Human Immunology 84 (2023) 327–336

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Review

Impact of T helper cells on bone metabolism in systemic lupus

erythematosus
Feng Chen a, Yukun Wu b, Guowu Ren a,⇑, Shuaibo Wen a
a
Guangxi University of Chinese Medicine, Nanning City, Guangxi Zhuang Autonomous Region 530001, China
b
Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning City, Guangxi Zhuang Autonomous Region 530011, China

A R T I C L E I N F O A B S T R A C T

Keywords: Systemic lupus erythematosus (SLE), an autoimmune disease affecting multiple organs and tissues, is often
T helper cells complicated by musculoskeletal diseases. T helper cells (Th) play an important role in mediating lupus.
Bone immunity With the rise of osteoimmunology, more studies have shown shared molecules and interactions between the
Systemic lupus erythematosus immune system and bones. Th cells are vital in the regulation of bone metabolism by directly or indirectly reg-
Bone metabolism
ulating bone health by secreting various cytokines. Therefore, by describing the regulation of Th cells (includ-
Osteoclasts
ing Th1, Th2, Th9, Th17, Th22, regulatory T cells (Treg), and follicular T helper cells (Tfh) in bone metabolism
in SLE, this paper offers certain theoretical support for abnormal bone metabolism in SLE and provides new
prospects for future drug development.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
2. Imbalance of bone metabolism in lupus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
2.1. Th1 cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
2.2. Th2 cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
2.3. Th9 and TH22 cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
2.4. Th17 cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
2.5. Treg cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
2.6. Tfh cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
4. Authorship contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335

1. Introduction SLE. Clinically, SLE‐induced joint pain, osteonecrosis, limb weakness

or pain, and increased risk of fractures seriously undermine the quality
SLE is a systemic autoimmune inflammatory disease. According to of life of patients [2]. Studies have shown that for SLE patients, the
statistics, there are at least 5 million lupus patients worldwide [1]. prevalence of osteoporosis (OP) complication is 16% and the morbid-
Musculoskeletal injury is one of the most common complications of ity of osteonecrosis (ON) ranges from 1.7% to 52% [3–4]. Th cells

⇑ Corresponding author.
E-mail address: rgw1997@163.com (G. Ren).

https://doi.org/10.1016/j.humimm.2023.04.003
Received 17 September 2022; Revised 17 March 2023; Accepted 10 April 2023
Available online 24 April 2023
0198-8859/© 2023 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.
F. Chen et al. Human Immunology 84 (2023) 327–336

Fig. 1. Summary of possible association mechanisms between Th subsets and bone metabolism in SLE.

express CD4 on the surface, so Th cells are also called CD4 + T cells. immune response of CD8 + T cells and other immune cells [5–6].
Activated CD4 + T cells can promote the continuous activation of B Abnormal activation of Th cells in SLE leads to a sustained autoim-
cells to produce autoantibodies, and at the same time coordinate the mune response, followed by cytokine release, complement activation,

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and autoantibody production, resulting in multiple tissue or organ 2.1. Th1 cells
damage. Bone is not only the motor system of the human body but also
an immune organ as bone marrow tissue is also rich in hematopoietic CD4 + T cells are activated by IL‐12 and IL‐18, which triggers their
stem cells and mature immune cells, of which immune T cells account own STAT4 transcription factors. STAT4 then activates the specific
for about 5%. Studies have shown that CD4 + T cells can differentiate transcription factors STAT1 and T‐bet of Th1 cells. This leads to the
into corresponding Th cell subsets according to environmental stimuli. differentiation of CD4 + T cells into mature Th1 cells, which secrete
Those subsets in turn secrete various cytokines and related ligands to IFN‐γ, GM‐CSF, IL‐2, TNF‐α, and other factors involved in immune
affect the life activities of osteoblasts, osteoclasts, and osteocytes, response and bone metabolism [15]. In SLE disease, there are two
which ultimately affect bone formation, resorption, and metabolism opposite trends in Th1 cell function. The number and frequency of
[7–8]. (See Fig. 1). Th1 cells in the peripheral blood of SLE patients are reduced, and
the production of IFN‐γ is decreased. This changes the balance of
Th1/Th2 cells to Th2 predominance [16,17]. Patients with lupus
2. Imbalance of bone metabolism in lupus
nephritis have high expression of IFN‐γ and IL‐18 and low expression
of IL‐4 in their blood. The damaged kidney tissue shows a correspond-
The bone formation ability of osteoblasts and the bone resorption
ing advantage of Th1‐type cell response [16,17].
ability of osteoclasts maintain the dynamic balance of the body’s bone
IFN‐γ is a positive feedback factor of Th1, which promotes the
remodeling function, and they are strictly regulated in time and space.
expression of IL‐18 and IL‐12 receptors to increase the proliferation
However, abnormal activation, proliferation, and differentiation of
and differentiation of Th1 cells. IFN‐γ can promote the expression of
osteoclasts, as well as decreased differentiation or apoptosis of osteo-
osteoblast differentiation genes, such as Runt‐related transcription
blasts can lead to impaired bone microarchitecture and loss of bone
factor 2 (Runx), osteoblast‐specific transcription factor (Osterix),
mass. The balance between bone formation and resorption is regulated
and osteocalcin (OCN); In addition, IFN‐γ activates the canonical
by the OPG/RANKL/RANK system composed of osteoprotegerin
JAK‐STAT1 pathway, which in turn initiates the degradation of
(OPG), receptor activator of NF‐κB ligand (RANKL), and receptor acti-
ubiquitin ligase TRAF6 by the ubiquitin–proteasome, thus ultimately
vator of nuclear factor‐κB (RANK); OPG inhibits osteoclast differentia-
inhibits the expression of downstream transcription factors NF‐κB
tion and promotes osteoblast proliferation and osteogenesis. As a type
and JNK, and inhibits osteoclast differentiation activity [18,19].
II transmembrane protein, RANKL can directly bind to RANK dis-
Osteoclasts are derived from bone marrow myeloid hematopoietic
tributed in the cell membrane of osteoclast precursors, thus inducing
precursor cells. Myeloid precursor cells differentiate into osteoclast
the differentiation and maturation of precursor osteoclasts and slowing
precursors (monocytes/macrophages), multiple monocytes and
down the apoptosis of mature osteoclasts [9]. OPG can reduce the
macrophages fuse and differentiate into osteoclasts; thus osteoclasts
binding of RANK to its ligand RANKL by competing with RANK to
or bone marrow macrophages (BMMs) can act as antigen‐presenting
occupy the target. Clinical studies related to lupus complicated with
cells (APCs) expressing MHC class I/II to activate T cells [20]. IFN‐γ
bone loss have shown that serum OPG decreases and the RANKL/
is an inducer of MHC class II expression and antigen presentation in
OPG ratio increases in SLE patients [10]. In terms of animal experi-
macrophages, IFN‐γ can promote TNF‐α, IFN‐γ, and RANKL expres-
ments, there is no unified animal model of SLE‐induced OP and ON.
sion in T cells by activating MHC class II in bone marrow macro-
The postmenopausal SLE model is composed of ovariectomized
phages. TNF‐α has a direct induction effect on the formation of
MRL/lpr mice [11]. Mice lacking IgG Fc gamma receptors (FcγRs)
osteoclasts; RANKL‐expressing T cells can promote osteoclast differ-
develop SLE lesions at 6 months, and those with SLE lesions exhibit
entiation through intercellular contact with RANK on the surface of
decreased bone mass at 6 or 10 months [12] (See Figs. 2 and 3). There
osteoclasts [20,21]. Notably, although osteoclast positive feedback
is an interactive microenvironment for osteoblasts, osteoclasts, macro-
promotes T cell secretion of IFN‐γ, IFN‐γ secreted by activated T
phages, T cells, B cells and other immune cells in blood and bone.
cells induces (see Fig. 4) indoleamine 2,3‐dioxygenase (IDO) expres-
Osteoblasts and osteoclasts are regulated by many immune factors
sion in osteoclast, and IDO depletes tryptophan in the microenviron-
(such as IL‐1, TNF‐α, IL‐17, etc.), such as activated Th cells highly
ment to inhibit the proliferation of activated T cells [21]. This
express RANKL and TNF‐α, which promotes osteoclasts formation
unique feedback regulation of osteoclasts may play a role in the
and osteoblasts disfunction [13,14]. Abnormal Th cell function is a
Th1 cell response in lupus. Normally, IFN‐γ inhibits osteoclast for-
characteristic pathology of lupus. This paper, by exploring the rela-
mation, but in the inflammatory environment of SLE, osteoclasts
tionship between the imbalance of Th cell subsets (Th1, Th2, Th9,
and dendritic cells activate Th1 cells as APC, expressing TNF‐α
Th17, Th22, Treg, Tfh) and the imbalanced bone metabolism in lupus,
and RANKL. The promotion of osteoclastogenesis by TNF‐α and
aims to further clarify the mechanism of action of the shared microen-
RANKL outweighs the inhibitory effect of IFN‐γ [22,23]. Further-
vironment between the immune system and the skeletal system in SLE.

Fig. 2. OPG/RANKL/RANK system disorder in SLE. The binding of RANKL to RANK on the surface of osteoclasts can induce their differentiation and proliferation.
OPG, secreted by osteoblasts, acts as a decoy receptor that binds to RANKL and prevents it from inducing osteoclast formation. However, in SLE, the RANKL/OPG
ratio is increased, leading to a dysregulation of the RANKL/RANK/OPG signaling pathway.

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Fig. 3. Mechanism of RANK signaling in osteoclasts. This figure was originally drawn in another article written by me and my collaborators and is cited here to
help readers understand the meaning of TRAF6 and some downstream factors in osteoclasts. First, because RANK lacks phosphorylated protein kinases in its own
structure, it needs TRAF6 to recruit enzymes or proteins such as TAK1, Src, GRB2 /GAB2 to activate downstream MAPK and NF-kB signals, resulting in the
activation of transcription factors NFATc1, c-Fos, c-Jun, etc., and ultimately promotes the differentiation and maturation of osteoclasts.

more, the co‐stimulation of osteoblasts by TNF‐αand IFN‐γ induces
the release of cytochrome c from mitochondria in osteoblasts, lead-
ing to osteoblast apoptosis [24].
2.2. Th2 cells
Th2 cells mainly secrete IL‐4, IL‐5, IL‐10, IL‐13, etc. IL‐4 activates
JAK1/3 after binding to its receptor, and JAK1/3 phosphorylates
STAT6 and up‐regulates GATA‐binding protein 3 (GATA3), lead to pro-
moting Th2 cell differentiation and expansion [25]. IL‐4 promotes the
expression of B‐cell MHC II antigens, FcεRII/CD23 and CD40, and
enhances the antigen‐presenting ability and proliferation of B cells.
Studies have shown that in SLE disease, Th2 cells infiltrate the renal
interstitial region and release IL‐4, and interact with renal cells to
induce renal fibrosis and glomerulosclerosis, thus the knockout of IL‐
4 can significantly abrogate these lesions [26,27]. IL‐4 inhibits
RANKL‐induced osteoclast differentiation and bone resorption by
phosphorylating STAT6. It can also induce osteoblast proliferation
while inhibiting its differentiation [28]. Co‐culture of Th2 cells with
osteoblasts showed that in the Th2 cell environment, the up‐
regulation of OPG expression outweighed the up‐regulation of RANKL
expression, resulting in a decrease in the RANKL/OPG ratio and pro-
moting osteoblast metabolism [29]. However, in the unique context
of SLE, the inhibitory effect of Th2 cells on osteoclasts may not hold
true. In SLE patients, elevated levels of IL‐4 and IL‐13 synergistically
promote B cell differentiation, leading to an increase in the production
of autoantibodies. Moreover, under the presence of RANKL, IL‐4 and
IL‐13 co‐stimulate M2 macrophages to differentiate into osteoclasts
[30–32] (See Fig. 5).
2.3. Th9 and TH22 cells
Th9 and Th22 cells are Th cell subsets that produce IL‐9 or IL‐22.
Naive CD + 4 T cells are stimulated by IL‐4 and TGF‐β, which activates
STAT6, GATA3 and IRF4 factors, leading to the differentiation of
CD + 4 T cells into Th9 cells [33]. Yang et al. found that the expres-
sion of CD4 + IL‐9 + Th9 cells in the spleen of MRL/lpr mice was
increased. This was related to the expansion of germinal center cells,
as IL‐9 can activate JAK/STAT3 of B cells to promote B cell prolifera-
tion and IgM and IgG secretion [34]. In terms of bone function, IL‐9
significantly enhances osteoclast activation of M−CSF/sRANKL and
up‐regulates the expression of matrix metalloproteinases (MMPs),

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Fig. 4. Mechanism of Th1 cells in SLE regulating osteocytes. In SLE, Th1 cells are abnormally activated, leading to an increase in the cytokine IFN-γ.In terms of
bone regulation, IFN-γ has a dual effect of promoting bone formation and inhibiting bone resorption. Additionally, IFN-γ activates Th1 and other immune cells
through a negative feedback mechanism, resulting in an excessive expression of RANKL on the surface of Th1 and other immune cells. This leads to a reduction in
the inhibitory effect of IFN-γ on bone resorption.

Fig. 5. Mechanism of Th2 cells in SLE in regulating osteocytes and immunity. In terms of immunity, IL-4 produced by Th2 cells can promote B cell activation and
affect renal tissue. In terms of bone metabolism, IL-4 can inhibit bone resorption and promote bone formation. However, in SLE patients, there is a high expression
of RANKL, IL-4, and IL-13, and the co-stimulation of RANKL, IL-4, and IL-13 can lead to osteoclast formation.

which worsen bone degradation [35] (See Fig. 6). Th22 cells are struc-
turally similar to Th17 cells and both produce IL‐22 while expressing
chemokine receptor (CCR) 4 and CCR6. However, Th22 cells also
express CCR10 and require TNF‐α and IL‐6 to stimulate the aryl hydro-
carbon receptor (AHR) for differentiation from CD4 + T cells. In SLE,
Th22 and IL‐22 levels are elevated and correlate with disease activity
[36]. Miyazaki et al. reported that co‐culture of Th22 cells and Th17
cells generated a significantly higher number of osteoclasts compared
to co‐culture of RANKL and M−CSF. They also found that IL‐22 facil-
itated the expression of cathepsin K (a marker of bone resorption) and
nuclear factor of activated T cells (NFATc)1(osteoclast differentiation
gene) mRNA in osteoclasts in a concentration‐dependent manner

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Fig. 6. Mechanism of Th9 and Th22 cells in regulating osteocytes and immunity in SLE. The cytokines IL-9 and IL-22 produced by Th9 and Th22 cells,
respectively, can promote B cell activation and macrophage chemotaxis. Additionally, both cytokines have the ability to promote bone resorption.

Fig. 7. Mechanism of Th17 cells regulating osteocytes in SLE. In systemic lupus erythematosus (SLE), there is an increased activation of Th17 cells which
subsequently generate IL-17. Within the immune response, IL-17 plays a role in promoting the translocation of B cells to germinal centers and can enhance Th17
activity through macrophage feedback. In terms of bone regulation, IL-17 can inhibit bone resorption, promote bone resorption, and interfere with the RANKL/
RANK signaling between osteoclasts and osteoblasts.

[37] (See Fig. 6). Th9 and Th22 are also involved in the process of
osteoclast formation, but the mechanism of Th9 and Th22 cells on
osteoclasts and other related cells in the SLE environment remains to
be further studied.
2.4. Th17 cells
CD4 + T cells are stimulated by TGF‐β, IL‐6, IL‐1β and IL‐23 to acti-
vate Th17 cell‐specific transcription factors ROR‐γt, STAT3 and differ-
entiate into Th17 cells. Th17 cells mainly secrete IL‐17 and IL‐22, IL‐
23 [38]. Th17 cell frequency and IL‐17 expression in the blood of
SLE patients are increased. IL‐17 can promote the B cell differentiation
and IgG expression of GC to aggravate the immune response [39].
Th17 cells promote bone resorption through at least four aspects: (1)
Cell contact induction: Th17 cells promote their differentiation by
increasing the expression of RANKL on the surface. RANKL on the sur-
face of Th17 cells binds to the RANK signal on the surface of osteo-
clasts and promotes the differentiation of osteoclast precursor cells

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into osteoclasts [40]. (2) Direct induction of IL‐17: IL‐17 secreted by
Th17 cells can directly act on the receptor (IL‐17R) on the surface of
osteoclasts to promote osteoclast differentiation and bone erosion
[41]. (3) Indirect induction by IL‐17: IL‐17 has been shown to induce
the expression of RANKL in osteoblasts. The RANKL/RANK signaling
pathway is indirectly activated between the surfaces of osteoblasts
and osteoclasts. Additionally, IL‐17 inhibits the expression of osteo-
blast factors, such as OCN and Osterix [42]. IL‐17 induces macro-
phages to secrete various inflammatory factors such as TNF‐α, IL‐1
and IL‐6, which in turn promote the formation of osteoclasts [43].
(4) Feedback effect: IL‐17 induces the production of inflammatory fac-
tors, such as IL‐1 and IL‐6, by macrophages. These factors promote the
activation of Th17 cells, which in turn promote osteoclast formation.
This creates a feedback loop of Th17‐IL‐17‐macrophage‐IL‐1, IL‐6‐
Th17 [39,44] (see Fig. 7).
2.5. Treg cells
Treg cells are mainly divided into three categories: natural Treg
cells (nTregs or tTregs), peripheral Treg cells(pTreg) and regulatory
Treg cells (iTregs); nTregs exist in the thymus,pTreg exist in peripheral
lymphoid tissue and iTregs are differentiated from naive T cells under
autoantigen or exogenous stimulation [45]. Studies have shown that
CD4 + T cells activate iTreg cell‐specific transcription factor (Foxp3)
when stimulated by IL‐2 and TGF‐β, and iTreg cells secrete IL‐10, IL‐
35, TGF‐β and other factors. Treg cells induce B cell apoptosis in a
perforin‐ and granzyme‐dependent manner, and can directly inhibit
B cell proliferation and plasma cell differentiation by secreting
TGF‐β; however, the lack or functional defect of Treg cells in SLE leads
to weakened immunosuppression [46,47].
Fig. 8. Mechanism of Treg cells regulating osteocytes and immunity in SLE. The cytokines TGF-β, IL-10, and IL-35 of Treg cells can regulate bone formation and
bone resorption through signaling pathways such as Smad, NF-KB, and wnt. However, in SLE, the decrease of Treg cells and their cytokine TGF-β leads to
weakened immune suppression and bone formation ability.
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Human Immunology 84 (2023) 327–336
There are four main mechanisms by which Treg cells affect bone
metabolism: (1) Cell contact apoptosis: Foxp3 + Treg cells express
cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4), which bind
to co‐stimulatory molecules CD80/CD86 on the surface of osteoclast
precursor cells. This induces the activation of IDO in osteoclast precur-
sor cells, which in turn induces apoptosis of osteoclast precursor cells
by degrading tryptophan [48]. In addition, CTLA‐4‐lg can inhibit the
expression of NFATc1, cathepsin K and the marker tartrate‐resistant
acid phosphatase (TRAP) in osteoclasts induced by RANKL [49]. (2)
Cytokine inhibition: Foxp3 + Treg cells secrete IL‐10, IL‐35, TGF‐β
and other factors to participate in the process of bone resorption and
remodeling metabolism. Studies have shown that IL‐10 decrease the
expression of osteoclast differentiation genes, such as NF‐κB, c‐Fos,
c‐Jun, and NFATc1, induced by RANKL [50]. IL‐35 can promote osteo-
blast differentiation by activating the Wnt/β‐catenin signaling path-
way [51]. TGF‐β activates intracellular effectors such as MPAK and
SMAD proteins to induce osteoblasts to secrete Osterix, Runx2 and
other osteopromoting factors [52] (see Fig. 8). (3) Imbalanced of
Treg/Th17 cells: The balance of Treg/Th17 cells is regulated by
TGF‐β signaling. In the absence of IL‐6, TGF‐β induces CD4 + T cells
to express Foxp3, which interacts with ROR‐γt and reduces Th17 cell
differentiation while promoting Treg cell differentiation. However,
in the presence of TGF‐β, IL‐6, and IL‐23, IL‐6 and IL‐23 induce the
expression of STAT3, which inhibits Foxp3 expression and promotes
Th17 cell differentiation. In SLE, the decreased ratio of Treg/Th17
cells, along with decreased TGF‐β and increased IL‐17 levels, aggra-
vates bone loss [48]. In addition, TGF‐β also has an activating effect
on TH17 cell differentiation. Relevant studies have shown that SMAD
induced by TGF‐β/SMAD signaling pathway is a co‐activator and co‐
inhibitor of Th17 cell differentiation, which can reversely modify the
induction of STAT3. Besides, TGF‐β upregulates the expression of
F. Chen et al.
Fig. 9. Mechanism of SLE Treg/Th17 cells and negative feedback loop regulating osteocytes. In SLE, there is an imbalance in Treg/Th17 differentiation. Firstly,
under stimulation conditions, initial CD4 + T cells tend to differentiate towards Th17. Secondly, IL-17 interferes with the inhibitory effect of Treg on bone
resorption.
ROR‐γt, IL‐17 and IL‐21 by activating other signaling pathways such as
JNK/c‐Jun and RhoA‐ROCK2 signaling [53,54]. (4) Negative feedback
loop: CD8 + regulatory T cells (Tcreg) are a type of Treg cells that
have similar but distinct functions. Both Treg cells and Tcreg cells
express CD25, FoxP3, and CTLA‐4, which can suppress the immune
response. Treg cells play a crucial role in inhibiting autoreactive T cell
responses, while Tcreg cells cannot maintain this inhibition in SLE dis-
ease. Additionally, Treg cells require MHC II for restimulation through
TCR, while Tcreg cells only need MHC I and no restimulation [55].
Osteoclasts are capable of endocytosing extracellular antigens, pro-
cessing full‐length proteins in a proteasome‐dependent manner, and
cross‐presenting antigens on MHC‐I to activate antigen‐specific
CD8 + T cells. In addition, osteoclasts secrete T cell chemokines
(CXCL10, CCL5) and express CD80, CD86 and CD40 [56]. This indi-
cates that osteoclasts have the effect of activating and recruiting Tcreg
cells. Activated Tcreg cells can inhibit osteoclast resorption by degrad-
ing osteoclast TRAF6 through the secretion of IFN‐γ. However, IL‐17
and TNF‐α can counteract the inhibitory effect of Tcreg cells on osteo-
clasts [57]. Antigen presentation studies on osteoclasts showed that
osteoclasts, similar to dendritic cells, can express MHC I/II to activate
CD4 + and CD8 + T cells, and osteoclasts secrete TGF‐β, IL‐6, TNF‐α
[58]. There is a negative feedback loop between Tcreg cells and osteo-
clasts, and this loop may be involved in Treg/Th17 cell balance, but
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Human Immunology 84 (2023) 327–336
the dysfunction of Tcreg and Treg cells and Treg/Th17 cell imbalance
in SLE disrupted inhibition of Treg cell osteoclast as well as negative
feedback loops. (See Fig. 9).
2.6. Tfh cells
When stimulated by IL‐6 and IL‐12, CD4 + T cells differentiate into
Tfh cells which express various unique genes and factors, such as
CXCR5, CD40L, ICOS programmed cell death‐1 (PD‐1), BCL‐6 and
IL‐21, etc. These factors will promote the formation of GC and the dif-
ferentiation of B cells in GC into memory B cells or plasma cells; the
binding of CD40L on the surface of Tfh cells to CD40 on the surface
of B cells induces the production of IgG by B cells [59–61]. Tfh cells
also promote B cell activation and differentiation into plasma cells
by secreting IL‐21.59–61 Tfh cells and osteoclast relation: Tfh cells
highly express RANKL to induce osteoclast differentiation, and IL‐21
can independently activate the phosphoinositide 3‐kinase (PI3K)/
AKT pathway to induce osteoclastogenesis without RANKL [62,63].
A study of OA also showed that Tfh cell frequency and IL‐21 expression
in the serum of OA patients were increased and positively correlated
with disease activity, CRP levels and WOMAC (bone joint score)
[64]. (see Fig. 10).
F. Chen et al.
Fig. 10. Mechanism of Tfh cells regulating osteocytes and immunity in SLE. In SLE, IL-21 secreted by TFH cells can promote B cell differentiation into plasma cells
and antibody production. IL-21 can also affect Treg function by interfering with mTORC. IL-21 has a role in promoting osteoclast formation.
3. Conclusion
In conclusion, as a systemic autoimmune disease, SLE often dam-
ages bones, and the imbalance of Th cell subsets is the major pathogen-
esis. It is of great significance to explore the mechanism of bone loss in
SLE. Therefore, based on the potential association mechanism of Th
cell subsets with bone remodeling and bone resorption in the state
of imbalanced Th cell subset in SLE, this paper will help to develop
new therapeutic strategies, such as bone marrow‐derived mesenchy-
mal stem cell transplantation for the treatment of SLE, or the improve-
ment of bone loss by intestinal flora which is a good representation of
the “bone immunology” treatment perspective. However, there are
still some limitations. First, this paper describes the abnormal state
of Th cells in SLE and then discusses the relationship between Th cells
and skeletal cells in this abnormal state, which cannot fully represent
the relationship between Th cells and skeletal cells in the SLE disease
environment. Second, other subtypes of T cells and immune cells are
poorly discussed, and the relationship between bone and the overall
immune system has not been elucidated. In the future, the research
on the interaction mechanism between various types of immune cells
and skeletal cells in autoimmune diseases should be increased to pre-
vent the occurrence and development of bone loss in SLE from the per-
spective of the bone immune microenvironment.
4. Authorship contributions
Guowu Ren conceived and designed the study. Shuaibo Wen and
Guowu Ren supervised the project.Guowu Ren and Feng Chen wrote
the manuscript. Guowu Ren drew the mechanism diagram. Wu Yukun
and Feng Chen contributed equally to the study.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.
Funding
No.
335
Human Immunology 84 (2023) 327–336
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgments
I would like to express my gratitude to my friends and family for
their help and support. I also want to extend my sincere appreciation
to the staff and reviewers of Human Immunology for their hard work on
this manuscript. Without your,s contributions, this manuscript would
not have been possible.
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