migration and infiltration of CD4+T cells to inflammatory sites. CCR7+ T cells migrate to specific tissues under the action of CCL21, which inhibits cell apoptosis, prolongs cell survival time and participates in the occurrence and development of SS by activating corresponding signal transducting pathways (Barone et al., 2005).
The prominent manifestation of abnormal humoral immunity in SS is hyperglobulinemia, which occurs in more than 90% of patients. The increase of IgG level was the most obvious. Meanwhile, hyperglobulinemia can promote erythrocyte sedimentation rate (ESR), and the levels of ESR and IgG are closely related to the degree of disease activity in SS. Studies have shown that the expression of CCR7 on CD4+T cells in SS patients is positively correlated with the levels of ESR and serum IgG. The expression of CCR7 on CD4+ T cells and the clinical manifestations in SS patients showed that the expression of CCR7 was positively correlated with the disease activity index. These results further demonstrate that the expression of CCR7 on CD4+ T cells is closely related to the disease activity of SS, and it is expected to be a new indicator for monitoring the disease activity of SS (Bombardieri et al., 2012). However, there is no significant correlation between the CCR7 level and the disease injury index, indicating that although CCR7 plays an important role in the pathogenesis of SS, but it is not a key factor in assessing disease severity. Taken together, the abnormally increased expression of CCR7 on CD4+T cells in SS peripheral blood may play a key role in the abnormal accumulation of lymphocytes to the affected glands to form lymphocytic infiltrating foci. Some scholars reported that high expression of CCL21 was detected in the salivary glands of SS patients, and the expression of CCL21 was related to lymphocyte infiltration. The expression of CCL21 was also correlated with the increased level of ESR, IgG, rheumatoid factor (RF), anti-SSA antibody and anti-SSB antibody. The focal index (FS) and disease activity index of SS were also correlated with the expression of CCL21. CCL21/ CCR7 chemokine axis is expected to be a new indicator for monitoring SS disease activity and predicting prognosis (Lee et al., 2017). However, the expression of CCR7 on CD4+ T cells was not associated with the degree of impairment of salivary and lacrist gland function. This also indicated that the pathological changes of a large number of CD4+ T cell infiltration in SS exocrine glands may be related to the abnormal expression of CCR7 on T lymphocytes of SS patients, which indirectly proved that CCR7 plays an important role in the abnormal aggregation of T cells into diseased tissues. T cells accumulate to the inflammation site, and the apoptosis of infiltrating T cells is inhibited under the regulation of CCR7, leading to the continuous and gradual enhancement of the inflammatory response, which may partly explain the reason why the high expression of CCR7 T cells are closely related to disease activity. In conclusion, the CCL21/CCR7 chemokine axis may be one of the momentous links in the pathogenesis of SS, and blocking the interaction of CCL21-CCR7 may have positive significance for the control of SS disease progression. Therefore, monoclonal antibodies against CCR7 and small molecule compounds that inhibit the binding of CCL21 to CCR7 are highly likely to be new therapeutic approaches for SS in the future (Psianou et al., 2018).
CCL21/CCR7chemokine axis and SLE
The main characteristics of SLE are auto-antibodies formation, multiple organs damage and multiple clinical inflammatory manifestations. Increasing evidences suggest that the infiltration of T cells and white blood cells into inflammatory tissues may play a key role in organ involvement of SLE (Fanouriakis et al., 2021). Chemokines and their receptors can migrate white blood cells to inflammatory sites, initiate T cell immune response and regulate the differential recruitment of Th1 and Th2 cells. At present, many studies have shown that the abnormal expression of CCL21 and CCR7 is closely related to SLE (Odler et al., 2017). The expression of CCL21 in peripheral blood may be a biomarker of lung involvement in SLE patients, as CCL21 and CCR7 have been identified as key participants in the progression of pulmonary fibrosis. CCR7 is expressed on lung fibroblasts and is important for the activation, survival and proliferation of lung fibroblasts (Watanabe et al., 2008). Moreover, It was found that CCL21 could not induce the migration of CD4+ and CD8+ T cells in normal body, could induce moderate migration of CD4+ and CD8+ T cells in inactive SLE patients, and could induce strong chemotactic movement of CD8+ T cells in active SLE patients. The expression of CCR7 on CD8+ T cells in the peripheral blood of active SLE patients was significantly higher than that of inactive SLE patients and normal control. The level of CCR7 mRNA on CD8+ T cells of active SLE patients was significantly increased, and was significantly positively correlated with SLE disease activity index score (Wieczorek et al., 2010).
The number of CD4+CD95+CCR7+cells in active and inactive SLE patients was significantly higher than that in normal control, the number of CD4+CD95+CCR7-cells in active SLE patients was higher than that in the inactive SLE patients and normal control, the number of CD4+CD95-CCR7+cells in SLE patients was lower than that in normal control, indicating that CD4+CD95+CCR7+cells were associated with auto-antibody reactions, while CD4+CD95+CCR7-cells were closely related to were inflammatory response. However, CCR7 monoclonal antibody can completely block the chemotaxis of CD8+ T cells induced by CCL21 in active SLE patients, suggesting that high expression of CCR7 on CD8+ T cells may be related to SLE activity. In summary, these results demonstrate thatCCL21/CCR7 chemokine axis plays a crucial role in the pathogenesis of SLE, and can provide an important reference for monitoring the disease activity of SLE (Xu et al., 2012).
CCL21/CCR7chemokine axis andpolymyositis
The self-invasive of CD8+ T cells is the basis of polymyositis (PM), and the main clinical manifestations are muscle damage in the proximal extremities. The number of activated T cells in the peripheral blood of PM patients increased significantly and moved to the local area of myositis (Cerezo et al., 2020). A large number of infiltrating cells, mainly CD8+ cytotoxic T lymphocytes and macrophages, were found in myocytes and subintima of PM. CD4+T cells were found in the perineal and perivascular regions. Immunohistochemistry and RT-PCR tests showed that the expression of CCL21 was found in the muscles of PM, and CCR7 expression was detected in infiltrating monocytes in the endomysium of PM.
Around the non-necrotic muscle tracts, more than half of CD8+ T cells expressed CCR7, and the phenotype of these cells was mostly CD45RO+CCR7+CD+8 T cells. A few monocytes, muscle fibers and vascular endothelium showed the immune activity of CCL21. These results suggested that the interaction between CCL21 and CCR7 may play a vital role in the pathogenesis of PM (Kuwabara et al., 2009). Since CCL21 mRNA is only weakly expressed in normal muscle tissues, while CCR7 mRNA is not expressed in normal muscle tissues, suggesting that the expression of CCL21 and CCR7 may be pathologically up-regulated in PM. Double immunostaining showed that a large number of CD8+ T cells in the endomysium expressed CCR7, and CCR7+memory T cells may infiltrate the endomysium of PM. Studies have found that CCR7+ memory T cells closely surrounded the muscle fibers expressing MHC I class. There could be multiple explanations for these findings. The first possibility is that CCR7 may be expressed on auto-invasive CD8+ T cells in PM. The second possibility is that CCR7+ memory T cells may respond to the antigens presented by muscle fibers, or some CCR7+ T cells may be naive T cells that are sensitized for the first time at the lesion (Lv et al., 2018).
Studies have found that the immunohistochemical expression of CCL21 in inclusion body myositis and dermatomyositis is different from that in PM, which may be a different pathological mechanism of the disease. Low-intensity expression of CCL21 and CCR7 was also detected by immunohistochemistry or RT-PCR in control diseases without inflammation (Rider et al., 2016). Like other chemokine systems, CCL21/CCR7 chemokine axis is multifunctional and may not only participate in immune cell recruitment, but may also participate in tissue homeostasis. Further study of the effect of chemokines on muscle fibers may help us understand the pathogenesis of PM and develop specific immunomodulatory therapies (Chen et al., 2015). A series of research results have indicated that the CCL21/CCR7 chemokine axis plays an important role in the pathogenesis of PM. These findings, together with our data on the up-regulation of CCL21/CCR7 chemokine axis, strongly suggest that CCL21/CCR7 chemokine axis may play an important role in monocytes recruitment and muscle tissue damage in PM (De et al., 2009, Miller et al., 2013).
CCL21/CCR7 chemokine axis and other diseases
In addition, CCL21/CCR7 chemokine axis are is closely related to autoimmune diseases such as SSc, vasculitis and osteoarthritis (OA) (Ciccia et al., 2017). Studies have found that CCL21/CCR7 chemokine axis can affect the connective tissue immune disorders of heart, lung, kidney and digestive tract in SSc. In early studies, the differences between children and adults with SSc showed that the number of resting regulatory T cells was decreased and the number of CD45RA+CD4+T cells was increased in children compared with adults, but CD45RA+CD4+T cells were characterized by high expression of CCR7. This change in T cell expression is conducive to initiating the activation of CCR7+CD4+ effector T cells in adolescent SSc (Gonzalez et al., 2019). In vasculitis, CCR7 has attracted much attention as a marker of B cells and memory T cells differentiation. Moreover, CCR7 was also found to be expressed in synovial tissues and synovial fibroblasts, which provided the basis for CCCL21/CCR7 chemokine axis and local lesions (Hoffmann-Vold et al., 2018). OA is also a major category of autoimmune diseases, and immune dysfunction plays a crucial role in the pathogenesis of OA. Therefore, the role of CCCL21/CCR7 chemokine axis in OA should not be ignored (Favero et al., 2019)(Figure 3).