TYPE Mini Review

PUBLISHED 02 February 2023

DOI 10.3389/fimmu.2023.1127417

Pathogenesis and treatment

OPEN ACCESS of Sjogren’s syndrome: Review
EDITED BY
Xiuzhen Sheng,
Ocean University of China, China
and update
REVIEWED BY
Dayong Liu, Qipeng Zhan, Jianan Zhang, Yubin Lin, Wenjing Chen,
Tianjin Medical University, China
Jian Li, Xinzou Fan and Dunfang Zhang*
National Institutes of Health (NIH),
United States State Key Laboratory of Biotherapy and Cancer Center, Department of Biotherapy, Collaborative
Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
*CORRESPONDENCE
Dunfang Zhang
izdf@163.com

SPECIALTY SECTION Sjogren’s syndrome (SS) is a chronic autoimmune disease accompanied by

This article was submitted to
Mucosal Immunity,
multiple lesions. The main manifestations include dryness of the mouth and
a section of the journal eyes, along with systemic complications (e.g., pulmonary disease, kidney injury,
Frontiers in Immunology and lymphoma). In this review, we highlight that IFNs, Th17 cell-related cytokines
RECEIVED 19 December 2022 (IL-17 and IL-23), and B cell-related cytokines (TNF and BAFF) are crucial for the
ACCEPTED 23 January 2023
pathogenesis of SS. We also summarize the advances in experimental treatment
PUBLISHED 02 February 2023
strategies, including targeting Treg/Th17, mesenchymal stem cell treatment,
CITATION
targeting BAFF, inhibiting JAK pathway, et al. Similar to that of SLE, RA, and MS,
Zhan Q, Zhang J, Lin Y, Chen W, Fan X and
Zhang D (2023) Pathogenesis and biotherapeutic strategies of SS consist of neutralizing antibodies and
treatment of Sjogren’s syndrome: inflammation-related receptor blockers targeting proinflammatory signaling
Review and update.
Front. Immunol. 14:1127417. pathways. However, clinical research on SS therapy is comparatively rare.
doi: 10.3389/fimmu.2023.1127417 Moreover, the differences in the curative effects of immunotherapies among SS
COPYRIGHT and other autoimmune diseases are not fully understood. We emphasize that
© 2023 Zhan, Zhang, Lin, Chen, Fan and targeted drugs, low-side-effect drugs, and combination therapies should be the
Zhang. This is an open-access article
distributed under the terms of the Creative focus of future research.
Commons Attribution License (CC BY). The
use, distribution or reproduction in other
KEYWORDS
forums is permitted, provided the original
author(s) and the copyright owner(s) are sjogren's syndrome, foxp3 + treg, th17 cells, JAK pathway, tumor necrosis factor, interferon
credited and that the original publication in
this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.

1 Introduction
Sjogren’s syndrome (SS) is a chronic autoimmune disease associated with functional disorders
of the exocrine glands (e.g., parotid and lacrimal glands) and extraglandular manifestations. In
1892, JH Mikulicz reported the first case of SS. In 1933, the Danish ophthalmologist Sjogren
reported on 19 female patients with dryness of the mouth and eyes, 13 of whom had rheumatoid
arthritis (RA). To distinguish this ailment from xerophthalmia (vitamin A-deficiency-related
dryness of the eyes), Sjogren defined the syndrome as keratoconjunctivitis sicca. KJ Bloch
presented the clinical features of the currently recognized syndrome and introduced primary
Sjogren’s syndrome and secondary Sjogren’s syndrome, which presents without and with an
independent connective tissue disease (CTD), respectively (1).
According to a worldwide epidemiological study based on PubMed and Embase data, the
incidence rate of SS is 6.92 per 100 000 person-years and the prevalence rate is 60.82 cases per
100 000 inhabitants, or 1 case per 1644 persons. Moreover, the age of patients peaks at 56. In

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Zhan et al. 10.3389/fimmu.2023.1127417

the last 15 years, the disease has affected females more than males (2). Because SS presents with multiple extraglandular manifestations
Patients with SS experience an enduring and intolerable pain with (Figure 1), the European Alliance of Associations for Rheumatology
multiple physical symptoms, such as dental caries, vaginal dryness, (EULAR) developed The EULAR SS disease activity index (ESSDAI)
and arthralgia (3). to assess disease activity in patients with sicca symptoms and simplify
Given the immense social and economic burden caused by SS, we diagnosis. ESSDAI evaluates the severity of disease within 12 clinical
aimed in this review to characterize the current paradigm of the domains (i.e., constitutional, lymphadenopathy, glandular, articular,
pathogenesis and treatment of SS to motivate and inform the cutaneous, pulmonary, renal, muscular, peripheral nervous system,
development of efficient treatment strategies, particularly central nervous system, hematological, biological), and it aims to
immunological treatments. obtain a standardized evaluation in clinical trials and practice (6).
The involvement of the nervous system was first reported in the
1980s (7). Several neurological diseases have since been associated
2 Brief review of clinical manifestations with SS (8–12), which indicates the importance of precise
neurological diagnostic assessments. Interstitial lung disease (ILD)
Sjogren’s syndrome is a systemic disease with heterogeneous is the most frequent and severe pulmonary complication of SS and
manifestations that involve disorders or damage to the tissues of contributes substantially to morbidity and mortality. In an Italian
the exocrine glands (Figure 1). The diagnosis of SS is a multistep cohort, approximately 20% of patients with comorbid SS presented
process, including the evaluation of oral and ocular dryness, detection with ILD, and approximately 10% presented with amyloidosis and
of anti-SSA/Ro and anti-SSB/La antibodies, and glandular biopsy. primary lung lymphoma (13). Efficient clinical examination,
Dryness of the eyes and mouth, which is caused by the dysfunction of including lung biopsy or screening of serological markers, could
salivary and lacrimal glands, is the most salient and common clinical assist in the early diagnosis and intervention of SS-ILD (13).
symptom. Severe sicca symptoms of the eyes and mouth profoundly Unfortunately, no effective treatment strategy exists for SS-ILD
impede quality of life. An aqueous-deficient mouth has a severe effect (14). As an autoimmune disease, SS can also lead to synovitis and
on oral health and is associated with an increased risk of developing RA, with the latter causing structural damage. A previous study
caries (4). A recent study reported that the oral microbiome of showed that the medication strategy of RA had some success in SS,
patients with SS who have salivary hypofunction was under stress but the best-performing regimen is unclear (15).
and dysregulated; Veillonella parvula is a potential biomarker of Renal complications have only been observed in less than 10% of
Sjogren’s syndrome (5). patients with SS. Tubulointerstitial nephritis (TIN), caused by

FIGURE 1
Typical glandular and extraglandular manifestations of SS.

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lymphocyte infiltration around the renal tubes, occurs in two-thirds autoimmune disease, and linked its expression to the clinical
of patients with SS and renal dysfunction (16, 17). However, the low manifestations (28). IFN-I plays an important role in the
prevalence of renal manifestations may be an artefact of the ineffective progression of SS by promoting the activity of immune cells, such
diagnosis of TIN (18). Non-Hodgkin’s lymphoma (NHL) is the most as NK cells, CD8+ T cells, and even macrophages. In addition,
severe extraglandular complication of SS, with the B cell type being dendritic cells, the main producers of IFN-I, were observed in the
predominant (occurs in approximately 5% of SS cases) (19). salivary glands of patients with SS, which suggests a role for IFN-I in
Hypergammaglobulinemia or the aberrant expression of other the formation of salivary gland lesions (29, 30) (31, 32).
antigens in the blood stimulate the expansion of rheumatoid factor- IFN activates the overexpression of canonical interferon-
reactive B cells (20). Meanwhile, B lymphocyte-activating factor stimulated genes (ISGs) through the Janus kinase (JAK)-STAT
(BAFF) and germinal center (GC)-like structures amplify the signaling pathway, which is defined as the “interferon signature.”
activation of B cells (21, 22). Some studies have reported that SS- IFN phosphorylates STAT1, STAT2, STAT3, and STAT5, which
NHL is also associated with abnormal activation of nuclear factor activate downstream signals leading to the activation of immune
kappa B (NF-kB) (23, 24). Additionally, a multicenter clinical study cells (33–35). This signature in gene expression is considered a
showed that more than a quarter of patients with SS presented biomarker of autoimmune diseases (36).
systemic symptoms beyond the current ESSDAI classification, Under physiological conditions, in vitro-derived pathogens or in
including cardiovascular; digestive; pulmonary; ear, nose, and throat vivo-derived apoptotic cells can trigger a rapid innate immune
(ENT); cutaneous; and urological features (25). response through pattern recognition receptors (PRRs), including
TLRs, RLRs, and NLRs (37). PRRs can recognize nucleic acids and
induce the production of numerous proinflammatory cytokines and
3 Pathogenesis type I IFNs; thus, aberrant activation of the self-antigen recognition
Toll-like receptor (TLR) leads to the development of autoimmune
3.1 Brief introduction disease (38).
Some studies have reported the enhanced expression of the cell
In a 2013 review by G Nocturne and X Mariette of the adhesion molecules VACM-1, ICAM-1, and programmed death
pathogenesis of SS (26), three key steps were identified based on the ligand-1 (PD-L1) in patients with SS (39–41). The aberrant
initial genome-wide association study (GWAS): aberrant activation of expression of these cytokines is mediated by IFN-I and IFN-II
the innate immune response, especially through the interferon (IFN) through the JAK-STAT pathway (42, 43). A recent study used
and NF-kB pathways, atypical recruitment to lymphoid follicles reactive oxygen species (ROS) and N-acetylcysteine (NAC) to
mediated by CXCR5, and T cell activation with ascending HLA induce or block the expression of ICAM-1 and PD-L1 and revealed
susceptibility along the IL-12–IFN-g axis. BAFF was considered to that the IFN signature that regulates the expression of ICAM-1 and
be vital in coordinating the innate and adaptive immune responses to PD-L1 in SS was related to oxidative stress (43–45).
the disease. They also highlighted the pathophysiological role of Several recent studies have suggested that IFN-III contributes to
natural killer (NK) and epithelial cells as well as the dysfunction of SS. Type III IFNs, which consist of IFN-l1, IFN-l2, IFN-l3, and IFN-
the neuroendocrine system. l4, are mainly produced by plasmacytoid dendritic cells (pDCs) (46,
Mavragani et al. reviewed the treatment strategies and molecular 47). pDCs respond to the secretion of IFN-III and show improved
targets of the innate and adaptive immunity pathways (27). Regarding survival under stimulation with IFN-III in vitro. IFN-III enhances the
the regulation of innate immunity, previous research focused on production of IFN-I and TNF-a in pDCs and promotes the
inhibiting the production of proinflammatory factors, such as IL-1, expression of CD80 and CD86, which contribute to the maturation
IL-6, and tumor necrosis factor-a (TNF-a), which has proven to be of pDCs (35). IFN-III regulates the immune response by upregulating
effective in other autoimmune diseases. IFN-associated pathway the polarization of Th1 and CD8+ T cells and downregulating Th2
inhibitors were another research topic of interest. For example, cytokines and Tregs (48).
downregulating the expression of the primary dendritic cell surface
receptor ILT7 to reduce TLR7/9-mediated IFN production was
considered a potential treatment route. Regarding adaptive 3.3 Genome loci associated with SS
immunity, previous research focused on antigen presentation, co-
stimulation, B-cell activation, T-cell proliferation, and germinal Etiological research has revealed the pathogenesis of SS at the
center formation. Overall, most strategies were aimed at regulating genomic level. A GWAS of autoimmune diseases identified an
aberrant inflammation. association between HLA regions and SS, including HLA-DR,
HLA-DQB1, and HLA-DQA1 (Table 1). The allele with the
strongest association was HLA-DQB1*0201 (Pmeta = 1.38 × 10–95).
3.2 IFN All HLA alleles were correlated with the expression of rs115575857.
In addition, six non-HLA regions that surpassed the suggestive
IFN is an immunoregulatory protein that promotes innate and threshold (Pmeta < 5 × 10–5) were also shown to be involved in SS,
acquired immunity and antiviral activation. IFN is categorized into including IRF5, STAT4, BLK, IL-12A, TNIP1, and CXCR5, with the
three types based on structure and origin, i.e., I, II, and III. In 1981, expression of IRF5 and STAT4 being the most significant contributors
researchers detected type-I IFN in the blood of patients with after HLA regions (Table 1) (49).

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TABLE 1 Genome loci associated with SS.

Gene loci SNP Encoding protein Effect pathway P value of Meta-analysis

rs112357081

rs3135394

rs115575857
HLA MHC-II Antigen presentation 7.65 × 10-114 ~ 1.37 × 10-85
rs3129716

rs116232857

rs9271588

rs3757387

rs4728142

IRF5 rs17339836 Interferon regulatory factor 5 Activate IFN 2.73 × 10-19 ~ 3.20 × 10-6

rs17338998

rs10954213

rs485497
IL-12A Interleukin-12 a T-cell-independent production of IFN 1.17 × 10-10 ~ 9.88 × 10–9
rs583911

rs2736345

BLK rs2729935 B lymphocyte kinase Activate B cells 4.97 × 10-10 ~ 7.96 × 10-8

rs6998387

rs7119038
CXCR5 CXC chemokine receptor 5 Mediate migration of B cells 1.10 × 10-8 ~ 6.82 × 10-8
rs4936443

rs6579837
TNIP1 TNFAIP3-interacting protein 1 Regulate NF-kB 3.30 × 10-8 ~ 5.32 × 10-7
rs7732451

rs10553577
STAT4 signal transducer and activator of transcription 4 Regulate differentiation of helper T cells 6.80 × 10-15 ~ 9.45 × 10-9
rs13426947

Various genome loci were reported to be associated with the pathogenesis of SS. Both HLA regions (HLA-DR, HLA-DQB1, HLA-DQA1) and non-HLA regions (IRF5, STAT4, BLK, IL-12A, TNIP1,
and CXCR5) were established as risk loci.

3.4 Type 17 helper T (Th17) cells/IL-17 been reported in several other autoimmune diseases, including
inflammatory bowel disease (IBD) (58, 59), autoimmune thyroid
Th17 cells are distinct from Th1/Th2 cells and regulate immune disease (AITD) (60), psoriasis (61), multiple sclerosis (62), and RA
responses independently (50, 51). Th17 cells polarize naïve T cells after (63, 64). In these diseases, function and stability of Treg cells are
stimulation by TGF-b and IL-6 from antigen-presenting cells (APCs). impaired, and the aberrant induction and proliferation of Th17 cells
IL-1b secreted from the ductal epithelium and IL-23 secreted from DCs result in the activation of other immune cells, which then drive an acute
also participate in Th17 cell polarization. IL-17 and IL-22 are produced autoimmune response. Metabolic pathways play an important role in
by and are the main effective cytokines of Th17 cells. Th17 cells mediate the regulation of the Th17-Treg cell network. Th17 cells are glycolysis-
inflammation by producing the proinflammatory cytokines TNF-a dependent; thus, by inhibiting the mammalian target of rapamycin
and IL-6 (52). Previous research revealed that IL-17/IL-23 expression (mTOR) pathway with rapamycin, glycolysis is inhibited and the
was enhanced in mouse models with SS, indicating that Th17 polarization of Th17 cells is decreased, whereas the expression of
participated in lymphocytic infiltration of salivary glands and Treg cells is increased (65). Tregs tend to increase glycolysis and
contributed to lesion formation (53, 54). Another study showed that enhance fatty acid oxidation, while Th17 cells rely on fatty acid
IL-22, IL-23, and IL-17 were increased in the peripheral blood of synthesis (66). However, current metabolic models of Th17/Treg cell
patients with SS, both at the protein and mRNA levels. Notably, in regulation through the glycolysis pathway are inconclusive.
addition to Th17 cells, NKp44+ NK cells can also produce IL-17 in Fortunately, Compass (67), a powerful algorithm based on scRNA-
patients with SS (55). Besides, Th17 cells are potent inducers of matrix sequencing and flux balance analysis, was recently produced to predict
metalloproteinase 1 (MMP1) and MMP3 (56), and a study has shown the relationship between cellular metabolic states and pathogenicity,
that SS is related to disorders of MMP3/tissue inhibitor of and has already been utilized in research on the Th17-Treg network.
metalloproteinase 1 (TIMP1) and MMP9/TIMP1 ratios (57). Type 17 follicular helper T (Tfh17) and IL-17-producing B (B17)
Both Treg and Th17 cells can be induced by TGF-b from activated cells also contribute to IL-17 production. A recent study revealed that
T cells, indicating that there might be a balance between these opposing the number of IL-17-producing cells increased in the peripheral blood
inflammation-related cells. An imbalance in the Th17/Treg ratio has and spleen of NOD/ShiLtJ mice with STZ-induced type I diabetes and

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SS. Surprisingly, the infiltration of IL-17-producing cells in the The role of the Wnt signaling pathway in T cell differentiation and
salivary glands increased in metabolically disordered murine immune regulation has been elucidated (86–88). The disorder of Wnt
models, and was also associated with greater severity of SS (68). It signaling inhibitors in autoimmune diseases was also noticed.
was subsequently found that the aberrant expression of IL-17 induced Proinflammatory cytokines promote bone damage by fostering the
by metabolic abnormalities contributed to cell lesions and inhibition production of Wnt signaling inhibitors, including secreted frizzled-
of tissue recovery in the salivary glands of patients with SS. related, Wnt inhibitory factor 1, sclerostin, and Dickkopf (DKK)
Furthermore, retinoic A deficiency can exacerbate the imbalance in family proteins (89–91). However, it was found that the role of DKK-
the Th17/Treg ratio in patients with SS (69). 1 is different in various autoimmune diseases (92). In a clinical study
of 98 SS patients and 165 healthy volunteers, three Wnt/b-catenin
signaling pathway-related genes, LRP5, FRZB, and ADIPOQ, were
3.5 TNF/BAFF shown to increase the risk of SS, although the biological functions of
these genes have not yet been established (91). It implicates Wnt
TNF-a is predominantly produced by macrophages and T cells in pathway might be involved in the pathogenesis of SS. However, not all
two forms: soluble TNF-a (sTNF-a) and transmembrane TNF-a studies support this idea. A clinical study reported that serum Dkk-1
(Tm TNF-a). sTNF-a is an effective regulator of inflammation and and sclerostin levels were decreased in SS and SLE, and the Wnt1 and
autoimmune diseases (70). TNF-a can bind with TNFR1 or TNFR2 Wnt3a levels had no significant changes (93).
and mediate inflammation by activating the NF-kB pathway and
mitogen-activated protein kinases (MAPKs) (71).
BAFF (or BLyS) is a member of the TNF family that plays a vital role in 3.7 IL-33/ST-2
B cell survival. Usually, BAFF is produced by neutrophils, macrophages,
monocytes, DCs, and follicular DCs (72). Increased levels of IFN-I, IFN-g, The IL-33-ST2 axis participates in the pathogenesis of SS by
IL-10, and G-CSF can induce the expression of BAFF, while TLR3, TLR4, promoting transcriptional activation of CD86 and CCL2 in salivary
or TLR9 participate in BAFF production (73, 74). B cells express BAFF epithelial cells and activation of the NF-kB pathway. IL-33, combined
receptors (BAFF-R or BR3), as well as TACI and BCMA. A previous study with IL-12 and IL-23, participates in the production of CD4+ T cell-
reported that BAFF binds to BAFF-R and enhances the conversion of NF- derived and NK/NKT-derived IFN-g (89, 94). An increase in serum
kB2/p100 to p52 (75). Additionally, BAFF binds to BAFF-R, activating the levels of IL-33 and ST2 has been reported in patients with SS (95). IL-33 is
PI3K-AKT1 pathway, which regulates the activation of myeloid cell a member of the IL-1 family and ST2 is one important member of IL-1
leukemia sequence 1 (MCL1) and inhibits BCL-2-interacting mediator receptor family (90). IL-33 induces phosphorylation of the NF-kB
of cell death (BIM). TNF receptor-associated factor 3 (TRAF3) and TRAF2 pathway and activates MAP kinases by interacting with ST2 to
are intracellular signaling molecules that bind to BAFF-R or TACI. BAFF- stimulate downstream Th2-related immune responses. A recent review
R interacts with BAFF and recruits TRAF3, resulting in the degradation of described IL-33 as an alarmin, that is, a DAMP. Local increases in IL-33
TRAF3 and inhibition of the NF-kB pathway. Nevertheless, the binding of expression can induce an immune response and result in organ lesions
TACI and BAFF results in the recruitment of TRAF2 or TRAF6 and (91). The IL-33-ST2 axis is a novel mode in the pathogenesis of SS and a
promotes the activation of the NF-kB pathway (72). potential therapeutic target in related salivary gland disorders.
BAFF participates in the pathogenesis of various autoimmune
diseases, including RA (76), SLE (77), Graves’ disease (78), and anti-
GBM disease (79). Overexpression of BAFF elevates MHC-II 4 Experimental therapeutic strategies
expression, enhances lymphocytic infiltration, and increases the of SS
number of germinal center (GC)-like structures in SS murine
models (80). Increased GC-like structures are associated with 4.1 Targeting the Treg/Th17
enhanced production of rheumatoid factor, anti-RO/SSA, anti-La/
SSB, and IgG in patients with SS (81). However, another study The Treg/Th17 plays a crucial role in the pathogenesis of
claimed that BAFF is unable to mediate the differentiation of B cells autoimmune diseases. Various drugs have been designed to target
from GCs, which suggests the involvement of the inhibitory BAFF- the molecular mechanisms involved in the polarization and activation
TACI pathway (80). Furthermore, BAFF stimulates monocyte of the Treg/Th17, including IL-17-related molecules (IL-17, IL-23),
through binding with BAFF-R and fosters the production of IL-6, transcription factors (RORgt, STAT3, Foxp3, and FoxO1), and
which induces the aberrant production of IgG from B cells in SS (82). intracellular signaling pathways (ROCK and MAPK) (96). However,
compared to RA, SLE, IBD, and psoriasis, clinical or preclinical drugs
for SS are rare. Nevertheless, previous pharmacological exploration
3.6 Wingless/integrated signaling pathway and clinical trials have provided promising results for SS therapy.
IL-38—a member of the IL-1 family and, which was named as IL-
The Wnt signaling pathway is involved in several biological 1F10 (97)—inhibits the secretion of Th17 cell-related cytokines,
processes, including cellular migration, proliferation, differentiation, including IL-6, IL-8, IL-17, IL-22, and IL-23, by binding with IL-36
apoptosis, tissue homeostasis and regeneration, and stem cell self- receptors (98). A previous clinical study reported a selective anti-IL-
renewal (83). Dysregulation of the Wnt/b-catenin pathway plays a 17A mAb, secukinumab, that can alleviate the symptoms of psoriasis
vital role in the pathogenesis of many cancers and autoimmune by blocking the expression of IL-17A, while that of IL-1 receptor
diseases (84, 85). antagonist (IL-1ra) and IL-38 was downregulated (Figure 2) (99).

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FIGURE 2
Overview of novel experimental therapeutic strategies of SS. There are various experimental drugs (e.g. JAK inhibitors) or schemes (e.g. targeting Treg/
Th17 and BAFF) being investigated for SS treatment. Besides, mesenchymal stem cell treatment is reported to be a promising scheme to treat SS.

A previous study tested the effect of IL-38 treatment on Th17 cell herbal medicine Stephania tetrandra S. Moore, fangchinoline, can
activity and found that the expression levels of IL-17 and IL-23 were be used to treat SS by inhibiting the Akt/mTOR pathway, which
decreased in a murine model of SS; IL-38 inhibited IL-17 expression inhibits the proliferation of neoplastic B lymphocytes (Figure 2) (105).
through the NF-kB and MAPK signaling pathways(Figure 2). They More than that, a recent study reported that SSA/Ro-antigen-
also found that IL-17 can upregulate the expression of IL-38 (54). This specific Treg cells can downregulate the production of CD4+ T cell-
hints at a potential approach for the treatment of SS. derived IFN-g and suppress inflammatory infiltration of the salivary
mTOR, a member of the phosphoinositol 3-kinase (PI3K) family, gland (106). Researchers reported that the combination treatment with
is an atypical serine/threonine kinase that plays a vital role in cellular anti-CD4 mAb and autoantigen-specific peptide Ro480 induces SSA/
metabolism and activity (100). mTOR likely prevents anergy Ro-antigen-specific Treg cells in vivo and suppresses CD4+ T cell-
induction by IL-2 expression in T cells. A previous study found related IFN-g production in salivary glands, providing a potential novel
that by blocking mTOR with rapamycin, the cell cycle of clonal T cells immunotherapeutic strategy for the treatment of SS (Figure 2) (106).
was inhibited, while it induced cell anergy even with costimulations
(101). In the process of naïve T cell differentiation, mTOR mediates
the transformation to Th17 or Treg cells by altering the sensitivity of 4.2 Mesenchymal stem cell treatment
T cells to TGF-b, which influences the effects of STAT3 signaling
(102). The inhibition of different mTOR complexes (including Mesenchymal stem cells (MSCs) exert immunomodulatory effects
mTORC1 and mTORC2) would activate different pathways of on both adaptive and innate pathways. MSC can manipulate the
polarization to Th17 cells, whereas a complete inhibition of mTOR balance between suppressive Treg cells and inflammatory T helper
can promote polarization to Treg cells (103). mTOR plays a role in cells (Th1, Th2, Th17, and Tfh) and ameliorate inflammatory
Th17/Treg balance, given that mTOR inhibitors interfere with the infiltration in the salivary glands (107, 108).
Th17/Treg ratio, which suggests a potential therapeutic target to Xu et al. revealed that immunomodulatory functions of MSCs are
ameliorate glandular lesions in patients with SS. Given the anti- impaired in SS-like murine models, and allogeneic bone marrow
inflammatory and immunomodulatory effects of metformin—an mesenchymal stem cells (BMMSCs) infusion can suppress SS-like
AMPK-dependent mTOR-STAT3 inhibitor—researchers examined inflammation, showing therapeutic effects of BMMSCs on SS (109).
its therapeutic effect in SS murine models and found that it Furthermore, they also elucidated that the stromal cell-derived factor-1
ameliorated inflammation in the salivary glands and, based on flow (SDF-1)/C-X-C chemokine receptor 4(CXCR4) axis plays an important
cytometry, regulated the Th17/Treg ratio (Figure 2) (104). Yu et al. role in MSC migration and restoration of salivary glands. More than that,
reported that an alkaloid extracted from the traditional Chinese they also treated twenty-four SS patients with umbilical cord-MSCs

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(UCMSCs), and all patients showed alleviation of SS symptoms and well and IFNa-mediated DNA hydroxymethylation and could potentially
tolerance of allogeneic UCMSCs (Figure 2) (109). treat SS (Table 2) (45, 132). Tofacitinib is also a candidate drug for SS,
Zoukhri et al. revealed that a biotherapeutic strategy involving given that it can reverse the expression of IL-6 in ATG5-deficient 3D-
bone-derived MSCs (BDMSCs) alleviated lacrimal glandular acini, which leads to the inhibition of inflammation (Table 2) (133).
manifestation in a SS murine model by inhibiting inflammation and
promoting the expression and activation of water channel aquaporin 5
(Figure 2) (110). Li et al. verified the immunomodulatory effects of 4.4 Targeting BAFF
UCMSCs and found that UCMSCs induced CD4+FoxP3+ Treg cells in
vitro and caused anergy of inflammation-related T cells in vivo, Belimumab is an anti-BAFF monoclonal antibody and a potential
accompanied by an increase in Treg cells (111). Hua et al. assessed biotherapeutic drug for SLE and SS (Table 2) (125, 135). A bi-centric
the effects of labial gland-derived MSCs (LGMSCs) and their exosomes clinical trial reported that, after a 28-week regimen of belimumab (10
on SS, and found that they ameliorated salivary gland inflammatory mg/kg, at weeks 0, 2, 4, and then every 4 weeks), 18 out of 30 patients
infiltration by inhibiting the polarization of Th17 cells and promoting achieved two of five primary endpoints. The mean and standard
the proliferation of Treg cells (Figure 2) (112). Furthermore, dental deviation of ESSDAI and EULAR Sjogren’s Syndrome Patients
pulp stem cells (DPSC) (113), murine embryonic MSCs (MEMSCs) Reported Index (ESSPRI) were both reduced (Figure 2) (125).
(114), and olfactory ecto-MSCs (OEMSCs) (115) can be used to treat SS Ianalumab is a BAFF-blocking monoclonal antibody that leads to
by interfering with inflammation-related cytokines (IL-4, IL-6, IL-12, B-cell depletion (Figure 2). A previous clinical study found that, in SS,
and IL-17a) and suppressive cytokines (IL-10 and TGF-b) ianalumab reduced the ESSDAI, ESSPRI, and serum immunoglobulin
(Figure 2) (116). levels (Table 2) (129).
Besides, Zheng et al. reported a Chinese herb-derived drug,
Artemisinin (ART), which is used to treat chloroquine-resistant
4.3 Inhibiting JAK pathway malaria originally, has immunosuppressive effects in the SS-like
murine model (Figure 2) (126). The study demonstrated that ART
JAK enzymes are involved in the JAK/STAT pathway through the downregulates BAFF-induced NF-kB activity in B cells through
phosphorylation of STAT, which leads to the activation of signals targeting TRAF6 ubiquitination, which results in the inhibition of B
transferred to the nucleus. The JAK family consists of four members, cell survival and proliferation. Therefore, the levels of B lymphocyte-
JAK1, JAK2, JAK3, and TYK2 (117). Membrane receptor subunits related immunoglobulin and autoantibody in the SS-like murine
usually bind to a specific JAK. For example, JAK3 can only selectively model were attenuated and lymphocytic infiltration in the salivary
binds to the gc chain, which is a common receptor chain of IL-2, IL-4, IL- gland was ameliorated (Table 2) (126).
9, IL-15, and IL-21 (118).
The JAK/STAT pathway regulates the production of ILs, TNFs, GM-
CSFs, and IFN-gs, which are associated with inflammation and 4.5 Others
autoimmunity (119). The JAK inhibitors tofacitinib (120), baricitinib
(120), oclacitinib (121), filgotinib (122), and upadacitinib (123) have been Bortezomib is a proteasome inhibitor used in the treatment of
applied in the treatment of autoimmune diseases (Figure 2). Renaudineau multiple myeloma (Table 2). A Mexican case report described a
et al. reported that AG490 and ruxolitinib, two JAK1/2 inhibitors, can female patient that suffered from SS for 16 years and presented with
reverse ROS-induced production of ten-eleven translocation 3 (TET3) sicca complex, extreme fatigue, Raynaud phenomenon, generalized

TABLE 2 Experimental Biotherapeutic Drugs of SS.

Drug Effect target Mechanism Feasibility* References

Rituximab CD20 Induce ADCC and CDC - (124)

Belimumab BAFF Inhibit the combination of BLyS and B cells + (125)

Artemisinin BAFF Downregulate the BAFF-induced NF-kB activity + (126)

Iscalimab CD40 Inhibit the combination of CD40 and CD40L – (127)

Tocilizumab IL-6 receptor Block IL-6R - (128)

Ianalumab BAFF receptor Block BAFF receptor + (129, 130)

Abatacept CD80&CD86 Inhibit activation of T cells + (131)

Ruxotinib JAK/STAT pathway Inhibit IFN and ROS related DNA hydroxymethlation * (45, 132)

AG490 JAK/STAT pathway Inhibit IFN and ROS related DNA hydroxymethlation * (45, 132)

Tofacitinib JAK/STAT pathway Decrease expression of IL-6 * (133)

Bortezomib Proteasome pathway Inhibit activation and nuclear translocation of NF-kB + (134)

* Experimental effects on treating SS. “-” means none or low effect. “+” means promising effect. “*” means unclear.

Frontiers in Immunology 07 frontiersin.org

Zhan et al. 10.3389/fimmu.2023.1127417

arthralgia, and heavy headaches. After ineffective conventional B cell-related signaling pathways and molecular events has drawn
glucocorticoid and rituximab therapy, doctors administered an increasing attention.
experimental regimen of bortezomib at a dose of 1.3 mg/m2 (2.0 Research on SS therapies is limited by a lack of systematic clinical
mg/dose) at days 1, 4, 8, 11, 22, 29, 36, 43, 50, and 57. Surprisingly, the trials compared with other autoimmune diseases, such as SLE, RA, and
patient’s headaches and fatigue were resolved after three months, and MS. Many potential therapeutic targets have been identified in the
serum globulin levels and viscosity decreased significantly (Table 2) pathogenesis of SS, and some targeted drugs have shown reasonable
(134). However, the efficacy and safety of bortezomib for the efficacy under experimental conditions in vitro or in vivo.
treatment of SS are still unconfirmed (Figure 2). Unfortunately, the translation of these drugs to clinical use is rare.
Rituximab—a chimeric monoclonal anti-CD20 antibody—has Additionally, it is unclear why immune inhibitors lack pharmacological
been reported to induce B-cell depletion and has been used to treat effect in SS compared to SLE, RA, and MS. Nevertheless, immune
autoimmune diseases (136, 137). It has also been used to treat SS over inhibitors can be used in the management of complications to improve
the last 20 years, but with limited clinical efficacy (Table 2) (124, 138). the prognosis and quality of life of patients with SS. For example, BAFF
Researchers have investigated a combination therapy with the anti- receptor blockers not only prevent inflammatory lesions but also
BAFF and anti-CD20 [NCT02631538]—belimumab and rituximab. protect against B-cell lymphoma; however, such therapeutic
The results of the clinical trial provide evidence that simultaneous strategies are rare. Combination therapies have shown some efficacy;
targeting of the BAFF axis and B cells is a promising treatment however, inappropriate combinations of drugs may cause excessive
strategy for SS (Figure 2) (139). The drugs in development for SS inhibition of the immune system, resulting in unexpected
treatment are summarized in Table 2. complications, such as secondary infections. Thus, targeted and low-
Various biotherapeutic drugs have been used to treat SS side-effect drugs should be the focus of future research.
experimentally. Some of them have been used to treat other
autoimmune diseases (e.g. Rituximab), and the others are novel drugs
targeting inflammation-related signaling pathways (e.g. AG490). Author contributions
However, not all of them have prospective effects on treating SS (e.g.
Iscalimab, Tocilizumab). QZ drafted the manuscript. JZ, YL, WC and XF edited the
manuscript. DZ supervised the work and edited the manuscript. All
authors contributed to the article and approved the submitted version.
5 Conclusion & discussion
As a systemic autoimmune disease, SS causes multiple organ lesions,
Funding
especially in salivary and lacrimal glands, which limits endocrine
This work was supported by the Key Project of the Science and
function. Besides focal inflammation in the salivary gland, acinar
Technology Department of Sichuan Province (NO. 2022YFH0100), the
atrophy, duct dilation, and fibrosis are commonly observed in SS
National Natural Science Foundation of China (NO. 82171829), the 1·3·5
patients. Due to a high disease specificity and limited invasiveness,
Project for Disciplines of Excellence, West China Hospital, Sichuan
labial salivary gland biopsy is widely accepted as the best method to
University (NO. ZYYC21012), and the Fundamental Research Funds for
diagnose SS currently (140). Lymphocytic infiltration around the striated
the Central Universities (20822041E4084).
ducts in salivary glands, or so-called periductal foci, is a critical hallmark
for the diagnosis of SS (141). Since adipose tissue replacement in the
salivary gland is related to the stages of SS, and adipocytes are detected in
Acknowledgments
IL-6-rich regions, detecting the degree of adipose tissue replacement
provides aid to improve diagnosis accuracy (142). In addition,
DZ sincerely wants to commemorate Dr. Sang-A Park, who
comorbidities, such as secondary pulmonary disease, kidney injury,
passed away suddenly on January 22, 2018.
and lymphoma, further reduce the quality of life of patients. The
pathogenesis of SS is characterized by the production of inflammatory
cytokines and lymphocyte infiltration. IFN and IL-17/Il-23 play pivotal Conflict of interest
roles in the formation of inflammatory lesions, and B cells are crucial for
infiltrative injury. Th17, B, and dendritic cells play critical roles in the The authors declare that the research was conducted in the
aberrant regulation of the immune system. absence of any commercial or financial relationships that could be
Similar to other autoimmune diseases, such as SLE, RA, and construed as a potential conflict of interest.
psoriasis, the traditional therapeutic strategy for SS is disease-
modifying antirheumatic drugs (DMARDs), such as glucocorticoids,
while novel biotherapeutic approaches take advantage of neutralizing Publisher’s note
antibodies and inflammation-related receptor blockers. Compared with
the traditional strategy, this new scheme is more targeted, which can All claims expressed in this article are solely those of the authors
promote safety and efficacy. Although considerable progress has recently and do not necessarily represent those of their affiliated organizations,
been made in the treatment of SS, disease-specific drugs are rare. Many or those of the publisher, the editors and the reviewers. Any product
SS drugs are currently undergoing clinical trials. As Th17 and B cells play that may be evaluated in this article, or claim that may be made by its
important roles in the pathogenesis of SS, the targeting of Th17 cell- and manufacturer, is not guaranteed or endorsed by the publisher.

Frontiers in Immunology 08 frontiersin.org

Zhan et al. 10.3389/fimmu.2023.1127417

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