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).